Medchem Flashcards
What is ADME of your product?
ADME – Therapeutic Radiopharmaceutical Injections (Aseptic, IV)
Absorption
- 100% bioavailability
Immediate systemic circulation
- Aseptic pyrogen-free
- No GI/barrier absorption phase
- Distribution
*Bloodstream → perfused organs
*Target-specific uptake (e.g. somatostatin, PSMA, thyroid)
*Vd depends on size/binding
*Free radionuclide = off-target (thyroid, bone, liver)
*Co-admin agents (e.g. amino acids for renal protection)
*Radiochemical purity = critical for correct biodistribution
Metabolism
*Minimal metabolism
*Stays chemically intact
*Iodide: organification in thyroid
*Peptides/antibodies: lysosomal degradation
*In vivo stability = QP release check
Excretion
*Renal (urine) or hepatobiliary (faeces)
*Effective half-life = physical + biological
*Rapid clearance (most in 24–48h)
*Radiation safety: excreta handling, shielding, patient isolation (if gamma)
*QP: ensure safe disposal, labeling, ARSAC/IRMER compliance
What are the control points for the manufacturing?
Critical Control Points – Aseptic Radiopharmaceutical Manufacturing
- Radioisotope Receipt & Handling
*Identity & radionuclidic purity check
*Shielding & contamination control
*Correct activity & calibration (traceable to national standards) - Aseptic Processing
*Grade A environment (e.g. isolator, LAF hood)
*Validated sterile filtration (0.22 μm filter)
*Media fill validation
*Cleanroom qualification (Grade B/C/D as applicable)
*Gowning, operator aseptic technique (training + requalification) - Radiolabeling Reaction
*Controlled temperature/time
*pH, reducing agent, buffer = optimal conditions
*Radiochemical purity critical for targeting
*Use of validated synthesis module/equipment - Radiochemical Purity Testing
*Instant TLC, HPLC
*Specification: typically ≥95%
*Detects free radionuclide (off-target risk)
*Must be complete before QP release - Final Sterile Filtration & Filling
*Aseptic technique
*Filter integrity test (pre/post)
*Closed vial systems, proper crimping
*Visual inspection: particulates, color, damage - Time-Critical Release & Transport
*Time from production to use is short (short half-life)
*Real-time release by QP (parametric, if sterility pending)
*Transport in approved, shielded containers
*Maintain chain of identity, temperature if needed - Batch Record & Traceability
*Full documentation: materials, process, QC
*Dose/activity traceable to patient
*Deviations investigated before release
Please talk through ADME of a product I had on my form.
Then proceeded to ask me about ADME in general (theory) and what is the importance of this knowledge for the OP. I talked about choices of formulation
Please talk about the controls around the manufacturing of the product?
Please talk about ADME in general (theory) and what is the importance of this knowledge for the OP?
talked about choices of formulation
What do you do when MACO is breached?
- I would raise a deviation immediately and quarantine any potentially affected product.
- I’d assess the extent of the failure and the products involved, conduct a risk assessment to evaluate the impact on patient safety and GMP compliance.
- Determine if any product released prior to the result could be affected — if so, initiate a recall assessment and engage with the Medical and Regulatory teams.
- Root cause investigation would follow — for example, ineffective cleaning, equipment design, operator error, or analytical method issue.
- Implement CAPAs: this may include revalidation, retraining, adjustment of procedures or cleaning agents, or redesign of equipment.”
Cleaning validation – Multi product oral suspension manufacturing site. MACO levels breached on annual cleaning validation.
What is cleaning validation, and why is it critical in a multi-product facility?
Cleaning validation is a documented process that demonstrates the effectiveness and reproducibility of cleaning procedures to prevent cross-contamination.
It’s especially critical in a multi-product facility where different APIs may have varying potencies, toxicity profiles, and carryover risks.
As a QP, I must ensure that cleaning procedures consistently remove product residues, excipients, and cleaning agents to levels that are safe, regulatory compliant, and not detectable beyond the MACO limit.
What are recovery studies, and how are they used in cleaning validation?
Recovery studies are performed to determine the efficiency of the sampling method, typically swabbing or rinsing.
Coupons made of the same material as the equipment are spiked with known amounts of residue, allowed to dry, and then sampled.
The percentage of recovered residue indicates how effective the sampling is.
The recovery factor is then applied to actual sample results. For example, if you recover 80%, the actual residue may be higher — so your result is adjusted by dividing by 0.8.
Low recovery can either invalidate the result or require more stringent cleaning targets
How to MACO calculations?
MACO stands for Maximum Allowable Carryover. It can be calculated in several ways, but the traditional approach is:
MACO = (PDE of previous product x Minimum batch size of the next product /Max daily dose of product B
The calculated value is then converted into a surface-specific acceptance limit based on equipment surface area or swabbed area, and cleaning validation results must fall below this value.
What is the difference between swab and rinse sampling? When would you use each?
Swab sampling is used to test small, hard-to-clean areas like joints, valves, and dead-legs. It provides a direct, localized measure of surface residue.
Rinse sampling captures residues from the entire internal surface area of equipment, especially where swabbing is impractical, such as pipes or reactors.
Both methods are complementary. In a multi-product facility, I would typically use both — swabbing for worst-case locations and rinses for overall system assurance
A Clean-in-Place (CIP) system failure was discovered in a multi-product facility — the spray ball in a critical vessel failed to rotate, resulting in an ineffective clean. Batches were released before this failure was identified. You’re the QP — what do you do?
My immediate priority is to assess the impact of the cleaning failure on product quality and patient safety.
I would:
1. Quarantine any impacted or in-process batches.
2. Initiate a deviation and investigation.
3. Assess how long the spray ball had been failing — i.e. what batch(es) may be affected.
4. Review cleaning validation and visual inspection records.
5. Evaluate whether the failure led to cross-contamination, microbial risk, or cleaning agent residues.
6. Assess if any affected batches have already been released
What validation aspects would you consider here?
This incident highlights a weakness in the cleaning system’s design qualification and routine verification.
As part of cleaning validation lifecycle per Annex 15, I would review:
* Installation Qualification (IQ) of the spray ball and CIP system.
* Operational Qualification (OQ) — was the rotation verified during validation?
* Performance Qualification (PQ) — was spray coverage assessed?
* Preventive maintenance frequency and whether spray ball rotation was part of routine checks.
* Visual inspection training and documentation for cleaning operators.
The outcome is a Class 1/Class 2 recall. What’s the difference between them?
- Class 1 recall: Life-threatening risk. Immediate recall needed. Examples: contamination with a toxic compound, undeclared allergen, microbial contamination in sterile product.
- Class 2 recall: Could cause illness or mistreatment, but not life-threatening. Still serious, but not immediate threat.
In this case, if the cleaning failure involved potential contamination with high-risk materials (e.g. penicillin, cytotoxic, or microbial residue in a sterile product), a Class 1 recall is appropriate.
What is your role as a QP in this recall situation?
As the QP, I must:
* Lead the product quality risk assessment.
* Initiate internal notification processes.
* Halt further distribution.
* Assess whether any other batches may be affected.
* Contribute to the recall classification discussion.
* Ensure appropriate communication with the QPPV if the product is licensed and patient safety is involved.
* Work with regulatory colleagues to notify DMRC (Defective Medicines Report Centre).
* Provide technical input for recall documentation and risk evaluation.
What would you present to the DMRC (what would you include in my proposal)?
- Recall class (1-4)
- Recall extend (wholesaler, pharmacy, patient)
Can you explain the concept of Pharmacokinetics and ADME?
Can you give examples of the different routes of excretion?
Can you describe wat bioavailability is vs bioequivalence?
What products have good bioavailability and which have bad?
I thought they meant actual products but they clarified dosage forms
Can you explain which Phase of Clinical Trials is likely to carryout Pharmacokinetics studies?
Can you explain the concept of Therapeutic Index (Narrow vs wide therapeutic window) and give examples of drugs that have a narrow therapeutic window?
- Drug/Drug interactions in polypharmacy
- Drug/Food interactions (grapefruit juice)
- Cross Contamination during manufacturing (MACOs) and cleaning validation
What is NOEL?
ICH on M7 TTC
New product in multipurpose facility, how would you do it?
What is first pass metabolism?
What is meant by therapeutic range?
Do you know what ‘buccal’ route of administration is?
Would this lead to quicker or slower bioavailability than a tablet you swallowed?
What contamination controls are in place in a solid oral dose site?
You mentioned pressure cascade – do you know what the difference should be?
You mentioned that some products need separate facilities – can you name any?
Thinking now about contamination control in a sterile site – what would be different?
Asked about absorption of nasal product . This led to talking about the absorption in CNS by passing the BBB.
This led to talking about the absorption in CNS by passing the BBB.
Discussed about what could limit the distribution. Discussed about how could you remove these limitations?
I talked giving examples of Theophylline, amitriptyline etc. Also, the deposition of the drug in the respiratory track how it could be improved. This took very long time.
Your site acquires a new paediatric suspension. What are your considerations?
Explain contamination control?
Tell us about your product, mode of action, ADME and contraindications ?
How do you set up a cleaning validation programme and what are HBEL calculations?
Tell me about your product, ADME, mode of action and composition?
You want to release your product before all release test results are completed, how will you go about this?
What about if you have an OOS result after you have release and it was administered?
Sterility test in your product. Why can you not follow the common sterility test?
Imagine you have a multi product facility, how will you go about performing cross contamination strategy?
How will you keep up to date your CCS ?
What about avoiding cross contamination in the biological starting material?
* What do you need to import products from USA
* What is HTA
* Explain warehouse controls and material traceability
What do you need to import products from USA?
* What is HTA
* Explain warehouse controls and material traceability
What is HTA?
Explain warehouse controls and material traceability?
As part of improvement company introduce new washer for glassware and equipment cleaning in production area. Explain the requirements.
You work at a facility that manufactures 1 product, which requires a simple hot water rinse clean. Your commercial team want to expand in to a multi-product facility with products that range from high dissolution products to insoluble powders. You’re going to use the same equipment and start to use acid/alkali detergent cleaning methods. How would you manage this?
o How would you set up a cleaning validation for the new products?
What products would you not want to manufacture in your multi product facility? Give examples.
Where would you find information on new drugs?
What specifically would you be looking for in an SmPC?
Can you discuss what your approach would be to cleaning validation in a multiproduct facility?
When would you look to use dedicated facilities?
How would you set up cleaning validation in multi product facility ?
How do you calculate PDE and Swab limit?
You are a QP in new multi product facility, how would you ensure setup. How would you consider sampling location
How would you set up environmental monitoring?
Cleaning Validation Failure
Question: What would you do if cleaning validation fails?
Model Answer: Raise deviation, perform root cause analysis (e.g., method, limit, execution). Adjust parameters or cleaning agents. Revalidate.
Tips: Avoid jumping to recall. Bring in MACO, swab vs rinse, single-use systems if needed.
Cross Contamination at Multi-Product Site
Question: Your product is contraindicated with another produced in same facility. How do you manage risk?
Model Answer: Use PDE calculations, assess risk via Chapter 3, 5, and EMA cross-contamination guide. Employ campaign-based production, dedicated areas/equipment, and cleaning validation.
Tips: Mention PDE report, MACO formula, EMA 2014 guideline. Focus on control measures. The PDE is calculated based on toxicological data and is defined by the following formula:
\textbf{PDE} = \frac{\text{NOAEL} \times \text{Weight}}{F_1 \times F_2 \times F_3 \times F_4 \times F_5}
Where:
• NOAEL = No Observed Adverse Effect Level (mg/kg/day)
• Weight = Average adult human body weight (typically 50–70 kg; use 50 kg for worst-case)
• F1 = Factor for extrapolation between species
• F2 = Factor for variability between individuals
• F3 = Factor for extrapolation from short-term to long-term exposure
• F4 = Factor for severity of toxicity
• F5 = Factor for nature of data (e.g., if NOAEL is not from human study)
2. MACO (Maximum Allowable Carryover) Formula:
\textbf{MACO} = \frac{\text{PDE} \times \text{Minimum batch size of next product}}{\text{Maximum daily dose of next product}}
Where:
• PDE = Calculated as above (mg/day)
• Minimum batch size of next product = Smallest batch size manufactured in shared equipment (mg or units)
• Maximum daily dose of next product = Max therapeutic dose for the patient (mg/day)
⸻
- Swab Limit (in mg/cm² or µg/cm²):
If you need to express MACO in terms of swab recovery area:
\textbf{Swab Limit} = \frac{\text{MACO}}{\text{Total shared surface area (cm²)}}
Why does a QP need to understand the ADME of a product?
Model Answer:
A QP must understand ADME to assess the potential impact of deviations or changes on the product’s safety, quality, and efficacy. For example, knowledge of metabolism pathways helps in evaluating cross-contamination risks, while understanding distribution can inform decisions on particulate contamination or extractables/leachables. ADME understanding supports pharmacovigilance, risk assessments, and clinical impact evaluations.
Tips:
• Emphasise decision-making in deviations, change control, and batch certification.
• Tie back to patient safety and QP legal duties under UK Human Medicines Regulations or EU Directive 2001/83/EC.
What’s the difference between PDE and HBEL in cleaning validation?
Model Answer:
PDE (Permitted Daily Exposure) and HBEL (Health-Based Exposure Limit) are often used interchangeably. HBEL is the general term for exposure limits based on toxicological data, while PDE is a specific calculation from HBEL principles, used in EMA and PIC/S guidance. Both determine acceptable carryover limits in shared facilities.
Tips:
• Quote EMA’s “Guideline on setting health-based exposure limits” (EMA/CHMP/CVMP/SWP/169430/2012).
• Mention that PDEs are product-specific and are central to MACO calculations in cleaning validation.
. Cleaning Validation / PDE vs HBEL
Q9. What’s the difference between PDE and HBEL?
• Model Reference: EMA “Guideline on setting health-based exposure limits” (EMA/CHMP/CVMP/SWP/169430/2012)
• Tip: Explain they are closely related; HBEL is a broader term; PDE is a type of HBEL for cleaning validation purposes. Mention toxicological basis.
How do you determine limits in cleaning validation using PDE?
• Tip: Mention calculation of MACO, worst-case product, toxicology input, cleaning procedures, visual inspection, and swab/rinse sample testing.
