Medchem

Question 1

What is ADME of your product?

Answer 1

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

Question 2

What are the control points for the manufacturing?

Answer 2

Critical Control Points – Aseptic Radiopharmaceutical Manufacturing

1. Radioisotope Receipt & Handling
   *Identity & radionuclidic purity check
   *Shielding & contamination control
   *Correct activity & calibration (traceable to national standards)
2. 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)
3. Radiolabeling Reaction
   *Controlled temperature/time
   *pH, reducing agent, buffer = optimal conditions
   *Radiochemical purity critical for targeting
   *Use of validated synthesis module/equipment
4. Radiochemical Purity Testing
   *Instant TLC, HPLC
   *Specification: typically ≥95%
   *Detects free radionuclide (off-target risk)
   *Must be complete before QP release
5. Final Sterile Filtration & Filling
   *Aseptic technique
   *Filter integrity test (pre/post)
   *Closed vial systems, proper crimping
   *Visual inspection: particulates, color, damage
6. 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
7. Batch Record & Traceability
   *Full documentation: materials, process, QC
   *Dose/activity traceable to patient
   *Deviations investigated before release

Question 3

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

Answer 3

Model Answer: ADME of My Product + Theoretical ADME + Relevance to QP

1. ADME of My Product – Ga-68 Aseptically Prepared Injection
   A – Absorption
   * Administered intravenously, so 100% bioavailability — it enters the systemic circulation immediately, bypassing absorption barriers like the GI tract.
   D – Distribution
   * Ga-68 is chelated to a peptide ligand that targets somatostatin receptors overexpressed on neuroendocrine tumour cells.
   * It shows receptor-mediated localisation at the tumour site after systemic distribution.
   M – Metabolism
   * The radiolabelled compound remains largely intact in plasma; minimal hepatic metabolism.
   * This stability is important to ensure clear imaging signal at the target site.
   E – Excretion
   * Primarily via the renal route, with the compound largely excreted unchanged in urine.
   * Rapid clearance from non-target tissues supports a favourable target-to-background ratio in PET imaging.
2. ADME in Theory (e.g. for oral tablet products)
   A – Absorption
   * Absorbed through the gastrointestinal tract, depending on solubility, permeability, and formulation factors (e.g. excipients, pH).
   D – Distribution
   * Drug distributes via systemic circulation, often binds to plasma proteins (e.g. albumin) before reaching target tissues.
   M – Metabolism
   * Mainly occurs in the liver by cytochrome P450 enzymes (e.g. CYP3A4, CYP2D6), converting the parent drug into active/inactive metabolites.
   E – Excretion
   * Eliminated via renal (urine) or hepatic (bile) pathways, sometimes as unchanged drug or metabolite.
3. Why ADME Knowledge is Important for a QP

As a QP, understanding ADME is essential for:
* Product knowledge: Understanding how the drug behaves in the body informs risk-based decision-making in manufacturing and QA.
* Deviation or defect investigation: If a product defect occurs (e.g. out-of-spec impurity, incorrect strength), knowing the ADME helps assess whether it may affect efficacy or patient safety.
* Shelf-life and impurity assessment: Helps assess the clinical impact of impurity profiles or stability trends, particularly for systemic vs locally acting drugs.
* Bioavailability and route of administration: Guides understanding of why certain specs or manufacturing steps are critical (e.g. particle size for oral absorption, sterility for IV injection).

Summary:
“ADME gives me, as a QP, the necessary background to assess product quality in the context of patient risk. It helps me bridge GMP issues with pharmacological impact — particularly important when dealing with deviations, shelf-life decisions, or novel formulations like radiopharmaceuticals.”

Question 4

Please talk about the controls around the manufacturing of the product?

Answer 4

As a QP, I would expect comprehensive controls covering the facility, personnel, equipment, materials, and process parameters to ensure aseptic assurance and product quality, in line with EU GMP Annex 1, ISO 14644, and radiation safety guidance.

1. Environmental and Facility Controls
   * Grade A environment (typically in an isolator or RABS) for aseptic filling, qualified as per ISO 14644-1 (≤3,520 particles ≥0.5 µm/m³ in operation).
   * Pressure differentials of 15–20 Pa maintained between rooms of different grades to ensure directional airflow from cleaner to less clean areas.
   Air change rate:
   o ≥20 ACH (air changes per hour) in Grade B and C areas to maintain air cleanliness.
   * Laminar airflow velocity:
   o Typically 0.45 m/s ±20% in Grade A areas to ensure unidirectional flow over critical zones.
   * Isolator integrity testing and glove integrity testing performed routinely to prevent breach of sterile barrier.
2. Personnel and Operational Controls
   * Line clearance:
   o Performed and documented before each batch to confirm that the area, equipment, and materials are free from previous product, labels, or contaminants.
   o It is a critical GMP step to prevent cross-contamination and mix-ups.
   * Operator aseptic technique:
   o All personnel are trained, qualified, and routinely assessed.
   * Transfer technique:
   o Materials transferred into Grade A via validated sporicidal wiping, pass-through hatches with unidirectional flow.
   * Gowning procedures:
   o Grade B gowning for entry into clean areas; strict procedures aligned with Annex 1.
   * Media fill validation:
   o Conducted under worst-case conditions to demonstrate the aseptic process can reliably produce sterile product.
3. Process and Material Controls
   * Sterile filtration:
   o Final filtration using validated 0.22 µm filter, with integrity testing (e.g. bubble point) before and/or after use.
   * Low bioburden starting materials:
   o Ensures pre-filtration microbial load is within defined limits.
   * Temperature control:
   o Controlled room temperature and validated temperature of reaction vessel during synthesis.
   * Radioactivity in-process checks:
   o Ensures correct activity per dose, labelling efficiency, and radiochemical purity.
4. Environmental Monitoring and Trending
   * Non-viable particle monitoring:
   o Continuous in Grade A; routine in Grade B/C.

• Viable monitoring:
  o Air sampling, settle plates, and contact plates during and after operations.
• Excursions investigated as deviations; data are trended for early detection of control loss.

Critical Process Parameters (CPPs) Include:

• Line clearance verification
• Isolator and glove integrity
• Filter integrity (pre-/post-use)
• Operator aseptic technique
• Transfer disinfection steps
• Pressure differentials and air velocity
• Environmental monitoring results
• In-process radioactivity checks
• Room and process temperature control

Summary:
“In aseptic radiopharmaceutical manufacturing, strict control of the environment, operators, materials, and process is essential. Line clearance is a key GMP step to prevent cross-contamination. As a QP, I would review these controls, batch records, and any deviations to ensure product sterility and compliance before certifying the batch.”

Question 5

What do you do when MACO is breached?

Answer 5

1. I would raise a deviation immediately and quarantine any potentially affected product.
2. 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.
3. 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.
4. Root cause investigation would follow — for example, ineffective cleaning, equipment design, operator error, or analytical method issue.
5. Implement CAPAs: this may include revalidation, retraining, adjustment of procedures or cleaning agents, or redesign of equipment.”

Question 6

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?

Answer 6

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.

Question 7

What are recovery studies, and how are they used in cleaning validation?

Answer 7

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

Question 8

How to MACO calculations?

Answer 8

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.

Question 9

What is the difference between swab and rinse sampling? When would you use each?

Answer 9

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

Question 10

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?

Answer 10

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

Question 11

What validation aspects would you consider here?

Answer 11

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.

Question 12

The outcome is a Class 1/Class 2 recall. What’s the difference between them?

Answer 12

• 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.

Question 13

What is your role as a QP in this recall situation?

Answer 13

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.

Question 14

What would you present to the DMRC (what would you include in my proposal)?

Answer 14

Reference: MHRA blog
- Description of defect
- Risk/Impact assessment
- Recall class (1-4)
- Recall extend (wholesaler, pharmacy, patient)
- Close report submited after complete of CAPA

Question 15

Can you explain the concept of Pharmacokinetics and ADME?

Answer 15

Explain the Concept of Pharmacokinetics and ADME

Pharmacokinetics (PK) is the study of how the body affects a drug - drug absoebed, distributed, metabolised and excreted - over time.
It describes the movement of a drug through the body using four key processes, summarised by the acronym ADME:
________________________________________
ADME – Key Components of Pharmacokinetics:
1. Absorption
o How the drug enters the bloodstream after administration.
o Depends on the route (e.g. oral, IV, IM) and formulation (e.g. tablet, injection).
o Influenced by solubility, permeability, and first-pass metabolism.
2. Distribution
o How the drug spreads through the body from the blood to tissues.
o Affected by blood flow, tissue binding, and plasma protein binding (e.g. to albumin).
3. Metabolism
o How the drug is chemically modified, primarily in the liver by enzymes (e.g. cytochrome P450s).
o Produces active or inactive metabolites.
4. Excretion
o How the drug or its metabolites are removed from the body, typically via the kidneys (urine) or bile (faeces).
Model Answer: What is Pharmacodynamics?

Pharmacodynamics (PD) is the study of how a drug affects the body — in contrast to pharmacokinetics, which is how the body affects the drug. (such as recepter binding and therapeuticresponce)
________________________________________
Key Elements of Pharmacodynamics:
1. Mechanism of Action (MoA)
o How the drug interacts with its biological target (e.g. receptor, enzyme, ion channel)
o E.g., beta-blockers binding to β-adrenergic receptors to reduce heart rate
2. Dose–Response Relationship
o Describes how the drug effect changes with dose
o Includes parameters like:
 EC50: concentration at which 50% of maximal effect is observed
 Emax: maximum achievable effect
3. Therapeutic Effect vs Side Effects
o PD helps define the therapeutic window — the range between effective and toxic doses
o Also helps understand on-target vs off-target effects

Question 16

Can you give examples of the different routes of excretion?

Answer 16

Drugs and their metabolites can be excreted from the body through several primary and secondary (minor) routes:

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Primary Routes:
1. Renal (Kidney – Urine)
• Most common route for water-soluble drugs and metabolites
• Examples: aminoglycosides, penicillin
• Can involve glomerular filtration, tubular secretion, or reabsorption
2. Hepatic (Biliary – Faeces)
• Lipophilic drugs/metabolites are excreted into bile and passed in faeces
• May undergo enterohepatic recycling
• Examples: rifampicin, some steroids, digoxin

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Secondary/Minor Routes:
3. Saliva
• Can be used in drug monitoring
• Some drugs (e.g. lithium, phenytoin) may be measurable in saliva
4. Sweat glands
• Minor excretion route
• Can cause skin irritation or odour (e.g. garlic, some chemotherapy drugs)
5. Tears
• Very minimal excretion
• Some drugs may cause ocular side effects due to presence in tear fluid
6. Breast milk
• Clinically important in lactating patients
• Lipophilic, weakly basic drugs can accumulate
• Examples: diazepam, codeine, some antibiotics
• Important for QP to assess during SmPC review if labelling error or exposure occurs
7. Exhalation (Lungs)
• Volatile or gaseous drugs (e.g. anaesthetics, alcohol)
• Also important for radiopharmaceuticals using gaseous isotopes

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Summary:

“The main excretion routes are renal and biliary, but other routes like sweat, saliva, breast milk, and breath may be relevant for certain drugs. Understanding excretion is important for assessing the impact of impurities, drug accumulation, or off-label use — all relevant for QP batch release and risk assessment.”

Question 17

Can you describe wat bioavailability is vs bioequivalence?

Answer 17

1. Bioavailability

Bioavailability refers to the proportion (%) of the active pharmaceutical ingredient (API) that is absorbed into the systemic circulation after administration and is available to exert its therapeutic effect.
• For intravenous (IV) administration: bioavailability is 100%
• For oral and other non-IV routes: bioavailability is often less than 100% due to factors like:
• Incomplete absorption
• First-pass metabolism in the liver or gut wall
• Degradation in the GI tract

Example: Oral morphine has lower bioavailability (~30%) compared to IV morphine due to significant first-pass metabolism.

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2. Bioequivalence

Bioequivalence refers to the comparison between two drug products (usually a generic vs reference product) to show that they have similar bioavailability, and therefore similar efficacy and safety profiles.
• It is established by comparing key pharmacokinetic parameters:
• Cmax (peak concentration in plasma)
• Tmax (time to reach peak)
• AUC (overall exposure over time)
• Regulatory standards typically require the 90% confidence interval for the ratio (test/reference) of Cmax and AUC to fall within 80%–125%

Example: A generic simvastatin must demonstrate bioequivalence to the branded product (Zocor) to be approved for substitution.

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Summary for Viva:

“Bioavailability is the percentage of the API that reaches systemic circulation. Bioequivalence compares two products to confirm they have similar bioavailability and are therefore interchangeable in terms of clinical effect.”

Question 18

What products have good bioavailability and which have bad?

Answer 18

Products with Good Bioavailability:
1. Intravenous (IV) injection or infusion
• 100% bioavailability by definition — drug is delivered directly into systemic circulation
• Example: morphine IV, radiopharmaceutical injections (e.g. Ga-68)
2. Intramuscular (IM) or Subcutaneous (SC) injections
• High bioavailability (often >90%), but slower onset than IV
• Example: insulin SC
3. Buccal or sublingual (oromucosal) dosage forms
• Bypasses first-pass metabolism; fast absorption
• Example: glyceryl trinitrate sublingual tablets, buprenorphine films
4. Inhaled products
• Rapid absorption through pulmonary route
• Example: salbutamol inhalers

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Products with Poor or Variable Bioavailability:
1. Oral dosage forms (e.g. tablets, capsules)
• Subject to first-pass metabolism, pH effects, solubility, and GI motility
• Bioavailability can range from very low to high depending on the drug
• Examples:
• Low: propranolol (~30%), bisphosphonates (~1%)
• High: paracetamol (~80–90%)
2. Rectal dosage forms
• Variable bioavailability depending on placement and formulation
• Partial avoidance of first-pass metabolism
• Example: diazepam rectal gel (moderate bioavailability)
3. Topical formulations
• Generally poor systemic absorption unless designed for transdermal delivery
• Example: hydrocortisone cream (local), vs fentanyl patch (systemic)

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Summary:

“Products administered IV have the highest bioavailability. Oromucosal and parenteral routes also tend to have high absorption. Oral and rectal forms show variable or reduced bioavailability due to first-pass metabolism and formulation factors. As a QP, understanding this helps assess formulation performance and risk during deviation or change control.”

Question 19

Can you explain which Phase of Clinical Trials is likely to carryout Pharmacokinetics studies?

Answer 19

Pharmacokinetic (PK) studies are primarily carried out during the preclinical and Phase 1 stages of drug development.

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1. Preclinical Phase (Non-clinical Studies)
   • PK studies are conducted in animal models to understand:
   • Absorption, Distribution, Metabolism, and Excretion (ADME)
   • Dose–exposure relationships
   • Potential accumulation or toxicity
   • Data is used to design safe starting doses for first-in-human studies.

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2. Phase 1 (First-in-Human Studies)
   • Conducted in healthy volunteers (except for oncology or high-risk drugs)
   • Aim is to assess:
   • PK parameters: Cmax, Tmax, AUC, half-life (t½), clearance, volume of distribution
   • Safety and tolerability
   • Bioavailability and dose proportionality

This phase provides human PK data to support dose selection for later phases.

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PK Studies in Later Phases (if applicable):
• Phase 2/3: PK studies may still be performed to:
• Assess PK in specific patient populations (e.g. renal/hepatic impairment)
• Evaluate drug interactions or food effects
• Phase 4: May include population PK or special subgroup analysis

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Summary:

“Pharmacokinetic studies are conducted in the preclinical phase in animals and in Phase 1 in humans to understand how the drug behaves in the body. This supports safe dose selection and informs formulation development — which is critical knowledge for a QP during IMP certification.”

Question 20

Can you explain the concept of Therapeutic Index (Narrow vs wide therapeutic window) and give examples of drugs that have a narrow therapeutic window?

Answer 20

The therapeutic index (TI) is a measure of a drug’s safety margin. It describes the range between the dose that produces a therapeutic effect and the dose that causes toxic or adverse effects.

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Definition:
• Therapeutic Index (TI) = TD₅₀ / ED₅₀
• TD₅₀ = dose that causes toxicity in 50% of the population
• ED₅₀ = dose that produces the desired effect in 50% of the population

In clinical practice, we often refer to the therapeutic window, which is the plasma concentration range where the drug is effective without being toxic.

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Narrow Therapeutic Index (NTI) Drugs:
• These drugs have a small margin between effective and toxic doses, so close monitoring is essential to avoid under- or overdosing.
• Require plasma concentration monitoring, dose adjustment, or patient-specific management.

Examples:
• Warfarin – risk of bleeding if too high, clotting if too low (monitored by INR)
• Digoxin – small margin between therapeutic and toxic cardiac effects
• Carbamazepine – seizure control vs CNS toxicity
• Lithium – used in bipolar disorder, requires regular serum level monitoring
• Theophylline – used in asthma/COPD, narrow margin of safety

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Wide Therapeutic Index Drugs:
• Large margin between effective and toxic doses
• Less risk if plasma levels fluctuate

Examples:
• Paracetamol (within standard dosing)
• Penicillin
• Ibuprofen (in healthy adults, within dosing guidelines)

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Why It Matters for a QP:

“Understanding therapeutic index helps the QP assess the impact of deviations or OOS results. For NTI drugs, even small manufacturing or dosing errors can have clinical consequences, so the risk-based approach to batch certification must be stricter.”

Question 21

What is NOEL?

Answer 21

NOAEL stands for No-Observed-Adverse-Effect Level.

It is the highest dose or exposure level of a substance at which no adverse effects are observed in the test population during non-clinical (toxicology) studies, typically in animals.

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Key Points:
• It is established from repeat-dose toxicity studies.
• Represents the threshold below which no harmful effects are seen, even with prolonged exposure.
• Reported in mg/kg/day for the tested species.

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Why is NOAEL important?

In the pharmaceutical industry, NOAEL is used to calculate the Permitted Daily Exposure (PDE) as per ICH Q3C and EMA guidelines.

PDE =
NOAEL × Body weight (kg)
÷
F1 × F2 × F3 × F4 × F5

Where F1–F5 are uncertainty (safety) factors based on:
• Species differences
• Study duration
• Route of administration
• Nature of toxicity
• Quality of data

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QP Relevance:

“As a QP, I would use NOAEL-derived PDE values to evaluate cross-contamination risks in shared facilities and to ensure cleaning validation meets health-based exposure limits (HBELs), in line with Annex 15 and EMA Q&A on cross-contamination.”

Question 22

What is ICH M7 and TTC?
What is difference between TTC and PDE?

Answer 22

ICH M7

ICH M7(R1) is a guideline titled:

“Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk”

It provides a risk-based approach for evaluating and controlling mutagenic impurities (MIs) that may pose a carcinogenic risk to patients, even at low levels.

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Key Concepts in ICH M7:
• Focuses on DNA-reactive impurities (e.g. alkylating agents, aromatic amines)
• Encourages the use of QSAR tools and bacterial mutagenicity assays (e.g. Ames test)
• Supports use of TTC (Threshold of Toxicological Concern) as an acceptable limit for unknown or unqualified mutagenic impurities

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TTC – Threshold of Toxicological Concern:
• TTC is a risk-based exposure limit used when specific toxicological data are lacking
• For most pharmaceuticals, ICH M7 defines the TTC for genotoxic impurities as:
• 1.5 µg/day
• This corresponds to a theoretical lifetime cancer risk of <1 in 100,000
• The limit may vary:
• Higher for short-term exposure (≤1 month)
• Lower for high-potency carcinogens (e.g. nitrosamines, aflatoxins)

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Why This Is Important for a QP:

“As a QP, I must ensure that any known or potential mutagenic impurities are assessed under ICH M7. If no toxicological data are available, I would apply the TTC limit of 1.5 µg/day and ensure that analytical methods are suitably sensitive. This is critical for patient safety and batch release decisions.”

What is the difference between PDE and TTC?

1. PDE – Permitted Daily Exposure
   • Defined in ICH Q3C, Q3D, and EMA cross-contamination guidelines
   • Represents the safe daily exposure limit to a substance based on actual toxicological data (usually NOAEL)
   • Used for known, well-characterised substances
   • Applied in:
   • Cleaning validation (e.g. shared equipment)
   • Elemental impurity limits (ICH Q3D)
   • Residual solvents (ICH Q3C)
   • Cross-contamination risk assessment (Annex 15)

Calculated from NOAEL using safety factors (F1–F5)

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2. TTC – Threshold of Toxicological Concern
   • Defined in ICH M7(R1)
   • Used for DNA-reactive (mutagenic) impurities when substance-specific toxicology data are unavailable
   • TTC is a generic conservative limit, set to ensure lifetime cancer risk is <1 in 100,000
   • For most drugs:
   • TTC = 1.5 µg/day
   • Not suitable for:
   • High-potency carcinogens (e.g. nitrosamines, aflatoxins)
   • Paediatric populations

PDE is a data-driven, substance-specific limit used for general toxicity. TTC is a default conservative limit used in ICH M7 for genotoxic impurities when no data exist. Both are important tools for ensuring patient safety — as a QP, I must apply the appropriate one based on the impurity type and data availability.”

Question 23

New product in multipurpose facility, how would you do it?

Answer 23

1. Initiate Change Control (CC)
   • Raise a formal change control to assess and document the full impact of introducing the new product across the site.
   • This would trigger risk assessments across quality, operations, regulatory, validation, and safety functions.

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2. Regulatory Impact Assessment
   • Marketing Authorisation (MA):
   • Assess if changes affect the MA (e.g. site of manufacture, equipment, testing, batch size).
   • Submit variation if required.
   • MIA(Manufacturing Licence):
   • Check whether the MIA includes the formulation and dosage form of the new product.
   • Submit an MIA variation to the MHRA if needed.

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3. GMP Impact Assessment

a. Facility & Equipment
• Is it a potent or sensitising product?
• Assess whether a dedicated facility or closed system is needed.
• Review HVAC segregation, pressure differentials, and airflow patterns.

b. Personnel
• Training needs for new product, process, and safety risks
• Perform COSHH assessment for operator exposure and PPE requirements

c. Documentation
• Update or create:
• CCS (Contamination Control Strategy)
• Cleaning SOPs
• Master Batch Records
• Validation protocols

d. Manufacturing Process
• Assess cleaning validation requirements:
• Perform risk assessment using worst-case approach across product matrix
• Use equipment train mapping to identify shared surfaces
• Assess cleanability, solubility, and potency
• If still worst-case: execute cleaning validation runs
• Line clearance procedures may need updating or strengthening

e. Quality Control (QC)
• Assess analytical method validation needs for new product
• Review equipment suitability and detection limits for residual testing

f. Outsourced Activities
• If any part is outsourced (e.g. testing, intermediate manufacture), verify:
• Supplier approval
• Technical agreements
• Audit reports

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4. Cross-Contamination Risk and Cleaning Validation
   • Conduct a cleaning validation risk assessment using:
   • Toxicological data (e.g. NOAEL)
   • Calculate PDE and MACO (Maximum Allowable Carryover)
   • Evaluate cleaning method effectiveness (e.g. using swab/rinse recovery studies)
   • Compare new product’s cleanability to existing worst-case
   • If it becomes the new worst-case, full cleaning validation is required

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5. Impact on Other Products
   • Assess risk of cross-contamination or product mix-up
   • Reassess product-to-product sequence rules
   • Review EM data and environmental capability to handle the new product

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Summary for Viva:

“I would initiate a formal change control and perform a comprehensive impact assessment across regulatory, facility, process, and quality systems. I’d evaluate cross-contamination risk using PDE-based cleaning validation principles, ensure training and documentation updates, and verify that the site remains compliant with GMP and the MIA.”

Question 24

What is first pass metabolism?

Answer 24

First-pass metabolism (also called first-pass effect) refers to the metabolism of a drug before it reaches the systemic circulation, primarily when the drug is administered orally.

⸻

How it works:
• After oral administration, the drug is absorbed from the gastrointestinal (GI) tract into the portal vein, which carries blood directly to the liver.
• In the liver, the drug undergoes enzymatic metabolism (mainly by cytochrome P450 enzymes).
• As a result, a significant portion of the drug may be inactivated or transformed into metabolites before reaching systemic circulation.

⸻

Impact on Bioavailability:
• First-pass metabolism reduces the bioavailability of the drug — meaning less active drug reaches the bloodstream.
• Drugs with high first-pass effect may require:
• Higher oral doses
• Alternative routes (e.g. sublingual, rectal, or IV)

⸻

Examples of drugs with high first-pass metabolism:
• Propranolol
• Glyceryl trinitrate (GTN) — given sublingually to avoid first-pass effect
• Morphine
• Lidocaine

⸻

Summary for Viva:

“First-pass metabolism refers to the liver’s enzymatic breakdown of a drug after oral administration and before it reaches systemic circulation. It reduces bioavailability and must be considered when designing dosage forms or evaluating formulation changes — which is highly relevant for QP decision-making.”

Question 25

What is meant by therapeutic range?

Answer 25

The therapeutic range (or therapeutic window) is the plasma concentration range of a drug that produces the desired therapeutic effect without causing toxic or adverse effects. ⸻ In other words: It is the range between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). • Below the range: the drug may be ineffective • Above the range: there is increased risk of adverse effects or toxicity ⸻ Why it’s important: • For drugs with a wide therapeutic range, plasma levels can fluctuate without serious consequences. • For narrow therapeutic index (NTI) drugs, the therapeutic range is small, so plasma levels must be tightly controlled. ⸻ Examples of NTI drugs: • Warfarin • Digoxin • Lithium • Carbamazepine • Theophylline ⸻ Summary for Viva: “The therapeutic range defines the safe and effective plasma concentration window for a drug. It guides dosing decisions, monitoring needs, and risk assessments during batch deviations or stability reviews — all highly relevant to QP responsibilities.”

Question 26

Do you know what ‘buccal’ route of administration is?

Answer 26

The buccal route involves placing a tablet or formulation between the cheek and gum, where the drug is absorbed through the buccal mucosa (lining of the inner cheek) directly into the systemic circulation. ⸻ Key Features: • Avoids first-pass metabolism – The drug bypasses the gastrointestinal tract and liver • Rapid onset of action – Due to the rich blood supply in the buccal area • Suitable for lipophilic, small-molecule drugs that can penetrate mucosal membranes ⸻ Examples of buccal formulations: • Buccal midazolam (e.g. for seizure control in paediatrics) • Buprenorphine buccal film (used in pain management and opioid dependence) ⸻ Summary for Viva: “The buccal route involves absorption through the cheek mucosa, allowing for rapid systemic delivery while avoiding first-pass metabolism. It’s an important route for drugs needing fast onset or where oral administration is unsuitable — relevant for QP review of route-specific formulations.”

Question 27

Would this lead to quicker or slower bioavailability than a tablet you swallowed?

Answer 27

Quicker - Intravenous injections, IM, SC, Buccal/Sublingual, Inhalation Slower - Transdermal Patches, CR/Modified Release Tablets

Question 28

What contamination controls are in place in a solid oral dose site?

Answer 28

1. Quality Management System Controls Robust deviation, change control (CC), OOS/OOT systems Batch record review and batch release process Self-inspection programme (using PIC/S or GMP Chapter 1 checklists) Data integrity controls 2. Facility and Environmental Controls Controlled dispensing areas with defined cleaning procedures Temperature and humidity monitoring appropriate for product Pest control system in place Restricted access to manufacturing and storage areas Where applicable — use of segregated or contained areas for potent compounds Cleaning validation and routine cleaning schedules 3. Personnel Controls Periodic GMP training Operator qualification (equipment use, cleaning procedures) Gowning appropriate to non-sterile manufacturing (e.g. hairnets, protective clothing, gloves) Hand washing procedures 4. Documentation Controls Contamination Control Strategy (CCS) documented and maintained Cleaning SOPs Line clearance procedures before and after production 5. Material and Supplier Controls Supplier qualification and approval Supplier audits based on risk Quarantine and segregation of raw materials, packaging, and returned goods 6. Cross-contamination Risk Controls Cleaning validation based on worst-case product Use of Maximum Allowable Carryover (MACO) calculations (based on PDE / toxicology data) Equipment train mapping Line clearance and visual checks 7. Ongoing Verification & Monitoring Internal audits / Gemba Walks to monitor compliance Trending of deviations, cleaning failures, or EM data Periodic review of cleaning validation and CCS

Question 29

You mentioned pressure cascade – do you know what the difference should be?

Answer 29

15 -20 pascals difference

Question 30

You mentioned that some products need separate facilities – can you name any?

Answer 30

Penicillins/beta-lactams - causing allergy Sensitising products (cytotoxic, biologics) - toxic reaction Highly potent APIs (Extremely low PDE/MACO) - Hormones, Oral contraceptives, Steroid, Immunosuppressive (ciclosporin)

Question 31

Thinking now about contamination control in a sterile site – what would be different?

Answer 31

Key Differences in Contamination Control at a Sterile Site: 1. Facility Design & Cleanroom Environment Grade A environment for aseptic filling (within isolator or LAF) Grade B background for aseptic preparation Grade C/D for supporting areas (component prep, formulation) Use of airlocks for personnel and material transfer Pharmaceutical transfer hatches with laminar airflow 2. HVAC & Environmental Controls HEPA-filtered unidirectional airflow over critical zones Air supply designed for no recirculation in critical areas Continuous pressure differentials (≥15 Pa) to protect cleaner areas Strict temperature and humidity control Continuous non-viable particle monitoring in Grade A Viable monitoring (settle plates, contact plates, active air sampling) during and after production 3. Equipment Controls Barrier technologies: e.g. Gassed isolators or RABS for aseptic filling Validated cleaning and sterilisation of equipment (autoclave/SIP/CIP systems) Sterile filtration: 0.22µm filters with pre- and post-use integrity testing 4. Utilities Controls Use of WFI (Water for Injection) for final rinses Clean steam generation for sterilisation Routine microbiological monitoring of water and clean utilities 5. Personnel Controls Operator GMP training plus aseptic technique qualification Regular media fill simulations to confirm aseptic process capability Microbiologist involvement in environmental monitoring (EM), data trending, and investigations Strict gowning procedures (Grade B gowning for access to Grade A/B) 6. Cleaning Validation & Cross-Contamination Control Cleaning validation based on worst-case approach Cross-contamination risk controlled via PDE/MACO calculations Low bioburden raw materials and sterile component preparation 7. Supplier Qualification & Material Control Supplier approval process with quality agreements Raw materials tested for low bioburden and endotoxin Qualified sterilisation methods for components and packaging Summary for Viva: “In sterile manufacturing, contamination control is more stringent because any contamination could directly impact product sterility and patient safety. Controls focus on facility design, environmental monitoring, aseptic process validation, and strict personnel qualification, all in line with EU GMP Annex 1 expectations. The site’s CCS must demonstrate a proactive and integrated approach to prevent microbial, particulate, and pyrogen contamination.”

Question 32

Asked about absorption of nasal product . This led to talking about the absorption in CNS by passing the BBB.

Answer 32

1. Local Absorption (Topical Effect) The drug is intended to act locally on the nasal mucosa. Used for conditions like rhinitis, nasal congestion, or allergies. Minimal systemic absorption. Example: Nasal corticosteroids (e.g., Beclometasone nasal spray) 2. Systemic Absorption (Through Nasal Mucosa) Some nasal products are designed for systemic effect. The nasal mucosa is highly vascularised, allowing the drug to be absorbed directly into the systemic circulation. First-pass metabolism is avoided because the drug bypasses the gastrointestinal tract and liver. This route allows rapid onset of action — useful for emergency medicines. Example: Nasal sumatriptan (for migraine) Nasal midazolam (for seizure control) Nasal desmopressin (for diabetes insipidus) 3. Absorbed via the olfactory of region of the nasal cavaity, allowing direct transport into teh CNS bypassing the BBB. (Nasal Midazolam) Summary for Viva: “Nasal absorption can be local or systemic. When systemically absorbed through the nasal mucosa, the drug bypasses first-pass metabolism, allowing rapid onset of action. This makes the nasal route useful for emergency medicines or when oral administration is not possible.” Nasal drug delivery primarily allows for local absorption or systemic absorption through the highly vascularised nasal mucosa, avoiding first-pass metabolism. However, certain drugs — especially small, lipophilic molecules or peptides — can be absorbed via the olfactory region of the nasal cavity, allowing direct transport into the CNS bypassing the blood-brain barrier (BBB). This is being investigated and used in some products for rapid CNS action, such as nasal midazolam or nasal ketamine for seizures or pain.”

Question 33

Discussed about what could limit the distribution. Discussed about how could you remove these limitations?

Answer 33

Factors that Limit Drug Distribution in the Body: 1. First-pass metabolism Drug is broken down by liver enzymes (CYP450) before reaching systemic circulation Propranolol, Morphine 2. Degradation in stomach acid Acid-labile drugs are degraded in low pH Erythromycin, Omeprazole 3. Poor membrane permeability Highly hydrophilic or large molecules may not cross cell membranes easily Peptides, Insulin 4. Plasma protein binding Only free (unbound) drug can distribute to tissues Warfarin is highly protein bound 5. Efflux transporters (P-gp) Pump drug back into gut or brain — limiting distribution Digoxin, Loperamide (at BBB) Strategy: 1. Prodrug - Mask the active drug — improves absorption/distribution — converted to active form in body Enalapril → Enalaprilat 2. Enteric coating Protects drug from stomach acid — dissolves in intestine Omeprazole tablets 3. Lipid-based formulation Improves membrane permeability and absorption of poorly soluble drugs Cyclosporine microemulsion 4. Nano-formulation / liposomes Improves delivery to target tissues, avoids degradation Doxorubicin liposomes 5. Bypass first-pass effect Change route of administration — e.g., sublingual, nasal, injection GTN sublingual, Insulin injection Summary for Viva: “Drug distribution can be limited by first-pass metabolism, acid degradation, poor permeability, or protein binding. Formulation strategies such as prodrugs, enteric coating, or alternative routes of administration can be used to overcome these limitations to improve bioavailability and therapeutic effect.”

Question 34

Your site acquires a new paediatric suspension. What are your considerations?

Answer 34

“For a new paediatric oral suspension product introduced at the site, my key concern is patient safety — children are more sensitive to impurities, contaminants, or dosing errors because of their lower body weight and developing physiology. Therefore, stricter contamination control and GMP controls would be needed in line with EU GMP Annex 9 for liquids.” 1. Contamination Control Considerations: Minimum Grade D cleanroom for filling (Annex 9). HVAC with appropriate pressure cascade and air change rates. Purified Water (PW) for formulation — water quality monitoring with trending. Cleaning validation — ensuring no carryover of active ingredient (especially if multi-product line). Validate mixing and filling process — including hold time study (to prevent sedimentation or microbial growth). Avoid glass apparatus unless necessary — due to breakage risk and particles. Avoid sharing equipment, use of single use system. Restrict wooden pallets or cardboard near controlled areas. Supplier qualification and tighter incoming goods checks — especially for excipients (sweeteners, flavours, preservatives). 2. Open CC + Additional GMP / Licence Impact: Review Marketing Authorisation (MA) — any variations needed (if site addition is required). Check MIA licence scope — does it cover oral liquids/suspensions? Ensure product-specific SOPs, batch records, and cleaning instructions updated. Consider if new storage conditions apply (e.g. fridge vs ambient). 3. Pharmaceutical Concerns: Uniformity of dose in suspension — ensure validated mixing and appropriate sampling technique for QC testing. Preservative efficacy testing if multi-dose product. Evaluate expiry/shelf-life stability. Final Viva Summary Statement: “Introducing a paediatric suspension requires enhanced contamination control because of the higher patient risk profile. I would ensure GMP controls align with Annex 9 expectations, validated cleaning, and water quality monitoring are in place, and assess licence impact. As a QP, I would also review formulation-specific risks such as hold time, sedimentation, and uniformity of dose.”

Question 35

Explain contamination control?

Answer 35

Model Answer: Explain Contamination Control Contamination control is a holistic, risk-based approach to prevent contamination during pharmaceutical manufacturing. It applies to preventing: Physical contamination (particles, glass, fibres) Chemical contamination (residual product, cleaning agents) Microbiological contamination (bacteria, fungi, endotoxins) Cross-contamination (mix-up with other products) It is a fundamental GMP principle, as described in EU GMP Annex 1 (Contamination Control Strategy, CCS). Contamination Control is Managed Through: 1. Quality Management System (PQS) Deviations, change control, CAPA, OOS/OOT Risk assessments and trending Data integrity controls 2. Facility and Equipment Controls Facility design — material/personnel flow, airlocks, room classification Pressure cascade and airflow direction Cleaning validation based on PDE/MACO principles Line clearance controls 3. Utility Controls Water system monitoring (PW, WFI) HVAC validation (HEPA filters, air changes) Clean steam, gases monitoring 4. Personnel Controls GMP and aseptic training Gowning qualification Operator behaviour monitoring (Aseptic technique for sterile areas) 5. Documentation Controls Site Contamination Control Strategy (CCS) document SOPs for cleaning, sanitisation, gowning, line clearance 6. Manufacturing Process Controls Cleaning procedures and validation Material transfer processes In-process controls Line clearance procedures 7. Quality Control (QC) Controls Environmental monitoring programme Microbiological testing Residual testing for cleaning validation 8. Supplier and Vendor Management Supplier qualification Audit programme Incoming material checks 9. Complaint and Recall Management Product complaint system Mock recall exercises Investigation of contamination-related complaints 10. Self-Inspection and Audit Internal audits and Gemba walks Review of contamination control practices Continual improvement culture Summary for Viva: “Contamination control is a holistic, site-wide approach managed through the PQS and supported by facility, personnel, equipment, and process controls. The site’s Contamination Control Strategy (CCS) brings together these controls in line with Annex 1 expectations to protect product quality and ultimately patient safety.”

Question 36

How do you set up a cleaning validation programme and what are HBEL calculations?

Answer 36

High-level Overview: 1. Risk Assessment: * Map the equipment train and calculate shared surface areas. * Identify the worst-case product based on factors like low solubility, high potency, toxicity, and cleanability. * Perform Health-Based Exposure Limit (HBEL) calculations using toxicological data to establish the Permitted Daily Exposure (PDE). * Use the PDE to calculate the Maximum Allowable Carryover (MACO): * The worst-case product (lowest MACO, most difficult to clean) is selected for validation. 2. Analytical Method Validation: * Use a validated, sensitive, and specific method capable of detecting residues below the MACO. * Ensure 70% swab recovery is demonstrated from representative surfaces. 3. Cleaning Validation Protocol: The protocol should clearly define: * Cleaning procedure and parameters. * Sampling methods (swab, rinse) and locations (worst-case points). * Analytical method to detect residues. * Acceptance criteria (MACO, visual, microbial limits). * Personnel training. * In-process verification (e.g. logbook entries, visual checks). * Deviation and CAPA handling during the validation process. * Execution of 3 consecutive successful cleaning runs under routine conditions. * Documentation in a cleaning validation report. 4. Ongoing Lifecycle Approach: * Periodic review of cleaning validation status. * Revalidation triggers: changes in product, equipment, cleaning agents, or process.

Question 37

Tell me about your product, ADME, mode of action and composition?

Answer 37

Product Overview: This product is an aseptically prepared radiopharmaceutical injection indicated for the treatment of cancer. It combines a radionuclide generated from an in-house Elution Generator (e.g., Ga-68 from a Ge-68/Ga-68 generator) with a monoclonal antibody (mAb) that targets specific tumour-associated antigens. ⸻ Mode of Action (MoA): The monoclonal antibody component binds selectively to a receptor or antigen overexpressed on cancer cells. Once the antibody binds to the tumour cell surface, the attached radionuclide delivers localised cytotoxic radiation—typically beta or alpha particles—resulting in targeted destruction of malignant cells while sparing healthy tissue. ⸻ ADME Profile: * Absorption: As the product is administered intravenously, systemic bioavailability is 100%, bypassing the absorption phase typical of enteral routes. * Distribution: The radiolabelled antibody distributes systemically via the bloodstream. Due to its high specificity and stability, it remains intact while circulating, allowing accumulation at tumour sites where the target antigen is present. * Metabolism: The product is highly stable in vivo, with minimal metabolism expected. The radionuclide-antibody complex is designed to resist degradation during systemic circulation. * Excretion: Unbound radionuclide is primarily excreted unchanged via the kidneys. Clearance rates depend on molecular size, charge, and protein binding characteristics. ⸻ Composition: * Radionuclide (e.g., Gallium-68 or other suitable radiometals) * Monoclonal antibody specific to tumour antigens * Formulation buffer: typically 0.9% sodium chloride or other isotonic saline solution * May include stabilizers or radioprotectants, depending on product formulation

Question 38

You want to release your product before all release test results are completed, how will you go about this?

Answer 38

1. Scope and Justification Applies only to products with: Very short shelf life (e.g. radiopharmaceuticals, some ATMPs) Time-critical clinical use Justification must be clearly documented in the SOP, risk assessment, and clinical protocol. 2. QMS Requirements A formal SOP must define the process for “release under quarantine” The QMS must include: Training records for staff involved Deviation handling and OOS procedure if post-release results fail Traceability and recall mechanism clearly defined 3. Risk Assessment and Controls Full risk assessment must be in place: Confirm that all critical quality attributes (CQAs) and CPPs are within specification prior to release (e.g. visual inspection, pH, radiochemical purity, filter integrity) Product is released under quarantine, e.g. with a tamper-evident POD lock Sterility test results pending but expected to pass based on: Validated aseptic process CCS controls Environmental monitoring (EM) within limits Media fills / APS data Control measure example: POD lock seal is applied and only released to the clinical site once sterility results are confirmed. The lock code is withheld until QA authorisation post-confirmation of test results. 4. QP Certification The QP must: Review batch records, EM data, filter integrity, process deviations, and all available QC data Provide conditional certification or hold the final certificate until test results are received, depending on internal policy 5. Post-release Monitoring If any test fails post-administration, a rapid recall and clinical incident review is triggered. Investigation must include communication with MHRA and clinical sponsor if applicable.

Question 39

What about if you have an OOS result after you have release and it was administered?

Answer 39

This situation requires immediate, structured action under the site’s QMS, with the QP taking leadership for risk mitigation, regulatory reporting, and patient safety. 1. Initiate OOS Investigation Follow your OOS SOP, in line with MHRA expectations: Confirm Phase 1: analyst/lab error? If no assignable cause, escalate to Phase 2 If it’s a microbial failure, immediately send for microorganism identification to determine the level of clinical risk (e.g., objectionable organism? environmental flora?). 2. Open a Deviation and Conduct Risk Assessment Log a formal deviation in your QMS Conduct risk and impact assessment: Regulatory risk: did the product meet MA and GMP at the time of release? GMP failure: was it a failure of your contamination control strategy (CCS), cleaning validation, or test method? Product risk: assess the clinical impact of the OOS parameter on patient safety 3. Notify Stakeholders Immediately inform the clinical team or sponsor if the product was used in a trial or treatment setting Provide clinical interpretation of the OOS and recommend appropriate follow-up actions (e.g., patient monitoring, clinical testing) 4. Notify the MHRA If there is a potential risk to patients, this becomes a reportable defect under the Defective Medicines Reporting Centre (DMRC) Submit a report via the Yellow Card portal, including: Batch number Nature of failure Investigation summary Interim and final CAPA Risk to patients and mitigation 5. Initiate Recall if Required If the impact assessment suggests that patient harm is possible, hold a recall decision meeting (multidisciplinary team including QP, RP, QPPV, sponsor, clinicians) Classify the recall (e.g., Class 1 or 2) and execute under MHRA guidance Follow up with final report to MHRA/DMRC 6. CAPA and CCS Review Implement CAPAs based on root cause: Lab retraining Environmental/sterility controls Supplier or raw material reassessment Review and update CCS or validation protocols if gaps are identified Trend the failure for future PQR and self-inspection review

Question 40

Sterility test in your product. Why can you not follow the common sterility test?

Answer 40

For aseptically prepared radiopharmaceuticals, the typical shelf-life is 6–8 hours due to radioactive decay (e.g. Tc-99m, Ga-68). However, compendial sterility tests (Ph. Eur. 2.6.1) require 14 days of incubation: 7 days at 20–25°C for fungal detection 7 days at 30–35°C for bacterial detection As a result, products are administered before sterility test results are available. This is justified only if: A validated aseptic process is in place A robust Contamination Control Strategy (CCS) exists All in-process controls and CQAs (e.g. filter integrity, visual inspection, RCP, endotoxin) pass prior to release This approach is managed under release under quarantine and supported by Annex 1 (2022) expectations for parametric release and rapid release systems

Question 41

Imagine you have a multi product facility, how will you go about performing cross contamination strategy?

Answer 41

Cross-contamination control in a multi-product site must be systematic, risk-based, and aligned with Annex 1 (2022) and Annex 15. My steps would be: 1. Risk Assessment of Products Assess API/excipient potency, toxicity, cleanability, solubility, and PDE: Calculate PDE using toxicology data (NOAEL × BW / F1–F5 factors) F1–F5 include interspecies variability, human variability, severity of effect, duration of exposure, and LOAEL correction Calculate MACO = PDE × min batch size of next product / max daily dose of next product 2. Shared Surface Risk Mapping Create an equipment matrix to define all shared surfaces Identify worst-case residues and hard-to-clean locations 3. Cleaning Validation Matrix Based on cleanability + toxicity, select worst-case product for full cleaning validation 4. Analytical Method Validation (per ICH Q2R2) Specificity (resolution > 1.4) Accuracy (3 levels × 3 replicates, RSD < 2%) Linearity (R² > 0.99, 5 concentrations) Precision (intra/intermediate, RSD < 2%) LOD/LOQ: 3:1 and 10:1 signal:noise 5. Cleaning Validation Execution Protocol to include: Cleaning procedure and swab/rinse sampling plan Acceptance criteria based on MACO Recovery >70% Visual inspection included Staff training, deviation management, CAPA Validation report and periodic review

Question 42

How will you keep up to date your CCS ?

Answer 42

The Contamination Control Strategy is a live document and must be actively maintained. I would: Link CCS review to: Change Controls Deviations / OOS / OOT Regulatory inspections / MHRA findings CAPA outcomes Use PQR review cycle to formally trigger CCS reassessment Ensure any new equipment, process, or facility change is assessed for CCS impact

Question 43

Scenario: What about avoiding cross contamination in the biological starting material?

Answer 43

1. Cell Bank Control (Annex 2, ICH Q5D): Use of Master Cell Bank (MCB) and Working Cell Bank (WCB) Fully qualified and tested for: Identity Purity Absence of adventitious agents Stored under defined, monitored conditions 2. Donor Screening (Annex 2, ATMP-specific expectations): For autologous CAR-T or other cell therapies, ensure: Donors are screened for HIV, HBV, HCV, HTLV, syphilis, etc. Testing meets regulatory expectations under HTA and Annex 2 All biological materials tracked via chain of identity and custody

Question 44

Scenario follow up: What do you need to import products from USA?

Answer 44

MA product - QP release under MIA Unlicensed - regulation 167 apply: MS - importing from onn-approvd country for import WDA - importing from approved country for import (i.e. EU an EEA)

Question 45

Scenario follow up: What warehouse controls and material traceability?

Answer 45

1. QMS & Governance QMS must cover: Deviation and change control system CAPA and complaint handling Regular QA/quality review meetings Warehouse should be included in self-inspection programme 2. Personnel & Training Staff must be: Trained and competency-assessed on GDP/SOPs Aware of falsified medicines risk and Yellow Card/DMRC reporting RP (if WDA site) or designated QA lead must oversee compliance 3. Facility & Equipment Controls Qualified storage areas with: Calibrated temperature and humidity monitoring Alert/alarm systems Pest control and cleaning logs Avoid floor storage and implement pallet racking Fridges or freezers used must be: Temperature-mapped and alarmed Backed by validated cleaning and defrosting procedures 4. Documentation Controlled SOPs covering: Goods-in Quarantine and release Environmental monitoring Temperature deviation handling Version control and training logs must be maintained 5. Process Controls & Traceability Clear batch traceability by: Assigning internal warehouse batch number Ensuring stock rotation (FEFO or FIFO) Goods-in check: quantity, identity, packaging condition, falsification risk Segregation of: Quarantined vs released Returns vs released Rejected or recalled stock Maintain full audit trail from goods-in to dispatch 6. Supplier & Customer Qualification Ensure bona fide checks for all customers and suppliers Supplier approval should include: Questionnaires Licences and GDP/GMP certificates Periodic re-qualification Due diligence for unusual orders or high-risk products (e.g. CD, high-value) 7. Recall and Complaint Readiness System must allow: Rapid batch identification and segregation Notification of affected customers Mock recall exercises Complaints and falsification reports escalated per MHRA/DMRC requirements 8. Self-Inspection Warehouse activities reviewed in regular self-inspection/audit programme Ensure follow-up of findings and CAPA closure

Question 46

As part of improvement company introduce new washer for glassware and equipment cleaning in production area. Explain the requirements.

Answer 46

The introduction of a new washer is a GMP-impacting change that must be controlled under the Pharmaceutical Quality System (PQS). The following steps are required: 1. Change Control (CC) Initiation Open a formal change control to manage the lifecycle of this change. Assign a cross-functional team (QA, production, engineering, validation) to assess and approve all stages. 2. Risk and Impact Assessment Assess the impact of the change on: a. Contamination Control Strategy (CCS) Assess whether the new washer introduces risks of cross-contamination or microbial contamination. Update the CCS document to reflect new cleaning systems, critical surfaces, cleaning agents, and rinsing water quality. b. Finished Product Quality Evaluate the risk of carryover of residues (e.g. detergent, product/API) affecting CQAs such as: Impurities Microbial limits Visual appearance c. Facility and Utilities Assess: Water quality used in the final rinse — must meet the same specification used in manufacturing (e.g. Purified Water for oral liquids) Any swage/pipework modifications, and ensure validation of drainability and slope Whether the new washer affects HVAC, cleaning zoning, or environmental controls 3. Equipment Qualification (per Annex 15) Follow a full V-model lifecycle: Phase Description URS Define user and functional requirements (load capacity, spray reach, temperature, cycle time) DQ Ensure washer design meets URS and GMP expectations IQ Verify correct installation: plumbing, software, alarms, water/power supply OQ Verify cycle parameters: time, temperature, detergent dosing, final rinse PQ Demonstrate performance in routine use — may include cleaning verification/validation 4. Cleaning Validation If shared equipment or multi-product use, perform cleaning validation: Use worst-case product (most potent, least soluble, most difficult to clean) Calculate MACO based on PDE using ICH Q3D / EU GMP Part III guidance Swab/rinse sampling with validated analytical methods (ICH Q2) Ensure residue levels are below acceptance criteria (MACO) and ≥70% recovery 5. Documentation Update SOPs: Cleaning procedures Visual inspection Equipment use and maintenance Train personnel and retain training records 6. Ongoing Monitoring Ensure periodic review through: Trending of cleaning verification results Inclusion in PQR/self-inspection programme Viva-ready phrasing: “Introducing a new washer requires change control, risk assessment, and full equipment qualification per Annex 15. I would evaluate its impact on the CCS, product quality, and facility systems. The washer must use a rinse quality equivalent to the product’s manufacturing grade — e.g. Purified Water. If shared, cleaning validation with MACO calculation using PDE principles is needed, aligned with EU GMP Part III and ICH Q2 for analytical method validation.”

Question 47

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?

Answer 47

1. Initiate Change Control * Raise a Change Control (CC) to formally document: * The shift from single- to multi-product manufacturing * Changes to cleaning procedures (e.g. hot water to acid/alkali detergents) * Introduction of higher-risk product types (insoluble, potent) * Assign a cross-functional team (QA, Production, Engineering, QC, Regulatory) ⸻ 2. Impact Assessment Conduct a full impact assessment covering: * Licence scope: Is a variation needed for new formulations or activities? * GMP/CCS: Reassess the Contamination Control Strategy (CCS) to ensure robust control across product lines. * Product risk: Assess the potential for carryover, degradation, or incompatibility. ⸻ 3. Cleaning Validation Matrix Develop a matrix that compares each product’s: * Solubility in cleaning agents (hot water, acid/alkaline detergents) * Potency and cleanability * Toxicological profile using NOAEL values * Use ICH Q3C/Q3D, EMA toxicology guidelines, and ECA cleaning validation guidance * Calculate PDE and MACO: * PDE = NOAEL × body weight / (F1 × F2 × F3 × F4 × F5) * MACO = PDE × min batch size of next product / max daily dose of next product ⸻ 4. Equipment Mapping and Sampling Strategy * Map the shared surface area using an equipment chain diagram * Identify: * Hard-to-clean areas * Dead legs, crevices, valve gaskets * Assess detergent compatibility with equipment material (avoid corrosion or residue buildup) * Define sampling locations using a risk-based approach (e.g. worst-case points, lowest flow areas) ⸻ 5. Worst-Case Selection for Cleaning Validation * Select the most difficult-to-clean product based on: * Poor solubility * High potency/low PDE * High risk of microbial/chemical carryover * This will be the validation challenge product. ⸻ 6. Analytical Method Validation * Validate cleaning analytical methods per ICH Q2(R2): * Accuracy (recovery >70%) * Linearity (r² >0.99) * Precision (RSD <2%) * Specificity (no interference) * LOD/LOQ: LOD < MACO; LOQ < acceptance level * Include swab and rinse recovery studies ⸻ 7. Cleaning Validation Protocol Develop a protocol including: * Cleaning procedure (detergent concentration, contact time, rinse conditions) * Sampling method: Swab (direct surface contact) or rinse (CIP systems) * Acceptance criteria: * Residue level < MACO * Visual cleanliness * Recovery > 70% * Number of runs: 3 consecutive successful cleaning runs for each product group * Personnel training and qualification of cleaning operators * Handling of deviations and CAPA * Defined process for periodic review and revalidation ⸻ 8. Continuous Oversight * Establish a periodic requalification plan (e.g. based on campaign length, product changeover, cleaning failures) * Link cleaning validation reviews to PQR and QRM processes * Update SOPs, training, and validation master plan (VMP), CCS document

Question 48

What products would you not want to manufacture in your multi product facility? Give examples.

Answer 48

Potent, High sensitised, toxic product

Question 49

Where would you find information on new drugs?

Answer 49

BNF, MHRA website, Smpc, EMA (EPAR), Scientific literature and Database, Company's website, Medical Rep

Question 50

What specifically would you be looking for in an SmPC?

Answer 50

Key Information I Would Check in the SmPC: 1. Product Identification Product name (strength & form) Pharmaceutical form (e.g., tablet, suspension, injection) Strength and unit (mg, µg, %) Marketing Authorisation Holder (MAH) 2. Composition List of active ingredients and excipients Information on allergens or excipients with known effect (e.g., lactose, ethanol, sodium content) 3. Route of Administration & Dosage Instructions Approved route (oral, IV, IM, sublingual) Posology (dosing regimen) Method of administration — including instructions for dilution or reconstitution 4. Storage Conditions & Shelf Life Storage temperature (e.g., 2-8°C, protect from light) In-use shelf life (after reconstitution or opening) Specific storage instructions (e.g., store in original package) 5. Pharmacokinetics / Pharmacodynamics Absorption, distribution, metabolism, excretion (ADME) Half-life — useful for assessing missed doses or OOS investigations 6. Special Warnings & Precautions Contraindications Drug-drug interactions Side effects / adverse reactions Special patient groups (e.g., paediatrics, renal impairment) 7. GMP Relevant Instructions Instructions for handling hazardous products (e.g., cytotoxic) Preparation instructions for healthcare professionals Waste disposal guidance Summary Statement for Viva: “As a QP, I would check the SmPC to confirm product identity, dosage form, strength, route of administration, storage conditions, excipients, and any GMP-relevant handling instructions. This ensures the batch I am certifying is compliant with the Marketing Authorisation and suitable for safe use by patients.”

Question 51

When would you look to use dedicated facilities?

Answer 51

When the product is: - Potent - High sensitised - Toxic

Question 52

How would you set up cleaning validation in multi product facility ?

Answer 52

In a multi-product facility, cleaning validation is essential to prevent cross-contamination, protect patient safety, and comply with EU GMP. I would follow a risk-based and scientifically justified approach, using: * EU GMP Annex 1 (2022) * Annex 15: Qualification and Validation * EMA Guideline on PDE (Part III) * ICH Q2(R2) for analytical method validation ⸻ 1. Risk Assessment and Equipment Mapping * Map out the equipment train to identify all shared product contact surfaces * Perform risk assessments to select the worst-case product(s) based on: * Potency / PDE * Solubility in cleaning agent * Cleanability (e.g. residue tendency) * Toxicological profile * Hard-to-clean areas and sampling accessibility ⸻ 2. Calculation of PDE and MACO * Obtain toxicological data and determine the NOAEL (No Observed Adverse Effect Level) * Use the following formula to calculate PDE: PDE=NOAELxBody weight/F1-5 Where: * F1 = Interspecies variability * F2 = Intraspecies variability * F3 = Severity of effect * F4 = Duration of dosing * F5 = Use of LOAEL instead of NOAEL (if applicable) * Then calculate MACO (Maximum Allowable Carry Over): MACO=PDExMinimum batch size of next product/Maxomum daily dose of next product 3. Cleaning Validation Protocol The protocol should define: * Worst-case product(s) from cleaning validation matrix * Cleaning procedure and cleaning agents used * Sampling method (swab for surface or rinse for inaccessible areas) * Recovery studies to verify sampling method (>70% acceptable) * Acceptance criteria: residue must be below MACO * Number of runs: typically 3 consecutive successful cleaning cycles ⸻ 4. Analytical Method Validation Methods must be validated per ICH Q2(R2) for: * Specificity * Accuracy (3 concentrations, RSD < 2%) * Linearity (R² ≥ 0.99) * Precision and reproducibility * LOD and LOQ (LOQ must be lower than MACO) ⸻ 5. Deviation and CAPA * Any deviations during validation must be fully investigated * Implement CAPAs and repeat the validation if required ⸻ 6. Lifecycle and Periodic Review * Cleaning validation must be re-reviewed periodically (e.g. during PQR or after product/process change) * Data may support bracketing or matrix approaches for future cleaning validations

Question 53

How do you calculate PDE and Swab limit?

Answer 53

PDE= NOAELxbodt weight /F1-5 (F1 - inter species, F2- intraspecies, F3- severity of effect, F4- duration of exposure, F5 - when LOAEL used), There is no fixed regulatory “limit” for swab recovery itself, but industry best practice expects a minimum recovery rate of ≥70% from surface recovery studies. This ensures the sampling method is accurate and reliable for detecting residual contaminants. ⸻ Clarifying Two Different Concepts: 1. Swab Recovery Rate (Validation of Sampling Method): * Before using swab sampling in cleaning validation, you must validate that the swab can effectively recover a known quantity of the target analyte (API, detergent, etc.) from the surface. * ≥70% recovery is generally accepted for: * Stainless steel surfaces * Flat, smooth areas * Recovery rates <70% may be accepted with scientific justification (e.g. rough surfaces or poorly soluble substances), but the acceptance limit must be adjusted accordingly. 2. Swab Result Acceptance Limit (MACO): * After cleaning, the residue measured from the swab sample must be below the MACO (Maximum Allowable Carry Over), which is derived from the PDE calculation. * Units are often expressed as µg/cm² or µg/swabbed area.

Question 54

You are a QP in new multi product facility, how would you ensure setup. How would you consider sampling location

Answer 54

1. Initiate Contamination Control Strategy (CCS) * Open a change control (CC) to cover the site setup and facility introduction. * Establish a CCS per EU GMP Annex 1 (2022, Section 2.5–2.6). * Use QRM principles (ICH Q9) to define: * Critical Control Points (CCPs) * Associated control measures and monitoring systems ⸻ 2. Perform Impact Assessment * Licence impact: * Ensure the site’s MIA or MIA(IMP) license covers the new dosage form and processes. * Engage regulatory affairs to confirm if MHRA variation is needed. * GMP/CCS assessment: * Evaluate need for product segregation via: * Dedicated areas or isolators (e.g., cytotoxics, hormones) * Use of single-use systems or campaign manufacture * Closed vs open systems * Product quality impact: * Risk of cross-contamination, especially with highly potent or sensitising APIs * Conduct toxicological evaluations and calculate PDE/MACO values to support cleaning validation ⸻ 3. Cleaning Validation and Sampling Strategy * Use Annex 15, PDE guidance, and QRM to plan cleaning validation: * Identify worst-case products (based on potency, solubility, cleanability) * Map equipment train and shared surfaces * Perform risk-based selection of sampling locations, including: * Hard-to-clean areas (e.g., gaskets, valves, blind spots) * Largest surface areas * Representative contact surfaces * Sampling methods: * Swab sampling for accessible surfaces * Rinse sampling for complex or closed systems * Validate swab recovery (>70% where possible) ⸻ 4. Facility and Process Setup * Follow Annex 1 (2022) CCS elements, including: * Facility design: material and personnel flow, pressure cascade, HVAC qualification * Process design: aseptic vs terminal sterilisation * Cleaning & disinfection: validated procedures with defined frequency and agents * Monitoring programmes: viable, non-viable, residue * Training & gowning qualification ⸻ 5. Control and Continuous Improvement * Review if CCS is effective via: * Routine trend review * Deviations and CAPA * Periodic review and update of the CCS (as a live document)

Question 55

How would you set up environmental monitoring?

Answer 55

Step 1: Classification and Qualification of Cleanrooms Classify cleanrooms as per ISO 14644-1 (particle limits) Conduct cleanroom qualification — including: Particle counts (at rest and in operation) Airflow visualisation (smoke studies) — using DOP testing (Dispersed Oil Particulate) to verify unidirectional airflow and identify stagnant areas Pressure differentials, temperature, humidity mapping Step 2: Risk Assessment to Define EM Locations “I would perform a risk assessment to identify critical monitoring locations, considering product and process risk.” Typical monitoring points: Close to the point of fill (most critical) Operator working zones Material and equipment transfer routes High traffic areas Room corners or difficult-to-clean locations Near bins or waste collection points Step 3: Define Monitoring Parameters Non-viable particles (continuous in Grade A) Viable monitoring: Settle plates Contact plates (surfaces, gloves) Active air sampling Environmental monitoring for: Temperature Humidity Differential pressure Airflow velocity Step 4: Set Alert and Action Limits Limits set based on: Room classification (Annex 1 & ISO 14644-2) Historic data (trending) Risk assessment Step 5: Trending and Data Review Regular review of EM results Investigation and CAPA for excursions Trending to detect early signs of loss of control EM results included in PQR / APR review Summary Statement for Viva: “I would set up an environmental monitoring programme based on risk, guided by ISO 14644 and Annex 1 expectations. Critical control points are identified by risk assessment and airflow visualisation studies, with appropriate alert/action limits set. Continuous data review ensures early detection of any loss of control, supporting the site’s contamination control strategy

Question 56

Cleaning Validation Failure Question: What would you do if cleaning validation fails?

Answer 56

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.

Question 57

Cross Contamination at Multi-Product Site Question: Your product is contraindicated with another produced in same facility. How do you manage risk?

Answer 57

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) ⸻ 3. 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)}}

Question 58

Why does a QP need to understand the ADME of a product?

Answer 58

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.

Question 59

What’s the difference between PDE and HBEL in cleaning validation?

Answer 59

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.

Question 60

. Cleaning Validation / PDE vs HBEL Q9. What’s the difference between PDE and HBEL?

Answer 60

• 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.

Question 61

How do you determine limits in cleaning validation using PDE?

Answer 61

• Tip: Mention calculation of MACO, worst-case product, toxicology input, cleaning procedures, visual inspection, and swab/rinse sample testing.

Question 62

Scenario follow up: What is HTA?

Answer 62

What is HTA? (Human Tissue Authority) The Human Tissue Authority (HTA) is a UK regulatory body responsible for overseeing the removal, storage, use, and disposal of human tissues and cells for specific purposes, including medical treatment, research, and education. ⸻ Relevance to ATMPs (Advanced Therapy Medicinal Products): In the context of ATMPs, such as CAR-T cell therapies or other tissue-engineered products, the HTA is responsible for: 1. Licensing establishments involved in: * Procurement (e.g. collection of patient tissue or cells) * Testing (e.g. for viral contamination) * Processing and/or storage of human tissues and cells prior to manufacture 2. Ensuring compliance with: * The Human Tissue (Quality and Safety for Human Application) Regulations 2007, which implement the EU Tissue and Cells Directive (2004/23/EC) in UK law. * Traceability and donor consent requirements. 3. HTA licensing is separate from MHRA MIA(IMP) or MIA licenses, and is usually required before the tissue or cells are transferred to a manufacturing site.

Question 63

Scinario: You have a beta -blocker product. You have received a complaint from the pharmacy that patients have palpitations and high blood pressure and pulse rate. Are you concerned as a QP? (about 15 minutes) a. Why are you concerned?

Answer 63

a. Why am I concerned as a QP? As a QP, I am seriously concerned because: * The reported symptoms are consistent with lack of therapeutic effect of a beta-blocker. * This could indicate a product quality defect (e.g. wrong strength, incorrect API, degraded product, batch mix-up, or counterfeiting). * These symptoms may present clinical risk, especially in patients with cardiovascular conditions. ⸻ b. What are my immediate actions? 1. Request full details from the pharmacy: * Product name, batch number, expiry date * Photographs of the product and packaging (including inner/outer box, blisters) * Source of supply (which wholesaler or direct from manufacturer?) * Whether the patient still has the product — and if a physical sample can be returned for testing 2. Check whether the batch was manufactured and QP-certified at my site: * If yes, pull the batch records, analytical results, and PQR for that batch * Check release testing, OOS/OOT results, change controls, deviations, and raw material batch links 3. Initiate a formal product complaint and quality defect investigation as per SOP. 4. Assess whether similar complaints have been received — search complaint database, product recall history, customer service logs. 5. Notify the QPPV if this could be a pharmacovigilance signal. ⸻ c. If initial review indicates a potential batch defect: * Quarantine any remaining stock of that batch * Inform the Regulatory Authority (e.g. MHRA’s DMRC) — even if investigation is ongoing, due to potential patient safety risk * Consider initiating a recall risk assessment meeting * Coordinate with medical, regulatory, pharmacovigilance, and commercial functions * Document all decisions with risk-benefit justification

Question 64

Scinario follow up: b. What is beta -blockers for?

Answer 64

Beta-blockers are a class of medicines primarily used to treat cardiovascular conditions, such as hypertension (high blood pressure), angina, arrhythmias, heart failure, and for secondary prevention after myocardial infarction (heart attack). They work by blocking beta-adrenergic receptors, primarily beta-1 receptors in the heart, leading to reduced heart rate, cardiac output, and blood pressure.

Question 65

c. Can you tell me how this may act on the body?

Answer 65

Beta-blockers act by antagonising beta-1 adrenergic receptors predominantly located on cardiac muscle. By blocking these receptors, they reduce the effects of sympathetic stimulation — leading to a decrease in heart rate (negative chronotropy), reduced myocardial contractility (negative inotropy), and slower conduction through the AV node. The net effect is a reduction in cardiac output and myocardial oxygen demand, which is beneficial in conditions like hypertension, angina, and heart failure.”

Question 66

d. So you have received this complaint now, what will you do?

Answer 66

Yes, I would be highly concerned as a QP. The reported symptoms could indicate the product lacks efficacy or contains the wrong strength or substance. I would first obtain the batch number, photos, and source, then check if we manufactured the batch and review all production records. I’d open a product complaint, initiate a deviation if needed, inform the QPPV, and assess whether to notify DMRC. Depending on the risk assessment, a recall may be necessary to protect patient safety.”

Question 67

e. Your pharmacist said he does not have the pack returned. What would you ask the pharmacist?

Answer 67

“I would politely request the pharmacist to check whether the patient still has the medicine in their possession. If so, I’d ask for a photograph of the product showing the packaging, blister, or label, especially the batch number, expiry date, and product licence number (PL). I would also confirm: * Where the medicine was obtained (e.g. wholesaler or direct from manufacturer) * Whether any other patients have reported similar issues * Whether the dispensing record/ purchase record is still available, which might also include batch traceability These details are essential to determine if the complaint relates to a batch manufactured and released by our site and whether further investigation, including recall risk assessment or notification to the MHRA/DMRC, is necessary.”

Question 68

f. You have got the batch number now, what checks would you perform?

Answer 68

1. Verify Batch Details * Confirm the batch exists in our system and was manufactured and QP-certified at our site. * Check the shelf life and expiry date to ensure the product was used within its approved stability window. * Confirm the product was released under the correct MA, and licence conditions were met. ⸻ 2. Retrieve and Review Batch Documentation * Pull the batch manufacturing and packaging records, including: * In-process and final QC results * Deviations, OOS/OOT results * Change controls, if any during the batch * Line clearance records * Cleaning validation, if multiproduct line * Confirm any linked raw material or intermediate batches and their compliance status. ⸻ 3. Initiate Complaint Investigation * Log a formal customer complaint in the QMS and assign to QA for investigation. * Evaluate if any similar complaints have been received for this or related batches (trend analysis). * Notify the QPPV, as the symptoms (palpitations, high BP) may constitute a pharmacovigilance signal. ⸻ 4. Assess Product Distribution * Check distribution records to determine where the batch was sent. * Quarantine any remaining stock if deemed necessary during investigation. ⸻ 5. Risk and Recall Assessment * Based on initial findings, assess the risk to product quality and patient safety. * If needed, initiate a recall risk assessment meeting and consider notification to the MHRA/DMRC.

Question 69

g. There was total 5 batches in campaign

Answer 69

1. Quarantine On-Site Batches * Quarantine any of the 5 campaign batches that are still at the manufacturing site or warehouse, preventing further distribution or release. ⸻ 2. Identify Released Batches * Review the batch release and distribution records to determine: * Which batches have already been QP-certified * Which batches have been distributed to market * Use ERP or batch tracking system to trace where each released batch went (wholesaler, hospital, country) ⸻ 3. Review Batch Documentation for Entire Campaign * Review manufacturing records, QC results, deviations, and line clearance for all 5 batches. * Look for commonalities: same shift, equipment, raw material lot, or operator. ⸻ 4. Evaluate Risk to Marketed Product * If the complaint batch is confirmed defective or under investigation, assess whether other campaign batches are at risk. * Based on risk, consider precautionary action: * Customer notification * Recall risk assessment * DMRC notification, if warranted

Question 70

h. Would you quarantine all 5 batches just based on one complaint?

Answer 70

– I said yes what you telling me there is a potential risk of patient harm, so I am not going to take any chances.

Question 71

i. Your site director is not a happy man and he wants these other batches to be sold.

Answer 71

I would respectfully explain to the site director that, as the QP, I am legally accountable under UK SI 2012/1916 and EU GMP (Annex 16) for ensuring that every batch released is of the required quality and manufactured in accordance with GMP and the Marketing Authorisation. Since a potential defect has been reported in one batch of a campaign, it is my duty to assess whether other campaign batches may also be affected. Until this investigation is complete, the remaining batches must be treated as potentially impacted. ⸻ Key Points I Would Communicate: 1. Patient Safety Comes First: “Any product quality concern must be thoroughly investigated before further distribution to avoid patient harm and regulatory non-compliance.” 2. GMP and QP Legal Duties: “Under Annex 16, a QP must not certify a batch if there is any unresolved concern that might compromise product quality.” 3. Reputation Risk: “Releasing potentially affected batches could lead to serious consequences — including patient harm, regulatory action, or forced recall — damaging both the company’s and product’s reputation.” 4. Regulatory Expectation: “If I knowingly certify a batch with a possible quality defect, I would be in breach of GMP and may face MHRA enforcement, including personal sanction.”

Question 72

j. 4 weeks later you got another 5 complaints related to the 1st batch.

Answer 72

1. Immediate Containment * Quarantine all remaining stock of the affected batch on site and, if possible, at distributors or wholesalers. * Stop further distribution or use of this batch pending investigation. * Check if any of the other 4 campaign batches might also be implicated and hold them as a precaution. ⸻ 2. Escalate the Investigation (Formal Deviation) * Escalate the issue to a formal deviation or quality defect investigation. * Assess whether the 5 new complaints are: * Consistent in nature (e.g., same defect or symptom) * From the same distributor or region * Possibly linked to storage, handling, or transport conditions ⸻ 3. Conduct a Full Root Cause Analysis (RCA using Ishikawa) QMS / Historical Quality Events * Check for recent deviations, change controls, previous complaints, PQR trends. Facility & Equipment * Was the equipment qualified and maintained? * Any delays in PPM, service findings, or outstanding CAPA? * Was the line clearance process robust before this campaign? Documentation * Review the batch manufacturing record: * Were all CPPs and CQAs within limits? * Any operator comments or unusual observations? * Cleaning verification data present and acceptable? Process * Is the process validated? * Were any changes implemented prior to or during this campaign? Personnel * Were operators qualified and trained? * Any recent changes in staffing, shifts, or workload that could lead to errors? QC * Any environmental monitoring excursions in the production, storage, or packaging areas? * Were analytical results OOS/OOT or showing unusual trends? Suppliers / Materials * Was the API and excipients from an approved supplier? * Any recent supplier change, CoA discrepancy, or open complaints? Self-Inspection * Any recent findings in internal audits that highlight systemic issues? ⸻ 4. Notify Stakeholders * Notify DMRC as a precaution if there’s risk to public health. * Alert the QPPV for potential pharmacovigilance signal. * Call a recall risk assessment meeting, involving Regulatory, QA, QP, Medical, and Supply Chain. * If risk confirmed, initiate recall (likely Class 2) and notify customers. ⸻ 5. CAPA and Preventive Strategy * Implement targeted CAPAs based on confirmed root cause (e.g., training, equipment upgrade, process review). * Conduct effectiveness checks and reassess CCS if contamination or cross-contamination is involved. * Consider enhancing sampling, QC release, and trend monitoring for future campaigns.

Question 73

k. Turns out your previous product on the line had been Digoxin. Are you concerned and why? What are narrow therapeutic index drugs?

Answer 73

Yes, I am concerned. Digoxin is a potent compound with a narrow therapeutic index (NTI), which means that the difference between the therapeutic dose and the toxic dose is small. Even minute levels of cross-contamination can cause serious clinical consequences, including cardiac toxicity. If digoxin residue remains on equipment and is transferred to the next batch, especially in a non-potent product, this poses a high risk to patient safety. This also suggests that the site’s Contamination Control Strategy (CCS) and cleaning validation programme may not be sufficiently robust for multiproduct manufacturing involving high-risk products. ⸻ Follow-up: What are Narrow Therapeutic Index (NTI) drugs? NTI drugs are medicines for which small variations in dose or blood concentration can lead to therapeutic failure or adverse drug reactions. These drugs require precise dose control and stringent manufacturing controls to avoid harm. Examples of NTI drugs include: * Digoxin * Warfarin * Carbamazepine * Phenytoin * Theophylline * Lithium

Question 74

l. The engineer said the spray ball not working. What would you like to do at this stage?

Answer 74

I said when did it stopped? Wider impact assessment, any other products affected?

Question 75

m. What advice you think QPPv is going to give you?

Answer 75

1. Signal Detection * Review Yellow Card reports, medical information enquiries, and complaints to detect any signal suggesting a link between the product and reported clinical events. * Evaluate case frequency, severity, and temporal trends. * Compare with baseline data or similar products. ⸻ 2. Benefit-Risk Assessment * Advise on whether the events reported represent a change in the benefit-risk profile of the product. * Support with review of SmPC, known pharmacological effects, and patient demographics. ⸻ 3. Product Quality vs Clinical Root Cause * Help differentiate between true product quality defect (e.g. under-dosing, degradation) vs possible clinical/pharmacological causes (e.g. patient non-compliance, drug interactions). ⸻ 4. Regulatory Reporting * Advise whether the issue should be escalated via a signal management process, updated in the Pharmacovigilance System Master File (PSMF), or notified to the MHRA or EMA. * Help prepare documentation if the case needs to be reported as a quality defect with pharmacovigilance relevance.

Question 76

n. What medical risk assessment is likely to say?

Answer 76

Key Points the Medical Assessment Would Likely Include: 1. Pharmacological Concern * Digoxin increases cardiac output by stimulating cardiac contractility (positive inotrope), whereas beta-blockers reduce heart rate and contractility. * Inadvertent administration of digoxin in patients prescribed a beta-blocker could worsen their clinical condition, especially in patients with arrhythmia or heart failure. 2. Risk to Vulnerable Populations * Many patients prescribed beta-blockers (e.g. for hypertension or cardiac disease) are elderly, and particularly vulnerable to even trace levels of potent contaminants. 3. Regulatory and Patient Safety Implication * Even without confirmed contamination, the risk alone would likely trigger a precautionary recall of the affected batch — especially if: * The cleaning validation was insufficient or not in place * MACO limits were exceeded or not calculated * There are complaints consistent with clinical digoxin exposure (e.g. palpitations, dizziness, nausea)

Question 77

o. Who are DMRC?

Answer 77

Key Functions of the DMRC: 1. Central Point for Quality Defect Notifications * Receives reports of suspected defective medicines from manufacturers, healthcare professionals, QPs, pharmacists, or patients via the Yellow Card scheme or direct contact. 2. Risk Classification * Works with the MAH/QP to assign a recall classification (Class 1, 2, or 3) based on patient risk. 3. Recall Coordination * Coordinates product recall communications to: * Wholesalers/distributors * Healthcare providers * Patients (if required) * Publishes recall alerts via MHRA drug alerts and CAS (Central Alerting System). 4. Interaction with MAH/QP * Reviews QP’s investigation findings, risk assessments, and justification for proposed actions (recall, quarantine, or no action). * May request additional data or impose enforcement actions.

Question 78

p. What level of recall and why?

Answer 78

1. Severity of Risk * The suspected issue involves cross-contamination with digoxin, a potent active substance with a narrow therapeutic index and a pharmacological effect opposite to that of the intended beta-blocker. * Even trace amounts of digoxin in a beta-blocker product could result in life-threatening cardiac events, including arrhythmias, bradycardia, or toxicity — especially in elderly or cardiac-compromised patients. 2. Route and Setting of Administration * The product is a self-administered tablet. * Once dispensed to the patient, no healthcare professional oversight is present to catch errors or intervene quickly. * This justifies a patient-level recall. 3. Nature of Discovery * The defect was identified through a patient complaint, not internal QC or proactive trending — which increases uncertainty and potential scope of exposure. 4. MHRA Guidance Alignment * As per the MHRA Guidance Note “Defective Medicines: Recall and Other Actions”, a Class 1 recall is appropriate when there is a reasonable probability that the use of, or exposure to, a defective product will cause serious adverse health consequences or death.

Question 79

q. What will you propose as a CAPA?

Answer 79

Corrective Actions (Immediate Response): 1. Stop Line and Quarantine Equipment * Halt the equipment involved and prevent further use until validated. 2. Enhanced Cleaning & Verification * Perform a full cleaning verification on the equipment, including swab and rinse sampling. * Use a validated analytical method with appropriate LOD/LOQ to detect digoxin residues. 3. Re-test at-risk batches (if possible) * Test retained samples of suspect batches for digoxin contamination. ⸻ Preventive Actions (Systemic Improvements): 1. Review and Revalidate Cleaning Procedures * Reassess the cleaning validation matrix to ensure worst-case products are correctly identified. * Revalidate cleaning procedures using digoxin as a worst-case, calculating MACO/PDE limits as per EU GMP Part III. * Reassess sampling points, recovery rates, and equipment design. 2. Evaluate Cleaning Agent Suitability * Re-evaluate the efficacy of cleaning agents against digoxin and consider using more effective agents or combinations (e.g., acid/base steps or enzymatic cleaners if appropriate). 3. CCS Update * Review and update the Contamination Control Strategy (CCS) in line with EU GMP Annex 1, including: * Cleaning validation * Equipment design * Changeover procedures * Use of campaign manufacturing or dedicated equipment for high-risk products. 4. Personnel Training * Provide refresher training to production and QA staff on: * Product changeover procedures * Cleaning verification * Visual inspection and documentation 5. Audit & Review * Schedule an internal audit to assess cleaning processes and facility design. * Increase frequency of QA line clearances and cleaning oversight for multiproduct equipment. 6. Effectiveness Checks * Define effectiveness criteria, such as: * Zero detectable residue in follow-up batches * No further complaints or deviation * Trend monitoring of cleaning-related deviations over 6–12 months

Question 80

Med prep1: what physical properties effect renal elimination?

Answer 80

1. Molecular Size * Small molecules are more easily filtered at the glomerulus. * Larger molecules or protein-bound drugs are less efficiently filtered unless secreted via active transport. ⸻ 2. Ionisation (pKa and Urine pH) * Only un-ionised (non-polar) forms of drugs can be passively reabsorbed in renal tubules. * The degree of ionisation depends on the drug’s pKa and urine pH (Henderson-Hasselbalch principle). * Weak acids (e.g. aspirin) are more ionised (less reabsorbed) in alkaline urine. * Weak bases (e.g. amphetamines) are more ionised in acidic urine. ⸻ 3. Lipophilicity * Lipophilic drugs are more likely to be reabsorbed in renal tubules. * Hydrophilic drugs tend to remain in urine and be excreted. ⸻ 4. Protein Binding * Only the free (unbound) drug can be filtered by the glomerulus. * Highly protein-bound drugs are eliminated more slowly by the kidney. ⸻ 5. Osmolarity and Urine Flow Rate * High urine flow rate can reduce tubular reabsorption and promote excretion. * Osmolarity can affect water reabsorption, indirectly influencing drug concentration and reabsorption.

Question 81

med prep2: What is a vasodilator? What do they do to help a patient? Any well known examples?

Answer 81

A vasodilator is a class of drug that relaxes and widens blood vessels, primarily by acting on smooth muscle in vessel walls. This leads to a reduction in vascular resistance, improving blood flow and lowering blood pressure. ⸻ How They Help Patients: * Reduce systemic vascular resistance, lowering blood pressure. * Improve oxygen delivery to tissues by enhancing circulation. * Used in conditions like: * Hypertension * Angina * Heart failure * Peripheral vascular disease ⸻ Mechanism of Action: * Vasodilators work by different mechanisms depending on the class: * Calcium channel blockers (e.g. amlodipine): inhibit calcium influx into vascular smooth muscle. * ACE inhibitors (e.g. enalapril): prevent angiotensin II-mediated vasoconstriction. * Nitrates (e.g. glyceryl trinitrate): increase nitric oxide, relaxing smooth muscle. * Direct vasodilators (e.g. hydralazine): act directly on vascular smooth muscle. ⸻ Well-Known Examples: * Amlodipine – calcium channel blocker for hypertension and angina * Nitroglycerin (GTN) – used in acute angina * Hydralazine – direct arterial dilator used in heart failure * Sodium nitroprusside – used in hypertensive emergencies

Question 82

Med prep3: what would be the bioavailability of an IV product?

Answer 82

Explanation: * Bioavailability is the fraction of the administered dose that reaches the systemic circulation in an active form. * With IV administration: * The drug is delivered directly into the bloodstream. * There is no absorption phase. * There is no first-pass metabolism through the liver or gut wall. * Therefore, 100% of the active drug reaches systemic circulation immediately. ⸻ Model Viva Summary: “For an IV product, bioavailability is 100% because the entire dose enters the systemic circulation directly without any loss due to absorption or first-pass metabolism.”

Question 83

med prep4: How is the bioavailability reached for a tablet? What would influence the absorption from the intestine?

Answer 83

1. Bioavailability of a Tablet: For an oral tablet, bioavailability is defined as the fraction of the administered dose that reaches the systemic circulation in an active form. * A tablet must first: 1. Disintegrate in the GI tract 2. Dissolve into solution 3. Be absorbed through the intestinal wall 4. Undergo first-pass metabolism in the liver before entering systemic circulation * As a result, oral bioavailability is often less than 100% due to: * Incomplete absorption * First-pass metabolism ⸻ 2. Factors Influencing Absorption from the Intestine: a. Physicochemical properties of the drug: * Solubility and dissolution rate * Lipophilicity (more lipophilic drugs cross membranes more easily) * Ionisation state (depends on pKa and intestinal pH) b. Physiological factors: * pH of the intestine (affects ionisation and solubility) * Gastric emptying rate and intestinal motility * Presence of food (can delay or enhance absorption) * Enzyme activity (e.g. CYP3A4 in gut wall) * First-pass metabolism in the liver c. Transporter-mediated uptake: * Carrier proteins or co-transporters may facilitate or hinder uptake * Efflux pumps (e.g. P-glycoprotein) can reduce absorption

Question 84

Med prep5: Can you give me an example of a drug-drug interaction in the intestine?

Answer 84

Mechanism: * Calcium ions from the antacid bind with tetracycline in the GI tract to form an insoluble chelate. * This reduces the solubility and absorption of the tetracycline. * As a result, plasma levels of the antibiotic drop, and its therapeutic efficacy is compromised. ⸻ Other Examples: 1. Omeprazole (PPI) + Ketoconazole: * Omeprazole raises gastric pH, reducing ketoconazole solubility (needs acidic pH), leading to reduced absorption. 2. Ciprofloxacin + Iron supplements: * Iron forms complexes with ciprofloxacin, decreasing its bioavailability. 3. Grapefruit juice + Cyclosporin (or statins): * Grapefruit juice inhibits intestinal CYP3A4, increasing bioavailability of drugs normally metabolised by it, which can cause toxicity.

Question 85

Follow-up: How would you set up a cleaning validation for the new products?

Answer 85

1. Risk Assessment and Equipment Mapping * Draw an equipment train map to identify: * All shared equipment surfaces * Hard-to-clean areas * Points prone to residue accumulation * Assess product changeover sequence and cleaning frequency. ⸻ 2. Worst-Case Product Selection * Create a cleaning validation matrix to compare existing and new products based on: * Solubility * Potency * Cleanability with current cleaning agents * Select the worst-case product (most difficult to clean + most toxic) for full validation. ⸻ 3. PDE & MACO Calculation * PDE is calculated using toxicological data: You’re on the right track — your answer covers the core principles. Below is a clear and structured model answer for QP viva or audit prep on cleaning validation for new products: ⸻ Q: How would you set up a cleaning validation for new products in a multi-product facility? ⸻ 1. Risk Assessment and Equipment Mapping * Draw an equipment train map to identify: * All shared equipment surfaces * Hard-to-clean areas * Points prone to residue accumulation * Assess product changeover sequence and cleaning frequency. ⸻ 2. Worst-Case Product Selection * Create a cleaning validation matrix to compare existing and new products based on: * Solubility * Potency * Cleanability with current cleaning agents * Select the worst-case product (most difficult to clean + most toxic) for full validation. ⸻ 3. PDE & MACO Calculation * PDE is calculated using toxicological data: \text{PDE} = \frac{\text{NOAEL} \times \text{Body weight}}{F1 \times F2 \times F3 \times F4 \times F5} * F1–F5 are safety factors: * F1 = interspecies variability * F2 = intraspecies variability * F3 = severity of effect * F4 = duration of exposure * F5 = if LOAEL used instead of NOAEL * MACO is calculated using: \text{MACO} = \frac{\text{PDE} \times \text{Minimum batch size of next product}}{\text{Maximum daily dose of next product}} ⸻ 4. Cleaning Validation Protocol * Develop a protocol that includes: * Cleaning procedure (manual or automated) * Sampling method (swab and/or rinse) * Acceptance criteria: * Residue levels must be below MACO * Recovery rate of swab method should be ≥70% * Analytical method validation (per ICH Q2): * Accuracy, linearity, precision, specificity, LOD/LOQ * Number of runs: typically 3 consecutive successful cleans ⸻ 5. Supporting Controls * Ensure: * Trained personnel * Logbooks and cleaning records reviewed * Deviations/CAPA managed per QMS * Ongoing verification/periodic review is defined in the procedure ⸻ Model Viva Summary: “I would start with an equipment train map and identify shared surfaces. I’d perform a risk assessment based on solubility, potency, and cleanability. Using NOAEL data, I’d calculate PDE and MACO and compare against existing products to choose a worst-case. A validated cleaning process and analytical method would follow, with a protocol outlining sampling, limits, and repeatability to ensure the process is robust.”

Question 86

Follow-up: What products would you not want to manufacture in your multi product facility? Give examples

Answer 86

1. High-Potency / Narrow Therapeutic Index Drugs These require strict containment due to risk from even trace contamination. * Examples: * Digoxin – cardiac glycoside with narrow therapeutic index * Warfarin – potent anticoagulant * Oral contraceptives – active at very low doses ⸻ 2. Highly Sensitising Drugs These can induce serious allergic reactions on trace exposure. * Examples: * Penicillins and cephalosporins – risk of anaphylaxis * Cytotoxic chemotherapy drugs – e.g., cyclophosphamide, methotrexate ⸻ 3. Biologics / ATMPs / Hormones Risk of cross-contamination and degradation due to biological activity. * Examples: * Insulin, erythropoietin * CAR-T cells (for ATMP context) ⸻ 4. Live Microbial Products Live organisms can persist and contaminate other batches. * Examples: * Probiotics * Vaccines containing live attenuated viruses

Question 87

Med prep7: Your company is taking a new product IMP – what considerations are you going to make before and then during GMP manufacture?

Answer 87

Q: Your company is taking on a new IMP. What considerations would you make before and during GMP manufacture? ⸻ 1. Pre-Manufacturing Phase a. Change Control * Raise a formal change control to assess and document all required actions. b. Licence and Facility Readiness * Ensure the site holds a valid MIA(IMP) licence that covers: * The formulation (e.g. sterile, solid oral, ATMP) * The activities: manufacture, packaging, labelling, importation * If importing from a third country (non-MRA), ensure: * QP IMP Declaration is completed based on an audit * Importation testing is conducted (unless justified otherwise) c. GMP Phase Planning * Trial phase (I/II/III) determines the level of: * Process validation (Phase I: verification only; later phases: validation expected) * Analytical method maturity: method verification vs ICH Q2(R2) validation ⸻ 2. Risk Assessment and Process Design a. Impact Assessment * Process design: scale, critical steps, hold times, equipment suitability * Patient safety: product is investigational – no efficacy proven, higher risk * Contamination Control Strategy (CCS): * Segregation for IMPs vs commercial products * Cleaning validation or verification (e.g. disposable equipment) * Blinding and Randomisation: * Risk to blinding integrity if unblinded staff involved in manufacture * Controls: dedicated equipment/rooms, restricted access, line clearance ⸻ 3. Analytical and QA Controls a. Development of CQAs and CPPs * Based on QRM and prior knowledge of API/formulation * Feed into process development and validation strategy b. Analytical Method Readiness * Follow ICH Q14 for method development * Validate per ICH Q2(R2) (or verify if compendial method is used) c. QP Oversight * Prepare for two-step release: 1. Regulatory Green Light (ethics + MHRA) 2. QP Certification

Question 88

Follow-up: You talked about a risk assessment for potency – why is that important?

Answer 88

1. Patient Safety * High-potency APIs (e.g. hormones, cytotoxics, immunosuppressants) can cause clinical effects at very low doses. * Even minute levels of cross-contamination could pose a risk to patients, especially if: * They are immunocompromised * The therapeutic window is narrow * The co-manufactured product has a very different indication ⸻ 2. Contamination Control * You must evaluate whether: * Dedicated facilities or equipment are required * Existing cleaning procedures and PDE/MACO limits are adequate * Supports decisions in the Contamination Control Strategy (CCS) per EU GMP Annex 1 and Chapter 5. ⸻ 3. Occupational Health and Safety * High-potency materials pose risk to personnel exposure: * Inhalation, skin contact, or accidental ingestion * Risk assessment may require: * Closed processing systems * PPE upgrades * Occupational exposure limits (OEL) and appropriate controls ⸻ 4. Regulatory Expectation * EU GMP Chapter 3 and 5 require risk-based justification for shared vs. dedicated use. * Potency is a key input into cleaning validation strategy and facility design decisions.

Question 89

Follow-up: Why is product type important?

Answer 89

Product type determines the pharmacological risk and GMP control strategy. It affects: ADME characteristics (Absorption, Distribution, Metabolism, Excretion), Potential drug interactions, and Contamination control measures during manufacture (e.g. aseptic vs. non-sterile, cytotoxic vs. conventional).

Question 90

Follow-up: Why would you not accept a celphasporin or b-lactam?

Answer 90

These are known sensitising substances that can trigger severe allergic reactions even at trace levels. EU GMP Chapter 3 and 5 require dedicated facilities or equipment unless a comprehensive risk assessment proves otherwise — which is rarely possible for β-lactams.

Question 91

Follow-up: Talk me through how you would design a cleaning validation strategy for this product?

Answer 91

Draw equipment chain to identify: Shared surfaces Hard-to-clean areas Frequency of use Contamination risks (chemical & microbiological) Assess product properties: Potency (e.g. therapeutic dose) Solubility Cleanability with existing cleaning agents 2. Toxicological Evaluation and Limits Calculate Permitted Daily Exposure (PDE) using toxicological data: PDE = NOAEL × body weight ÷ (F1×F2×F3×F4×F5) F1: Interspecies variation F2: Intraspecies variation F3: Toxicity severity F4: Duration of exposure F5: Data uncertainty factor (e.g. LOAEL instead of NOAEL) From PDE, calculate MACO (Maximum Allowable Carryover): MACO = PDE × Minimum batch size of next product ÷ Maximum daily dose of next product 3. Select Worst-Case and Validate Use a cleaning validation matrix to select the worst-case product. Conduct full cleaning validation for that product. 4. Analytical Method Validation (ICH Q2(R2)) Accuracy: 3 concentrations × 3 replicates, RSD < 2% Linearity: ≥ 5 points, r² > 0.99 Precision: Repeatability + intermediate precision, RSD < 2% Specificity: resolution > 1.5–2.0 LOD/LOQ: signal-to-noise ratio 3:1 and 10:1 Must be sensitive enough to detect residues below MACO 5. Cleaning Validation Protocol Includes: Cleaning procedure Sampling method: swab or rinse Analytical method Acceptance criteria: < MACO Swab recovery > 70% Visual cleanliness At least 3 consecutive successful cleans Handling of deviations and CAPA Periodic review of validation status Update CCS if changes arise

Question 92

Follow-up: What limits would you use?

Answer 92

PDE and MACO

Question 93

Follow-up: What is PDE?

Answer 93

What are PDE and MACO? PDE (Permitted Daily Exposure): The maximum acceptable daily intake of a substance without adverse effects. MACO (Maximum Allowable Carryover): The calculated limit of residual product that can be carried over into the next product batch based on PDE.

Question 94

Follow-up: Would you do any physical tests?

Answer 94

Yes. A visual inspection is performed as a first-line assessment of cleaning effectiveness — it’s fast, low-cost, and regulatory-required (per Annex 15). However, it must be supplemented by analytical methods.

Question 95

med prep8: Scinario - You are a QP for a liquid manufacturer, you have a new product coming on line and it is a paediatric leukaemia treatment.

Answer 95

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Question 96

Follow-up: What are your concerns as a QP and how would you bring this product on line?

Question 97

Follow-up: What are the controls required to be in place for this product?

Answer 97

1. Initiate Change Control Raise a formal change control for product introduction. Engage QA, production, QC, engineering, validation, and regulatory. 2. Licence and Regulatory Assessment Confirm MIA (or MIA(IMP)) includes: The product type (cytotoxic) Dosage form (liquid) Activities (e.g., importation, formulation, packaging, testing, certification) If required, submit variation to MIA. Ensure all sites have valid GMP certification. 3. GMP and CCS Considerations Update the Contamination Control Strategy (Annex 1) to reflect: High-potency nature of cytotoxic product Risk of cross-contamination Paediatric population: low-dose, high-risk Implement: Dedicated or disposable equipment Segregated areas, or closed systems with validated cleaning Validated cleaning process based on MACO calculated from PDE (per Annex 15 & EMA PDE Guide) 4. Water Quality and Microbial Controls Purified Water: Used for product formulation and cleaning/rinsing Must comply with Ph. Eur. spec: Conductivity < 5.1 µS/cm TOC < 500 ppb Microbial count < 100 CFU/mL Must be produced and maintained under a qualified system, with validated sanitisation Routine Microbial Monitoring: Daily monitoring at key user points and loop return Trend analysis, alert/action levels defined Cleaning validation/verification: Demonstrate removal of API and microbial control Final rinse water must meet Purified Water spec 5. Manufacturing Controls (Annex 9 & Annex 1) Grade D cleanroom minimum; assess need for Grade C or RABS Closed system preferred for mixing and transfer CIP/SIP for equipment and pipelines Avoid: Glass apparatus Particle-shedding tools (e.g., wooden pallets) Define: Hold time Mixing speed and duration Sampling plan for dose uniformity (start, middle, end) Environmental Monitoring: Particle and microbiological monitoring (settle plates, contact plates, active air sampling) per Annex 1 Table 1 Set alert/action limits using 3σ trending approach 6. Paediatric-Specific Considerations Child-resistant packaging Dosing device (oral syringe with dose accuracy) Excipient suitability: Refer to EMA Excipient Guidelines Avoid harmful excipients (e.g., benzyl alcohol, polysorbate if not justified) 7. QRM and Continuous Improvement Risk assessment using ICH Q9: Define CCPs, control measures, and monitoring frequency System in place for: Deviation handling CAPA CCS review and update Self-inspection findings and effectiveness checks

Question 98

Follow-up: What is added during the manufacture of a suspension?

Answer 98

A: The following excipients and components may be added to ensure physical and microbiological stability, patient acceptability, and therapeutic efficacy: 1. Active Pharmaceutical Ingredient (API) Insoluble drug dispersed in a liquid phase. Requires adequate particle size control for uniformity and suspension stability. 2. Wetting Agents (Surfactants) Help disperse the hydrophobic API in the aqueous vehicle. Examples: Polysorbate 80, sodium lauryl sulfate 3. Suspending Agents (Viscosity Modifiers) Prevent sedimentation and maintain uniform distribution. Examples: Xanthan gum, carboxymethylcellulose, methylcellulose 4. Flocculating Agents (if needed) Promote loose aggregates (flocs) to avoid caking. Examples: Electrolytes (NaCl), polymers, surfactants 5. Buffers and pH Adjusters Maintain pH for stability of API and excipients. Examples: Citric acid, sodium citrate, phosphate buffer 6. Preservatives Prevent microbial growth, especially in multi-dose products. Examples: Parabens (methylparaben, propylparaben), benzoic acid 7. Sweeteners and Flavouring Agents Improve palatability, especially for paediatric use. Examples: Sucrose, sorbitol, flavours (e.g., orange, strawberry) 8. Colouring Agents For aesthetic and patient acceptability. Must be pharmaceutically approved and safe for paediatrics. 9. Vehicle (Dispersion Medium) Usually purified water or an aqueous base. May contain glycerin or sorbitol for taste and stability.

Question 99

Follow-up: What additional items would you consider as this is going to be given to a child?

Answer 99

Dosing device (oral syringe with dose accuracy)

Question 100

med prep9: You are now asked to perform a cleaning validation of the bulk vessel used to manufacture the suspension.

Answer 100

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Question 101

Follow-up: What are your considerations?

Answer 101

Here is a reviewed and refined model answer for your cleaning validation viva scenario, including all follow-up questions. This aligns with EU GMP Annex 15, Annex 9, and the EMA PDE guideline. Q: You are now asked to perform a cleaning validation of the bulk vessel used to manufacture a suspension. What are your considerations? 1. Initiate Change Control and Planning Raise change control for the cleaning validation activity. Ensure validation plan is approved by QA. 2. Risk Assessment (Annex 15 + Annex 9) Perform risk assessment addressing: a. Equipment Chain and Shared Surface Draw an equipment train diagram to identify shared equipment and surfaces. Highlight difficult-to-clean areas, such as: Dead legs Spray balls Inlet/outlet valves Gaskets and sight glasses b. Product Risk Profile Assess: Potency Solubility Cleanability with existing cleaning process (e.g., hot water, detergent) Frequency of manufacturing Toxicological risk (for MACO) 3. PDE and MACO Calculations Determine the PDE (Permitted Daily Exposure) using NOAEL and applying safety factors (F1–F5). Calculate MACO using: \text{MACO} = \frac{\text{PDE} \times \text{Minimum batch size of next product}}{\text{Maximum daily dose of next product}} Ensure the worst-case product is used for validation (as per the cleaning validation matrix). 4. Cleaning Validation Strategy If the suspension is the worst-case (e.g., difficult to clean, potent), perform full cleaning validation (≥3 successful runs).

Question 102

Follow-up: What sampling method would you use?

Answer 102

Rinse Sampling Suitable for large surface areas like bulk vessels. Efficient when swabbing is not practical. Rinse final rinse water from the vessel post-cleaning. Supplement with swab sampling for worst-case locations (if required).

Question 102

Follow-up: What tests would you perform?

Answer 102

Sampling Recovery Test Spike known amount of API onto stainless steel coupon. Perform the rinse or swab recovery. Calculate % recovery: \text{Recovery (\%)} = \frac{\text{Recovered Amount}}{\text{Spiked Amount}} \times 100 Acceptance: ≥70% Visual Inspection Ensure surfaces are visibly clean. No visible residue = basic GMP requirement. Analytical Testing (validated per ICH Q2) Use validated method (e.g., HPLC/UV). Ensure LOQ < MACO. Verify specificity, linearity, precision, accuracy. Microbial/Endotoxin Testing (if required) For products where microbial carryover is a risk.

Question 103

Follow-up: What is the safety limit for carryover?

Answer 103

MACO (Maximum Allowable Carry Over) Defined based on PDE of the worst-case previous product. Ensures that any residue left behind does not pose risk to the next product. Serves as acceptance criterion for analytical results in validation runs.

Question 104

Med prep 10: Describe pharmacovigilance and the key aspects of pharmacovigilance system.

Answer 104

Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or other drug-related problems. It plays a vital role in ensuring the ongoing safety of medicinal products after they are placed on the market. UK SI 2012/1916 part 11. Key aspects of a pharmacovigilance system include: Qualified Person for Pharmacovigilance (QPPV): Responsible person in the UK or EU who acts as the single point of contact for competent authorities (e.g., MHRA). Pharmacovigilance System Master File (PSMF): A detailed document describing the pharmacovigilance system, maintained and readily accessible. Risk Management Plans (RMPs): Required for new products or when safety concerns are identified; outlines how risks will be monitored and mitigated. Periodic Safety Update Reports (PSURs): Regular reports submitted to MHRA summarising benefit–risk balance. Signal Detection and Management: Continuous analysis of safety data to detect new or changing risks. Spontaneous Reporting and Literature Monitoring: Including Yellow Card Scheme in the UK. Post authorisation safety studies

Question 105

med prep11: A site which manufactures HRT wants to introduce NSAID manufacture. What recent updates to legislation would impact this?

Answer 105

The introduction of NSAID manufacture at a facility already producing hormone replacement therapy (HRT) raises cross-contamination concerns, as: HRTs are highly potent compounds. NSAIDs may be hypersensitising to some individuals. Regulatory considerations: Annex 1 (2022) and Chapter 5 of EU GMP now require manufacturers to apply a contamination control strategy (CCS) for shared facilities. The PDE-based approach (as per EMA guideline on setting health-based exposure limits) is mandatory to determine if dedicated facilities or equipment are required.

Question 106

med prep12: Scenario, you have manufacturing facility where multi-products are manufactured. How would you ensure that there is no cross contamination? How would you perform cleaning validation of such facility and where do you find latest guidelines?

Answer 106

To prevent cross-contamination in a multi-product facility: Implement a Contamination Control Strategy (CCS) as per Annex 1 (2022). Conduct Quality Risk Assessment (ICH Q9) covering: Facility design and segregation Personnel and material flow Cleaning and disinfection Product characteristics (potency, sensitisation, solubility) Equipment and process design Perform cleaning validation: Identify worst-case product using a cleaning validation matrix Conduct PDE and MACO calculations Define sampling method (e.g. swab/rinse), validated analytical method (ICH Q2), and pass/fail criteria. Ongoing CCS monitoring via: Deviation/CAPA review Self-inspection Regulatory updates Periodic CCS review Guidance: EU GMP Annex 1 (2022), Annex 15, Chapter 5, EMA Health-Based Exposure Limits Guideline, PIC/S PI 052.

Question 107

Med prep13: Can you describe the classification of products manufactured at your site? In the light of health based exposure limits how would you minimise cross contamination? What is your understanding of PDE? Can you write down the calculation used for health based limits?

Answer 107

At our site, we manufacture sterile injections, including radiopharmaceuticals. These products are classified based on dosage form, risk to patient, and therapeutic use. To minimise cross-contamination: Apply a risk-based cleaning validation strategy. Use PDE-based MACO limits to determine if shared equipment is acceptable or dedicated facilities are required. PDE (Permitted Daily Exposure) is calculated as: \text{PDE} = \frac{\text{NOAEL} \times \text{Body Weight}}{F_1 \times F_2 \times F_3 \times F_4 \times F_5} Where: NOAEL: No Observed Adverse Effect Level F1: Inter-species factor F2: Intra-species factor F3: Severity of the effect F4: Duration of treatment F5: Use if NOAEL is not available Then: \text{MACO} = \frac{\text{PDE} \times \text{Min batch size of next product}}{\text{Max daily dose of next product}} Guidance: EU GMP Part III, EMA PDE Guideline, PIC/S PI 052.

Question 108

Med prep14: What is the difference between PK and pharmacodynamics? How would you use PK information in formulation?

Answer 108

Model Answer: Pharmacokinetics (PK) refers to how the body affects a drug — encompassing: Absorption Distribution Metabolism Elimination (ADME) Pharmacodynamics (PD) refers to how the drug affects the body, such as: Mechanism of action Receptor binding Dose-response effects Use of PK in formulation: Optimise drug absorption (e.g., improve solubility for poorly absorbed drugs) Design controlled release or enteric-coated forms to match the absorption profile Determine bioavailability and dosing frequency Adjust excipients and particle size to influence dissolution and absorption

Question 109

Med prep15: Scenario - You receive notification from your QPPV that they have detected signals for lack of efficacy for one of your tablet products. This product is presented as a sterile injectable and an OSD. The signals are only indicating an issue with the tablets

Answer 109

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Question 110

Follow-up: What is a QPPV (legal basis) and what do they do?

Answer 110

A QPPV (Qualified Person for Pharmacovigilance) is a legally required role for every Marketing Authorisation Holder (MAH), as per UK Human Medicines Regulation 2012 (SI 2012/1916). Key responsibilities: Ensure an effective pharmacovigilance (PV) system is in place and functioning. Maintain and regularly update the Pharmacovigilance System Master File (PSMF). Act as the single point of contact with the MHRA or other competent authorities. Oversee adverse drug reaction (ADR) reporting, including: Individual Case Safety Reports (ICSRs) Periodic Safety Update Reports (PSURs) Risk Management Plans (RMPs) Perform signal detection and analysis. Ensure compliance with post-marketing surveillance obligations.

Question 111

Follow-up: What are your concerns as a QP?

Answer 111

Is this truly our product? Confirm batch number, expiry date, and verify product provenance (risk of falsified medicine). Is the product within shelf life? Consider degradation. Is the issue isolated to the tablet form? Could indicate a formulation or manufacturing-specific defect. GMP concerns: Inadequate API assay Poor dissolution or disintegration Storage or temperature excursion Possible mix-up or cross-contamination Patient risk due to lack of efficacy must be assessed urgently. Immediate actions would include: Quarantine any remaining product on site. Open deviation and initiate a product quality investigation. Liaise with the QPPV for further signal data and assess need for recall.

Question 112

Follow-up: What in the API may have caused this?

Answer 112

Potential API-related causes include: Low assay or underdosing Degradation due to poor stability or interaction with excipients or packaging (e.g. moisture ingress) Incorrect polymorph or particle size, affecting solubility/dissolution Enzymatic or acid degradation in the GI tract (if not formulated with protection) API interactions in the gut leading to inactivation Non-homogenous distribution in granulation or compression process A laboratory investigation of assay, dissolution, and impurity profile would be critical.

Question 113

Follow up - I see from your form you have regular interactions with your PV department. Can you tell me a bit more about these.

Answer 113

Regular interaction with the PV department is essential to: Share quality-related complaints to distinguish between clinical vs product quality signals. Collaborate on risk assessments during recalls or signal detection. Feed trending data into the Product Quality Review (PQR). Ensure QPPV is aware of all relevant deviations, OOS, and complaints that may impact safety or efficacy.

Question 114

Follow up: Would you expect your SOPs to tell you when to contact PV. What SOPs would you expect to see this in.

Answer 114

Customer complaint procedure, Recall procedure, PQR

Question 115

Follow-up: Should the PV group have SOPs. What would you expect to see in these SOPs.

Answer 115

Yes, the PV group must have SOPs as part of the PV system described in the PSMF. Key SOPs to expect: Adverse event (AE) and serious AE reporting – timelines and escalation pathways. Signal detection and management – how new safety signals are identified and assessed. Risk Management Plans (RMPs) – preparation, maintenance, and submission. PSUR preparation and submission – timelines and responsibilities. PV system audits – frequency, scope, and CAPA handling. PV-related training – ensuring staff are competent in safety reporting. Interface with QP and Quality systems – how complaints or recalls are coordinated with QA.

Question 116

med prep16: What are the main differences between each formulation and their ADME profile absorption, distribution, metabolism, and excretion"?

Answer 116

Metabolism Excretion IV injection (sterile) Intravenous 100% bioavailability Rapid via plasma Hepatic (Phase I/II) Renal (urine), biliary (faeces) Oral solid dose (tablet/capsule) Oral Variable (dependent on dissolution & 1st pass metabolism) Bound to plasma proteins (e.g. albumin) Hepatic Renal/biliary Semisolid (cream/ointment) Topical Minimal systemic absorption Localised effect Minimal systemic metabolism Local clearance or via skin IM injection Intramuscular Slower than IV, faster than oral Depot absorption Hepatic Renal Nasal Nasal mucosa Rapid absorption (bypasses 1st pass) Systemic Hepatic Renal Eye drop Ophthalmic Poor systemic absorption Local Limited systemic metabolism Tear drainage Inhaler Pulmonary Rapid via alveoli Systemic Hepatic Renal

Question 117

med prep17: How are HBELs are calculated and who is responsible for calculation?

Answer 117

Health-Based Exposure Limit (HBEL) is calculated as the Permitted Daily Exposure (PDE): PDE = (NOAEL × Body Weight) / (F1 × F2 × F3 × F4 × F5) F1 – Interspecies factor F2 – Intraspecies variability F3 – Toxicity severity F4 – Duration of exposure F5 – Adjustment if NOAEL not available (use of LOAEL) Responsibility: HBELs should be determined by a qualified toxicologist or someone with relevant expertise (not the QP). The QP ensures the value is used appropriately in cleaning validation/MACO calculation.

Question 118

med prep 18: What do you understand by a narrow therapeutic index?

Answer 118

Therapeutic Index (TI) = TD50 / ED50 TD50 = Dose at which 50% of population experiences toxicity ED50 = Dose at which 50% experiences therapeutic effect Narrow TI drugs: Small margin between effective and toxic dose. Require stringent controls (e.g. Digoxin, Carbamazepine). Wide TI drugs: Larger safety margin (e.g. Amoxicillin, Cetirizine). Cleaning implications: Narrow TI drugs require more stringent cleaning validation and carry higher cross-contamination risks.

Question 119

Follow-up: Give an example of a product with narrow and a wide therapeutic index

Answer 119

Narrow TI drugs: Small margin between effective and toxic dose. Require stringent controls (e.g. Digoxin, Carbamazepine). Wide TI drugs: Larger safety margin (e.g. Amoxicillin, Cetirizine).

Question 120

Follow-up: You have a multiproduct facility – how would you develop a cleaning validation programme?

Answer 120

Cleaning Validation in a Multiproduct Facility 1. Risk Assessment: Draw equipment chain and identify shared surface Identify hard-to-clean areas and dead legs Assess each product’s: Solubility Potency Cleanability Toxicity (via NOAEL/PDE) 2. PDE & MACO Calculations: MACO = (PDE × Min batch size of next product) / Max daily dose of next product 3. Cleaning Validation Matrix: Identify worst-case product (lowest MACO, poor solubility) 4. Analytical Method Validation (ICH Q2): Accuracy: 3 concentrations, 3 replicates (RSD <2%) Linearity: R² > 0.99 Precision: Repeatability & Intermediate (RSD <2%) Specificity: Resolution >1.5 LOD/LOQ: S/N = 3:1, 10:1 5. Cleaning Validation Protocol: Define: Cleaning method Sampling method (swab/rinse) Acceptance criteria (e.g., 70% recovery, visual clean) Staff training, deviations, CAPA Three consecutive successful runs Periodic review and CCS update

Question 121

Follow-up: How do you determine which product is hardest to clean?

Answer 121

poor solubility, high potency, high toxicity, cleanbility, warst case MACo, equipment/facility/surface interaction, compatibility with cleanin gagent

Question 122

Follow-up: What statistics will you use for assessing/trending cleaning validation?

Answer 122

Accuracy - % recovery (measured amount /known spiked amount)x100, %RSD Prescision - % RSD Linearity - coefficient of determination, >0.99 Specificity - resolution betwen peak >1.5 LOD/LOQ - signal to noise ratio - 3:1, 10:1 Conrl chart, run chart, Cp/CPk

Question 123

Follow-up: You introduce a product with a narrow therapeutic index into your facility. What options are available to you?

Answer 123

Controls: Consider dedicated facility/equipment Enhanced cleaning validation or verification Enhanced PPE and COSHH risk assessment CCS updated and QRM performed

Question 125

Complaint received for lack of efficacy—what are potential causes?

Answer 125

• Confirm it’s genuine (not counterfeit, expired, or misused). • Ask for sample/photo. • Investigate retention sample and stability. • Review BMR, API content, and any deviations. • Investigate preservative system, microbial content. • Check for shipping/storage damage. • Then move to in-house manufacturing issues

Question 126

What is Therapeutic Index (TI)?

Answer 126

Therapeutic Index (TI) is a measure of a drug’s safety margin — it compares the amount of drug that causes a therapeutic effect to the amount that causes toxicity. ⸻ Definition: TI = TD₅₀ / ED₅₀ Where: • TD₅₀ = dose that causes toxicity in 50% of the population • ED₅₀ = dose that produces the desired effect in 50% of the population ⸻ Interpretation: • A high TI means the drug is relatively safe (large gap between therapeutic and toxic doses). • A low TI means the drug has a narrow safety margin and requires close monitoring (e.g. warfarin, digoxin, lithium). ⸻ Example: • Paracetamol has a high TI — it’s generally safe within normal doses. • Digoxin has a low TI — small dose increases can lead to toxicity.

Question 127

What is narrow therapeutic index?

Answer 127

Examples: Digoxin, Warfarin. Definition: NTI drugs have a narrow therapeutic window — the plasma concentration range between effective dose and toxic dose is very small. Draw a typical dose-response curve: • X-axis: Time • Y-axis: Plasma concentration • Show sub-therapeutic, therapeutic window, and toxic range.

Question 128

13. Scenario – A patient on Carbamazepine (CR tablet) is experiencing seizures. What is your line of investigation?

Answer 128

o I followed a structured approach: clarifying questions, concerns, immediate actions (quarantine, complaint raised), investigation using DMAIC, CAPA, and effectiveness checks. I concluded with a Class 1 recall at the patient level, which they were satisfied with. o Note: During the investigation accessors also checked knowledge on AQL set up for new packaging supplier. Went through ISO2859 very briefly. Scenario Setup (Extracted): “Someone on carbamazepine controlled-release tablets from your company is experiencing seizures. What would you do?” This was presented as an open scenario, without initial clarification. The candidate had to: * Ask clarifying questions * Identify the product and its characteristics * Risk assess and make QP-level decisions ________________________________________ Clarifying Questions Asked by the Candidate: 1. What is the batch number? 2. Is it a counterfeit product? 3. Was the batch released under my certification? 4. Is this an isolated case or part of multiple complaints? 5. What is the expiry date and storage history? 6. Where was the complaint received (UK, overseas)? 7. What is the product formulation? o Answer from assessor: Controlled-release carbamazepine tablet. 8. How was the complaint received? Who submitted it? ________________________________________ Immediate Actions Taken by Candidate: * Quarantined the batch due to the risk of therapeutic failure. * Explained that carbamazepine is a narrow therapeutic index (NTI) drug, and loss of seizure control can be fatal. * Emphasised that controlled-release failure suggests issues with dissolution profile or release kinetics. ________________________________________ Investigation Approach (Structured): 1. Complaint Handling: * Logged the complaint in the QMS. * Retrieved retention samples, COA, and batch records. 2. Testing Strategy: * Tested: o Complaint sample o Retention sample o Marketed units (if available) * Focused on CQAs: Assay, Dissolution, LOD, Uniformity of dosage units. 3. Initial Risk Assessment: * Assessed whether dose dumping or delayed release occurred. * If dissolution deviated from specification, confirmed as root cause of clinical failure. ________________________________________ Root Cause Identification (As Scenario Unfolded): * Assessors revealed: Primary packaging supplier changed. * Candidate asked: o “Was the new foil validated?” o “Any AQL failure at incoming goods?” * Result: Foil had micro pinholes → compromised controlled-release properties. * Multiple similar complaints were emerging. * Candidate escalated to Class 1 recall. ________________________________________ Final Regulatory Actions Proposed: * Immediate recall at patient level (Class 1) due to risk of seizures. * Notified: o Defective Medicines Report Centre (DMRC) o QPPV, if applicable o Senior QA management and medical information * Assessed market share and supply continuity. * Confirmed the foil was not used in other batches or products. ________________________________________ Model Answer: Carbamazepine Seizure Scenario “First, I would clarify the batch details, formulation type, and nature of the complaint. Carbamazepine is a narrow therapeutic index drug, and in a controlled-release formulation, maintaining consistent drug release is critical to prevent loss of seizure control or dose dumping. Given that the patient experienced seizures, my immediate concern would be patient safety. I would quarantine the batch, initiate a complaint investigation, and test both complaint and retention samples for key CQAs such as dissolution, assay, and uniformity. In this case, I would focus particularly on the dissolution profile, as any deviation could indicate a failure of the release-controlling mechanism. If the foil used in primary packaging was changed, I would confirm whether container-closure system qualification was performed, and whether CCIT (Container Closure Integrity Testing) was done. Upon confirming micro pinholes and repeated complaints, I would classify this as a Class 1 recall, due to the life-threatening nature of uncontrolled seizures. I would inform the DMRC, document all actions taken, and ensure that the CAPA includes supplier requalification, packaging material validation, and enhanced QA oversight.

Question 129

Cleaning Validation: tell me references and structure

Answer 129

Guidance documents referenced: EU GMP Annex 15, EMA cleaning validation guideline. PIC/S Aide-memoire Key discussion points: Initial steps: Identify toxicity, potency, solubility, cleanability. Calculate PDE (Permitted Daily Exposure). MACO and shared surface area calculations. Worst-case product selection for validation. Analytical method requirements: LOQ must be below MACO; methods must be validated. Include excipients and cleaning agents if they are hardest to clean. Cleaning methods: Swab vs. rinse samples. Visual inspection must always be passed. Sampling strategy: Include difficult-to-clean parts (hoses, buckets, brushes). Operator training emphasized. Protocol elements: Equipment list, cleaning steps, sampling sites, analytical methods, acceptance criteria, deviation handling, CAPA, and revalidation conditions. Bracketing strategy discussed for product families. Importance of keeping cleaning SOPs simple to avoid operator confusion and deviations.

Question 130

Tell me where cross-contamination occurs in Oral medicine?

Answer 130

Cross-contamination in OSD and Liquid Manufacture Sources identified: Equipment (e.g., FBD filter bags, sieves, bowls). Personnel movement between rooms. Improper cleaning or poorly stored cleaning equipment. Transfer systems (pipes, IBCs). Facility setups discussed: Manual transfers vs. vacuum systems. CIP (Clean-In-Place) and disassembly concerns. Air/utility systems: Compressed air filtration and supply discussed as potential contaminants.

Question 131

Explain therapeutic window.

Answer 131

Therapeutic Window Definition: Narrow range between minimum effective concentration (MEC) and minimum toxic concentration (MTC). Narrow therapeutic index (NTI) drugs require tight dose control. Consequences: Overdosing leads to toxicity; underdosing leads to inefficacy. Therapeutic Index (TI): Ratio between toxic and effective doses; low TI = high risk.