Pharmaceutical formulation and processing Flashcards

Question

You are a virtual QP, and you received a call from your multiproduct CMO that they found a yellow powder during granulation of your product which is white powder. What do you do? What are your concerns? I was shown a picture of a granulator with the yellow contaminant. Then I was shown another picture showing the root cause of this issue – which was a valve connector that accumulated product residues previous batch.

Answer 1

1. Immediate QP Actions – Information Gathering & Containment Ask critical questions: * What is the affected product (name, strength, formulation)? * What is the indication and patient population (e.g. immunocompromised, paediatric)? * Are there market alternatives or a risk of shortage? * Was any of the affected batch released or distributed? Immediate containment: * Stop the manufacturing line * Quarantine the batch and any associated raw materials * Request photos and batch documentation (e.g. BPR, cleaning log) ________________________________________ 2. Initial Concerns and GMP Risk * Cross-contamination risk in a multi-product facility * Possible residue from a previous product trapped in a valve connector * Compromised product quality: visible foreign material (yellow powder) * Potential MACO/PDE breach if the previous product was a highly potent or sensitising compound ________________________________________ 3. Deviation and Risk Assessment Open a deviation describing: * Who, What, When, Where, and How the issue was discovered * Reference photo of the valve connector contamination Traceability and impact review: * What was the previous product? Was it yellow? * How many batches were made after the previous product? * Is the previous product highly potent or allergenic? * Calculate or review PDE/MACO values * Review equipment cleaning logs, line clearance records, and BPRs Risk assessment by impact area: Area Impact MA Product likely OOS due to visible contamination and foreign material GMP Evidence of CCS failure, inadequate line clearance or cleaning Patient High risk due to unknown contaminant; toxicology of yellow product must be considered 4. Product Disposition and Immediate Mitigation * Check reference samples of potentially affected batches * Quarantine any unreleased product made on the same line * If any batches were released, perform: o Retrospective risk assessment o QPPV signal review o Stability and retain sample review o If patient risk can’t be excluded, proceed with recall ________________________________________ 5. Investigation Using Ishikawa (Fishbone) RCA Category Questions to Ask QMS Were deviation, OOS, and change control processes followed? Is there a PQR trend? Personnel Were operators trained on cleaning verification and visual inspection? Facility & Equipment Is the granulator qualified? Any PPM missed? Was the valve identified as a cleaning challenge? Documentation Any comments in the BPR or cleaning logs? Were line clearance checks signed off? Process Is cleaning validation robust and covering worst-case residues? QC Testing Were impurities or unexpected peaks noted in release testing? Supplier / CMO Oversight Any audit findings at the CMO? Goods-in checks compliant? Complaints Any related product complaints, ADRs, or signals reported to QPPV? 6. Corrective and Preventive Actions (CAPA) 1. Immediate Engineering Fix – Clean and repair/replace valve connector 2. Retrospective Impact Review – Identify all batches possibly affected; escalate to recall if needed 3. Recall – Hold multidisciplinary recall meeting (including QA, RA, QPPV, medical, senior leadership); assess recall class and level o Likely Class 2 (patient-level recall) o Notify DMRC before execution 4. Cleaning Process Review – Re-validate cleaning, particularly difficult-to-clean areas like valve connectors 5. Update Cleaning SOPs – Include targeted checks for valve assemblies 6. Re-train Operators – On enhanced cleaning verification and visual inspection points 7. Increase Line Clearance Checkpoints – Especially in critical mechanical interfaces 8. Audit the CMO – Targeted audit focusing on cleaning and multiproduct segregation 9. CAPA Effectiveness Check – Schedule internal inspection, QA sign-off, and post-CAPA review 10. DMRC Closing Report – Submit full investigation, recall summary

Answer 2

Reviewed Answer (Improved from Yours): “No, the QP is not responsible for determining the PDE value. PDE calculations require toxicological expertise, which falls outside the QP’s core competence. This is the responsibility of a qualified toxicologist or pharmacologist, often as part of the product development or cleaning validation team.” ⸻ Model Answer for UK QP Viva: Q: Who is responsible for determining the PDE value? Is it the QP’s role? A: The Permitted Daily Exposure (PDE) value is a toxicologically derived limit used for risk-based cleaning validation and cross-contamination control. It is not the responsibility of the QP to calculate or derive the PDE. The PDE must be established by a qualified toxicologist or professional with expertise in pharmacology and toxicology, in accordance with: * EMA Guideline on setting health-based exposure limits (EMA/CHMP/CVMP/SWP/169430/2012) * ICH Q3D (for elemental impurities) * PIC/S PI 046-1 (for cleaning validation) However, the QP is responsible for: * Ensuring that a robust risk-based CCS is in place * Verifying that PDEs have been used correctly in MACO calculations * Confirming that cleaning validation reports and SOPs reflect the established PDE values * Making an informed decision during batch certification if cross-contamination risk is acceptable ⸻ Viva-Ready Summary: “PDE values must be determined by a toxicologist, not the QP. My role as a QP is to ensure that validated PDEs are used in cleaning validation and that the process is adequately controlled to prevent cross-contamination.”

Answer 3

1. Diluent / Filler * Purpose: Increases bulk to ensure tablet is of practical size, especially when API dose is small. * Examples: Lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate ⸻ 2. Binder * Purpose: Binds powder particles together during granulation to form a cohesive tablet. * Examples: Povidone (PVP), starch paste, hydroxypropyl cellulose (HPC), purified water (used as a granulating liquid) ⸻ 3. Disintegrant * Purpose: Promotes breakup of tablet in GI tract to ensure rapid drug release. * Examples: Starch, crospovidone, sodium starch glycolate, croscarmellose sodium ⸻ 4. Glidant * Purpose: Improves powder flow during tablet compression. * Examples: Colloidal silicon dioxide, talc ⸻ 5. Lubricant * Purpose: Prevents sticking to punches/dies during compression; reduces friction. * Examples: Magnesium stearate, stearic acid ⸻ 6. Coating Agent * Purpose: Improves appearance, masks taste, protects from moisture/light, or provides functional release. * Examples: Hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (enteric) ⸻ 7. Antioxidant / Preservative (if needed) * Purpose: Prevent degradation or microbial growth (mostly for moisture-sensitive or multi-dose formats) * Examples: Tocopherol (vitamin E), butylated hydroxytoluene (BHT)

Answer 4

A: A glidant is an excipient added to improve the flow properties of powders or granules, particularly during die filling. This helps ensure uniform weight and content in tablets. A lubricant, on the other hand, is used to reduce friction between the tablet surface and compression tooling (punches and dies) during the compression and ejection process. This prevents sticking, picking, and tool wear.

Answer 5

“Creams are semi-solid emulsions with higher water content and lighter texture, while ointments are more occlusive and oil-based, typically containing >80% oil. This affects their skin absorption and clinical use.”

Answer 6

The phase into which the API is added depends on its solubility profile: * If the API is lipophilic (oil-soluble), it should be dissolved or dispersed in the oil phase, which is typically prepared in the oil-phase mixing vessel. * If the API is hydrophilic (water-soluble), it should be added to the aqueous phase, usually prepared in the water-phase vessel. This ensures the API is properly solubilised or uniformly dispersed, which supports content uniformity and bioavailability.

Answer 7

Dosage Form Water Content Texture Use / Application Ointment < 20% (very low water) Thick, greasy Occlusive barrier, used for dry or scaly lesions Cream ~30–60% (emulsion) Semi-solid, spreadable Moderate areas, easier absorption, cosmetically acceptable Lotion > 60% (fluid emulsion) Thin, pourable Hairy or large areas, for widespread application Q: How would you manufacture a typical cream? A: 1. Weigh ingredients according to formulation. 2. Prepare two separate phases: * Oil phase: includes lipophilic API (if applicable), white paraffin, emulsifier (e.g. Span 60), heated to ~70°C. * Aqueous phase: includes purified water, water-soluble API (if applicable), preservatives (e.g. methylparaben), also heated to ~70°C. 3. Add aqueous phase into oil phase slowly under controlled mixing (paddle or anchor stirrer). 4. Use a homogeniser to ensure uniform emulsion and consistent texture. 5. Allow to cool gradually while stirring to maintain emulsion stability. 6. Fill into final containers (e.g. aluminium tubes or jars) under clean conditions. Q: List typical excipients used in cream manufacture with examples Function Example Aqueous phase Purified water Oil phase (emollient) White soft paraffin, cetostearyl alcohol Emulsifier Polysorbate 80 (Tween 80), Span 60 Preservative Methylparaben, propylparaben Viscosity modifier Carbomer, xanthan gum Buffer (pH control) Sodium phosphate Q: What is cracking in cream and what causes it? A: Cracking refers to physical separation of the oil and water phases in an emulsion. It results in loss of uniformity and visual instability (e.g. watery layer forms). ⸻ Causes of Cracking: * Inadequate homogenisation or mixing * Incorrect order of addition of phases * Improper temperature control during emulsification * Poor emulsifier selection or concentration * Microbial contamination degrading emulsion * Storage conditions outside labelled range ⸻ Key Areas to Investigate: * Formulation robustness (emulsifier system, ratio of phases) * Excipient/API quality (e.g. pH, degradation risk) * Critical Process Parameters (CPPs): * Mixing speed * Temperature control * Shear force * Holding time * Order of ingredient addition * Container-closure compatibility (may affect phase separation) * Cleaning and contamination risk (possible destabilisation by residues)

Answer 8

Q: What is the difference between creams, ointments, and lotions? Dosage Form Water Content Texture Use / Application Ointment < 20% (very low water) Thick, greasy Occlusive barrier, used for dry or scaly lesions Cream ~30–60% (emulsion) Semi-solid, spreadable Moderate areas, easier absorption, cosmetically acceptable Lotion > 60% (fluid emulsion) Thin, pourable Hairy or large areas, for widespread application Q: How would you manufacture a typical cream? A: 1. Weigh ingredients according to formulation. 2. Prepare two separate phases: * Oil phase: includes lipophilic API (if applicable), white paraffin, emulsifier (e.g. Span 60), heated to ~70°C. * Aqueous phase: includes purified water, water-soluble API (if applicable), preservatives (e.g. methylparaben), also heated to ~70°C. 3. Add aqueous phase into oil phase slowly under controlled mixing (paddle or anchor stirrer). 4. Use a homogeniser to ensure uniform emulsion and consistent texture. 5. Allow to cool gradually while stirring to maintain emulsion stability. 6. Fill into final containers (e.g. aluminium tubes or jars) under clean conditions. ⸻ Q: List typical excipients used in cream manufacture with examples Function Example Aqueous phase Purified water Oil phase (emollient) White soft paraffin, cetostearyl alcohol Emulsifier Polysorbate 80 (Tween 80), Span 60 Preservative Methylparaben, propylparaben Viscosity modifier Carbomer, xanthan gum Buffer (pH control) Sodium phosphate Q: What is cracking in cream and what causes it? A: Cracking refers to physical separation of the oil and water phases in an emulsion. It results in loss of uniformity and visual instability (e.g. watery layer forms). ⸻ Causes of Cracking: * Inadequate homogenisation or mixing * Incorrect order of addition of phases * Improper temperature control during emulsification * Poor emulsifier selection or concentration * Microbial contamination degrading emulsion * Storage conditions outside labelled range ⸻ Key Areas to Investigate: * Formulation robustness (emulsifier system, ratio of phases) * Excipient/API quality (e.g. pH, degradation risk) * Critical Process Parameters (CPPs): * Mixing speed * Temperature control * Shear force * Holding time * Order of ingredient addition * Container-closure compatibility (may affect phase separation) * Cleaning and contamination risk (possible destabilisation by residues)

Answer 9

Q: What are the different phases in creams and ointments? A: Creams and ointments are both semi-solid dosage forms, but they differ in their phase composition, particularly the oil and water content: ⸻ 1. Creams – Emulsion-based (Biphasic) Creams are emulsions, typically containing both an oil phase and a water phase, forming either: * Oil-in-water (O/W) cream: More cosmetically acceptable; non-greasy * Water-in-oil (W/O) cream: More occlusive; used for dry skin Phase % Content Water phase Typically 30–60% Oil phase Typically 40–70% Creams require emulsifiers to stabilise the emulsion and prevent phase separation. ⸻ 2. Ointments – Monophasic (Usually Anhydrous or Water-in-Oil) Ointments typically consist of a hydrophobic oily base with very little or no water content. They are used for dry, scaly, or damaged skin and act as occlusive barriers. Phase % Content Oil phase ≥80% (e.g. white soft paraffin, petrolatum) Water phase Usually <20%, or absent in anhydrous types In some medicated ointments, a small amount of water may be dispersed or incorporated.

Answer 10

The talk led to nitrosamine contamination and recall.

Answer 11

The key steps are: 1. Blending of the API with excipients (e.g. diluents, disintegrants). 2. Addition of a binder solution (e.g. purified water with povidone or starch paste) to form a wet mass. 3. Wet massing or kneading to ensure uniform distribution of moisture. 4. Granulation through a sieve or screen to form granules of desired size. 5. Drying using a fluid bed dryer or tray dryer to remove excess moisture. 6 .Sizing or milling to break up oversized granules and achieve a consistent particle size distribution. 7. Final blending with external phase (e.g. lubricants like magnesium stearate, glidants). 8. Compression into tablets using a tablet press. 9. Optional: Film coating or enteric coating, if needed.

Answer 12

For tablets, CQAs typically include: Uniformity Tablet weight variation Disintegration time Dissolution profile Hardness Friability Content uniformity Appearance Moisture content CPPs are process parameters that, when varied beyond a certain limit, may impact one or more CQAs. CPPs during wet granulation include: Blending time and speed (affect content uniformity) Binder addition rate and volume Granulation endpoint (e.g. torque, wet mass consistency) Drying temperature and time (affects moisture content, stability) Milling screen size and speed (affects granule size distribution) Compression force and dwell time (affects hardness, disintegration) Tablet press speed (impacts weight uniformity and friability)

Answer 13

Excipients are pharmacologically inactive substances that are intentionally included in a pharmaceutical dosage form alongside the active pharmaceutical ingredient (API). While they do not exert therapeutic effects themselves, they play essential roles in ensuring the safety, quality, and performance of the medicine. ⸻ Functions and Rationale for Use of Excipients: Excipients are used to: 1. Provide Bulk * Especially important for low-dose APIs to make the product large enough for accurate handling and administration (e.g., fillers like lactose or microcrystalline cellulose in tablets). 2. Aid Manufacturing * Improve flowability, compressibility, and prevent sticking during tablet or capsule production (e.g., lubricants like magnesium stearate). 3. Improve Stability * Protect the API from degradation due to heat, light, moisture, or oxidation (e.g., antioxidants, desiccants, pH modifiers). 4. Enhance Dissolution or Bioavailability * Improve solubility or release of the API in the body (e.g., disintegrants like sodium starch glycolate or surfactants). 5. Control Release Profile * Modify how the drug is released (immediate, sustained, or delayed release) using matrix-forming polymers or coatings. 6. Improve Patient Acceptability * Mask unpleasant taste, improve texture, or provide color or flavor (especially in oral liquids or chewable tablets). 7. Prevent Microbial Growth * In multi-dose or aqueous formulations, preservatives (e.g., benzalkonium chloride) are used to prevent microbial contamination. ⸻ Conclusion: Although excipients have no direct clinical or pharmacological effect, they are critical to the quality, safety, manufacturability, and performance of the final product. Their selection is carefully justified and controlled during formulation development and must be appropriate for the intended route of administration and patient population (e.g., paediatrics).

Answer 14

Definition: An Atypical Active Pharmaceutical Ingredient (Atypical API) is a substance not originally developed or manufactured to be used as a conventional API, but which exhibits pharmacological activity and is intentionally included in a medicinal product for therapeutic effect. These substances may have been historically used as: * Excipients * Food or cosmetic ingredients * Industrial materials However, when used for a pharmacological purpose, they must be assessed and controlled as APIs. ⸻ Examples of Atypical APIs: * Caffeine (commonly a stimulant in food, but used as an API in analgesics) * Ethanol (used as antimicrobial or solvent with pharmacological effect) * Glycerol (used as demulcent or laxative) * Sorbitol (osmotic laxative) * Menthol (topical analgesic) ⸻ What to Expect in a Dossier (e.g., CTA Module 3 or IMPD): Even if an Atypical API is not manufactured under full ICH Q7 GMP, the dossier must demonstrate suitability and control. A risk-based approach is accepted, especially for clinical trials. The following should be included: 1. General Information * Substance name, structure, chemical properties, pharmacopoeial monograph (if applicable) 2. Manufacturer Details * Name and address of all manufacturing/testing sites * A QP declaration or justification for GMP compliance 3. Manufacturing Process * Flow diagram and description * Description of any critical process controls (if available) 4. Process Validation or Quality Risk Assessment * If full validation is not available, a justification for suitability of the process 5. Specification and Analytical Method Validation * API specification: identity, assay, impurities, residual solvents * Analytical method validation or verification 6. Impurity Profile * Identification and limits for known and potential impurities * Justification if the impurity profile is limited (e.g., food-grade substance) 7. Container Closure System * Description of packaging and materials of construction * Suitability for storage and protection 8. Stability Data * Shelf-life or retest period, storage conditions * May be based on literature, in-house studies, or pharmacopoeial data ⸻ Additional Requirement: * QP Declaration for API Site * A Qualified Person must review and confirm the acceptability of the API source, especially where the site is not GMP-certified. This may include a risk-based assessment or audit, as per MHRA expectations and EU GMP Part II.

Answer 15

Purpose of Granulation: Granulation is a key step in solid dosage form manufacturing, particularly for tablets. It involves the agglomeration of fine powders into granules with improved physical and mechanical properties. The main reasons for granulating include: 1. Improve Flow Properties * Granules have better flowability than fine powders, which improves die filling and weight uniformity during tablet compression. 2. Enhance Compressibility * Granules deform more uniformly under pressure, leading to consistent tablet hardness and mechanical strength. 3. Improve Disintegration and Dissolution * Proper granule size and porosity aid in faster disintegration and dissolution of the API. 4. Prevent Segregation * Uniform granules reduce the risk of content uniformity failure, particularly for low-dose APIs. 5. Reduce Dust and Improve Safety * Minimises the risk of dust-related exposure and improves handling characteristics. ⸻ Consequences of Poor Granulation: Inadequate or poorly controlled granulation can lead to multiple quality and performance issues, including: 1. Poor Tablet Hardness or Friability * Tablets may be too soft (leading to chipping or breakage) or too hard (resulting in poor disintegration). 2. Poor Content Uniformity * Segregation of fine and coarse particles can lead to variable API content across tablets. 3. Inconsistent Disintegration and Dissolution * Variability in granule size and porosity can cause batch-to-batch inconsistency in drug release. 4. Manufacturing Problems * Poor flow may cause die filling issues, weight variation, or sticking during compression. 5. Stability Issues * Non-uniform moisture content or high surface area due to fines can accelerate degradation. ⸻ Conclusion: Granulation is a critical step to ensure consistent tablet quality, manufacturability, and therapeutic performance. A robust granulation process must be controlled for parameters such as granule size distribution, moisture content, and binder concentration, and should be validated during process development.

Answer 16

A: Excipients in core tablets are selected based on their functional roles in ensuring manufacturability, stability, and performance of the dosage form. Key excipient categories and examples include: 1. Filler / Diluent Purpose: Increases bulk to make the tablet of practical size, especially when API dose is low. Examples: Lactose monohydrate, microcrystalline cellulose (MCC), dibasic calcium phosphate 2. Binder Purpose: Binds powder particles together to form granules or compressible mass. Examples: Povidone (PVP), starch paste, hydroxypropyl cellulose 3. Disintegrant Purpose: Facilitates tablet break-up in the gastrointestinal tract to release the API. Examples: Starch, crospovidone, croscarmellose sodium, sodium starch glycolate 4. Glidant Purpose: Improves powder flow during die filling in tablet compression. Examples: Talc, colloidal silicon dioxide 5. Lubricant Purpose: Reduces friction between the tablet mass and the compression tooling (punches and dies), preventing sticking or picking. Examples: Magnesium stearate, stearic acid 6. Coating Agent (if applied post-compression) Purpose: Masks taste or odour Improves appearance Provides protection from moisture, light, or gastric acid Enables controlled or delayed release Examples: Sugar – conventional coating Cellulose acetate phthalate (CAP) – enteric coating Hydroxypropyl methylcellulose (HPMC) – film coating Ethylcellulose – sustained-release coating 7. Antioxidants / Preservatives (used only when required) Purpose: Prevent degradation due to oxidation or microbial contamination (less common in solid oral forms). Examples: Tocopherol (vitamin E), butylated hydroxytoluene (BHT), parabens

Answer 17

Yes. A coating solution typically contains the following functional excipients, depending on the type of coating (film, enteric, or controlled release): 1. Film-forming polymer (main structural component) Purpose Examples: Film coating-Hypromellose (HPMC), hydroxypropyl cellulose (HPC) Enteric coating-Cellulose acetate phthalate (CAP), methacrylic acid copolymers (Eudragit L/S) Controlled release-Ethyl cellulose, polyvinyl acetate 2. Plasticiser (to improve film flexibility) Examples: Polyethylene glycol (PEG), triethyl citrate, dibutyl sebacate 3. Solvent or vehicle Examples: Purified water, ethanol, isopropanol (aqueous or organic-based depending on solubility) 4. Colourants or opacifiers (optional) Examples: Titanium dioxide, iron oxide pigments What am I particularly concerned about as a QP? As a QP, I would be particularly concerned about GMP control of the coating process, since coating can directly impact product performance, dose release, and patient safety. Key Process Parameters (CPPs) of Concern: Critical Parameter- Why It Matters Pan rotation speed- Affects mixing, uniformity, and risk of coating defects Spray rate & atomisation pressure-Impacts droplet size, risk of over-wetting or bridging Inlet air temperature / drying rate-Critical for solvent evaporation and film formation Gun-to-bed distance-Influences spray coverage and agglomeration Coating thickness & uniformity-Affects disintegration, drug release profile, and stability Coating solution homogeneity-Ensures uniform polymer dispersion — especially with pigments

Answer 18

1. Water for Injection (WFI) Purpose: Used as the solvent before freeze-drying. Removed during lyophilisation. 2. Bulking Agent Purpose: Provides body to the cake and supports structural integrity after lyophilisation. Examples: Mannitol, glycine, sucrose 3. Cryoprotectant / Lyoprotectant Purpose: Protects sensitive APIs (e.g. proteins) during freezing and drying phases. Examples: Sucrose, trehalose, lactose These stabilise the molecule by forming a glassy matrix. 4. Buffer Purpose: Maintains pH during freezing and storage. Examples: Sodium phosphate, citrate buffer, histidine 5. Surfactant (if required) Purpose: Minimises surface adsorption of the API (especially proteins) to glass or rubber stoppers. Examples: Polysorbate 80 (Tween 80), Polysorbate 20 Used at low concentrations (e.g. 0.01–0.1%) What you would NOT usually see: Preservatives: Not usually included unless multi-dose Colorants: Rare in injectables Oils/emulsifiers: Not typical unless the formulation is a lipid-based emulsion (unusual for lyophilised injectables)

Answer 19

Lyophiliser Use and Sterilisation – Key Points: Design goal: Minimise operator intervention to reduce contamination risk. Sterilisation frequency depends on: Design of the lyophiliser Risk of contamination during loading/unloading Manual loading/unloading (no barrier): Must be sterilised before each load Automated or barrier-isolated systems: Sterilisation frequency can be less frequent Must be risk-assessed, justified, and documented in the Contamination Control Strategy (CCS)

Answer 20

1. Dispensing (Weighing) Purpose: Accurately weigh API and excipients (e.g. diluents, binders, disintegrants) as per the batch manufacturing record. 2. Blending Purpose: Uniformly mix the API with excipients to ensure homogeneity prior to granulation. 3. Wet Granulation Purpose: Add a granulating solution or binder (e.g. PVP in water) to form a cohesive wet mass. Equipment: High shear granulator or planetary mixer. 4. Drying Purpose: Remove moisture from the wet mass using tray drying or fluid bed drying. Ensures proper granule flow and compressibility. 5. Milling / Sieving Purpose: Break up oversized agglomerates and standardise particle size using a mill or sieve. Prepares granules for uniform die filling during compression. 6. Compression (Tableting) Purpose: Compress dried granules into tablets using a tablet press. May include in-process checks (e.g. weight, hardness, thickness, disintegration). 7. Coating Purpose: Apply a film or functional coating to: Mask taste or odour Improve appearance Provide enteric or controlled release Method: Spray coating in a pan coater or fluid bed coater, with simultaneous drying using heated air.

Answer 21

1. API and Excipient Quality (Raw Material Attributes) Particle size, flowability, hygroscopicity, and polymorph can influence blending and granulation. Direct impact on content uniformity and granule formation. 2. Blending CPPs: Blending speed and time Too little mixing = poor uniformity Over-mixing = segregation or degradation (especially of actives or lubricants) 3. Wet Granulation CPPs: Binder solution addition rate and volume Impeller/chopper speed (if high-shear) Granulation end-point (e.g. torque or mass consistency) Controls granule size, cohesiveness, and moisture content 4. Drying CPPs: Inlet/outlet air temperature Drying time Critical for controlling residual moisture — too much leads to sticking, too little can cause friable tablets 5. Milling / Sieving CPPs: Mill speed, screen size, shear force Affects granule size distribution, impacting flowability and tablet weight uniformity 6. Compression CPPs: Compression force Pre-compression settings Tablet press speed Affects tablet hardness, friability, and disintegration 7. Coating CPPs: Spray rate Atomisation air pressure Inlet air temperature Pan speed Gun-to-bed distance Critical for coating uniformity, avoiding defects like bridging, peeling, or mottling

Answer 22

In-process controls during compression ensure that each tablet meets specification for dose uniformity, physical integrity, and performance. Key IPCs include: 1. Tablet Weight Ensures dose uniformity (especially critical for low-dose products) Controlled by fill depth and monitored regularly 2. Tablet Hardness / Crushing Strength Reflects mechanical strength and influences disintegration and dissolution Affected by compression force and dwell time 3. Thickness Related to tablet weight and compression force Ensures proper fit in packaging and consistency in appearance 4. Friability Assesses resistance to chipping or breaking during handling Typical limit: ≤ 1% weight loss (as per Ph. Eur.) 5. Disintegration Time (for IR tablets) Ensures the tablet breaks down within the specified time Not always checked at line but part of routine batch QC 6. Compression Force / Main Compression Pressure Critical CPP that affects tablet hardness, weight, and uniformity Monitored by compression machine (some systems have feedback loops) 7. Turret Speed / Press Speed Influences dwell time and output rate Too fast = risk of capping/lamination or poor weight control 8. Lubricant Level (e.g. Magnesium Stearate) Must be accurately blended and not overused, as excess can: Affect tablet hardness Retard dissolution Lead to punch sticking if insufficient Optional / Product-specific IPCs: Appearance (colour defects, mottling) Tablet Identification (embossing, printing) Weight variation trend analysis using statistical tools Viva-ready summary: “IPCs for compression include tablet weight, hardness, thickness, friability, and compression force. Turret speed and lubricant level are critical to ensure consistent mechanical properties and manufacturability. These controls are essential to maintain tablet quality and patient safety.”

Answer 23

1. Filler (Diluent): Purpose: Adds bulk to allow compression of the tablet when the drug dose is small. Examples: Lactose, microcrystalline cellulose, dibasic calcium phosphate, starch. 2. Binder (Granulating Agent): Purpose: Helps powders adhere during granulation and improves tablet cohesion. Examples: Purified water (for wet granulation), polyvinylpyrrolidone (PVP), starch paste, hydroxypropyl methylcellulose (HPMC), sucrose solution. 3. Disintegrant: Purpose: Promotes tablet breakup after ingestion to aid dissolution. Examples: Cross-linked PVP (crospovidone), sodium starch glycolate, croscarmellose sodium, starch. 4. Lubricant: Purpose: Reduces friction between tablet and die wall during compression and ejection. Examples: Magnesium stearate, stearic acid, sodium stearyl fumarate. 5. Glidant: Purpose: Improves powder flowability during tableting. Examples: Colloidal silicon dioxide, talc. 6. Coating Agents: a. Film coating: Hydroxypropyl methylcellulose (HPMC), polyethylene glycol. b. Enteric coating: Cellulose acetate phthalate (CAP), methacrylic acid copolymers (Eudragit L/S). c. Controlled release: Ethylcellulose, HPMC, polyacrylate derivatives. 7. Preservative / Antioxidant: Purpose: Prevent degradation, particularly in moisture- or oxidation-sensitive products. Examples: Butylated hydroxytoluene (BHT), sodium metabisulfite. 8. Surfactant: Purpose: Improves wettability and dissolution. Examples: Polysorbate 80, sodium lauryl sulfate. 9. Colourants: Purpose: Aesthetic and identification. Examples: Iron oxides, titanium dioxide, FD&C dyes. 10. Sweeteners / Flavouring agents (for chewable or dispersible tablets): Examples: Sucrose, mannitol, aspartame, saccharin sodium, vanilla, mint.

Answer 24

A glidant improves powder flowability, which directly supports: Uniform die filling, and therefore Content uniformity (especially for low-dose actives) Consistent tablet weight However, glidants also indirectly help tablet compression by: Preventing powder bridging or rat-holing in hoppers/feed frames Ensuring smooth feeding into the dies So in summary: Primary role of glidant: Promote flow, leading to content uniformity and consistent tablet weight Secondary benefit: Improves processability during compression by preventing flow interruptions In contrast, a lubricant is essential during the compression stage to: Reduce friction and sticking to tooling Avoid defects like picking, sticking, or tablet capping

Answer 25

My immediate concern is that the blending time deviation could impact the critical quality attribute (CQA) of content uniformity, particularly if the formulation contains a low-dose or poorly flowing API. Over-lubrication — especially with hydrophobic lubricants like magnesium stearate — can lead to API segregation, reduced tablet hardness, and impaired dissolution. I would instruct the operator to quarantine the batch, stop the line, and raise a deviation. Before proceeding, I would review the process validation protocol or QbD/DoE studies to determine whether the process has a proven acceptable range (PAR) for blending time — for example, 5 ± 1 minute. If 6 minutes is within validated limits, I may permit continuation under controlled deviation, provided enhanced IPC checks are implemented. If the extra minute is outside the validated range, I would not proceed without further assurance. In that case, I would initiate a risk-based investigation, starting with blend uniformity testing before compression. I would sample the blend from multiple locations (top, middle, bottom) using a sampling thief and assay each for API content only, using a validated method (typically HPLC). The acceptance criteria would be 90–110% of label claim with RSD ≤ 5%. If blend uniformity passes, I would consider trial compression of a small quantity of tablets and perform IPC checks for weight, hardness, content uniformity, and possibly dissolution. I would also investigate the equipment failure using an Ishikawa approach — examining equipment qualification, PPM records, alarm logs, and any relevant QMS trends. Depending on the outcome, I would implement CAPA — e.g., updating PPM frequency, reviewing auto-stop functions, and retraining staff. If batch quality cannot be assured, it would be rejected. Throughout, I would maintain detailed documentation, involve QA, and ensure the batch is not released until full assessment is completed and the QP is satisfied that patient safety and product quality are not compromised.

Answer 26

In a multiproduct manufacturing facility, cleaning validation is essential to prevent cross-contamination, protect patient safety, and ensure regulatory compliance. The approach must be risk-based and aligned with: EU GMP Volume 4 Part I (Ch.5) and Part II (for APIs) Annex 15 – Cleaning Validation Annex 1 (2022) – Contamination Control Strategy (CCS) EMA Guideline on Shared Facilities (2014) ICH Q9 (QRM) and ICH Q7 (for APIs) 1. Contamination Control & Risk Assessment Cleaning validation must be part of the Contamination Control Strategy (CCS) under Annex 1 (2022). Start with a risk assessment to identify: Shared equipment trains (equipment mapping) Worst-case products based on: Potency/toxicity (e.g., NOAEL) Solubility (in cleaning agent) Cleaning difficulty (stickiness, staining) Batch size and dose of next product Hard-to-clean surfaces or worst-case sampling points 2. Health-Based Exposure Limits – PDE and MACO Calculate the PDE (Permitted Daily Exposure) using toxicological data: PDE = NOAEL × Body Weight ÷ (F1 × F2 × F3 × F4 × F5) F1 = Interspecies variability F2 = Intraspecies variability F3 = Duration of exposure F4 = Severity of toxicity F5 = Database quality Use EU GMP Vol. 4 Part II, Chapter 5, or EMA Shared Facility Guidance for detailed calculation methodology. Then calculate MACO (Maximum Allowable Carry Over): MACO = (PDE × Minimum batch size of next product) ÷ Maximum daily dose of next product Use surface area if required: distribute MACO over shared surface area 3. Cleaning Validation Strategy Define worst-case product(s) for cleaning validation based on: Hardest to clean Poorest solubility Most toxic/potent Smallest acceptable MACO Create a Cleaning Validation Matrix to define shared equipment paths and worst-case scenarios. 4. Cleaning Validation Protocol Develop a protocol that includes: Scope & objectives Selection of product and equipment Sampling plan: Swab sampling (preferred for hard-to-clean areas) Rinse sampling (if applicable) Swab recovery rate must be ≥70% Number of runs: At least 3 successful consecutive validation runs Analytical method: Validated for specificity, sensitivity, and LOD/LOQ Must detect API/residue at below MACO level Acceptance criteria: Based on MACO/PDE or 10 ppm / 1/1000 dose if justified Equipment hold time study (dirty and clean hold) Personnel training and qualification Deviations and CAPA management if protocol criteria are not met Periodic re-validation/review (based on change control, PQR trends, cleaning failures) 5. Verification and Lifecycle Management Perform periodic review of cleaning validation (e.g., during PQR or upon new product introduction) Include ongoing cleaning verification as part of routine manufacturing Update cleaning procedures or retrain staff if verification failures occur Ensure continued alignment with CCS and QRM principles Model Viva Summary: In a multiproduct facility, I would approach cleaning validation using a risk-based strategy aligned with Annex 1, Annex 15, and the EMA shared facilities guideline. I would calculate PDE based on toxicology data (NOAEL), derive MACO, and use this to assess worst-case products across the shared equipment chain. A cleaning validation matrix would identify worst-case scenarios for validation. The protocol would include validated analytical methods, swab recovery studies, clear acceptance criteria based on MACO, and a minimum of three consecutive successful validation runs. Cleaning verification, staff training, deviation handling, and lifecycle reviews would be built into the PQS and linked to the CCS.

Answer 27

A dedicated facility is required when the risk of cross-contamination cannot be adequately controlled through standard GMP measures, cleaning validation, or risk-based controls. This typically applies to products with high pharmacological activity, sensitising potential, or serious consequences from cross-contamination. I would consider a dedicated facility for: Highly potent or toxic products: Where the PDE (Permitted Daily Exposure) is extremely low Example: Oral contraceptives, cytotoxic chemotherapy (e.g., vincristine, doxorubicin), warfarin Sensitising agents: Products that can trigger hypersensitivity or allergic reactions even at trace levels Example: Penicillins, cephalosporins, beta-lactam antibiotics Biological or immunological products: Certain live viral vaccines, ATMPs, or biological toxins where cleaning verification may not be possible or sufficient Product-specific regulatory requirements: For example, the manufacture of beta-lactam antibiotics must be in a dedicated facility as per EU GMP Chapter 5.19 Inability to verify cleaning effectiveness: If the product is highly adsorptive, forms residues difficult to remove, or analytical methods are not sensitive enough to detect residues below MACO This requirement is supported by: EU GMP Chapter 3 and Chapter 5 EMA 2014 Shared Facilities Guideline Annex 1 (2022) — which states that the CCS must justify shared use vs segregation

Answer 28

Microbial contamination in tablet manufacturing is a key risk in non-sterile dosage forms, especially when water or natural-origin materials are used. My main areas of concern would include: 1. Bioburden of Raw Materials: APIs and excipients may carry microbial contamination from their source or manufacturing. Particularly at risk: starch, cellulose, sugars, and other natural materials. Controlled via: Supplier qualification, CoA review, incoming QC testing (Ph. Eur. 5.1.8 if applicable). 2. Water Quality: In wet granulation, water used for binder solution must be at least Purified Water grade. Poor water quality is a common microbial source. Systems must be maintained, monitored, and sanitised routinely (per EU GMP Annex 1 and 8). 3. Personnel and Environment: Operators may be a source of contamination through skin, hair, respiratory droplets, or inadequate gowning. Environmental controls, gowning procedures, and hygiene training are critical. 4. Equipment and Facility Cleanliness: Residual product or moisture in equipment may promote microbial growth. Clean, dry, and well-maintained surfaces (especially post-wet granulation) are key. 5. Manufacturing Process Design: Open vs closed process: Open granulation or blending systems have higher exposure risk. Minimise hold times of moist granules to reduce microbial proliferation. Microbial control in tablet manufacturing is governed by: Ph. Eur. 5.1.4 (Microbiological Quality of Non-Sterile Dosage Forms) Internal alert/action limits based on product risk Environmental monitoring, if appropriate (especially if manufacturing high-risk non-sterile products) Summary Viva Statement: I would monitor microbial contamination risks in tablet manufacturing by controlling API/excipient bioburden, using purified water in wet processes, maintaining clean equipment, and ensuring personnel hygiene. Risk factors like use of natural excipients, open processing, and moist granules would be managed through QRM, cleaning validation, and incoming material control. Limits are set in accordance with Ph. Eur. 5.1.4 and justified per product risk.

Answer 29

As a QP, I would investigate all factors that could affect disintegration and dissolution, focusing on both formulation and process. Dissolution failure is often linked to poor tablet breakup or drug release, which may result from issues in compression, granulation, or excipient functionality. Key Investigation Areas: 1. Compression Process Compression Force / Hardness: Excessive force may produce overly hard tablets, reducing porosity and impeding water penetration. (reduced porosity - no space for water penetration - increased dissolution/disintegration). This can delay disintegration and reduce dissolution. Dwell Time / Press Speed Too long dwell time may overcompress tablets, again affecting porosity and disintegration. In-Process Control (IPC) Trends Review tablet hardness, thickness, and weight variation over the batch. Check if compression settings were changed mid-campaign. 2. Disintegration Testing Disintegration time trend should be reviewed across the batch. Was disintegration time already drifting near the upper limit before the OOT? 3. Granule Properties 3-1. Granule Moisture (LOD) Over-dried granules can reduce compressibility and lead to hard, non-disintegrating tablets. (Reduced moisture - reduced internal cohesion of molecules - need higher compression pressure - loss of porosity - reduced water penetration) 3-2. Particle Size Distribution (PSD) Coarser particles (i.e. bigger particles) may reduce surface area and slow dissolution. 4. Excipients Functionality Disintegrant type and quantity Check if there was a supplier or batch change in superdisintegrants like crospovidone, sodium starch glycolate, etc. Lubricant Over-blending Excessive blending with magnesium stearate can hydrophobise (barrier) the tablet surface, reducing water uptake and slowing dissolution. 5. Coating (if applicable) If coated, ensure the coating thickness or polymer type hasn’t affected drug release. Over-coating or wrong coating formulation may delay drug dissolution. Immediate Actions: Quarantine affected batches Open an OOS and deviation investigation Review root cause using Ishikawa (compression settings, granules, excipient changes, operator actions) Retest reference samples if available If patient risk cannot be ruled out, recall assessment may be required

Answer 30

As a QP, I would conduct a risk-based audit to investigate the root cause of the broken tablets, using EU GMP Volume 4 (Chapters 1–9) and GDP principles. My approach would include the following steps: 1. Pre-Audit Preparation Review the supplier’s: Site Master File (SMF) Quality Policy and Quality Manual Product Quality Reviews (PQR) for the affected product Relevant CQA and CPPs linked to tablet integrity (e.g. hardness, friability, coating) Use this to identify high-risk areas and tailor audit priorities. 2. Define Audit Scope and Focus Areas Prioritise areas impacting: Tablet mechanical strength (granulation, compression, coating, packing) Storage, handling, and distribution conditions Root cause trends for breakages, including previous deviations, OOS, and CC reports 3. On-site Audit Activities a. Quality Management System (QMS) Review records related to: OOS, deviations, change controls Complaint investigations Batch release documentation Examine SOPs for manufacturing, packaging, handling, and transport of tablets b. Gemba Walk / Floor Review Observe: Compression and coating process controls Tablet hardness, friability and in-process checks (IPCs) Packaging line set-up and protection mechanisms Assess: Equipment condition and calibration Operator technique and training records c. Staff Interviews Speak with operators and supervisors to identify: Unwritten practices Potential procedural gaps 4. GDP and Distribution Controls Check if: Tablets are packaged adequately to prevent breakage Storage and transport conditions are appropriate and qualified Palletisation, vibration protection, and handling SOPs are followed Transit testing (if available) has been conducted 5. Post-Audit Actions Issue a report with: Observations, CAPA recommendations, and any critical/major non-conformances Agreement on follow-up plan and timelines Viva-ready summary: “I would take a risk-based audit approach using EU GMP and GDP. I’d review QMS records, CPPs related to tablet strength, and observe manufacturing and packing processes. I’d also assess handling, storage, and transport conditions, as broken tablets could result from manufacturing or distribution weaknesses.”

Answer 31

HH, CC, GG, F, W, P Controls for Cream/Ointment (CoE) Manufacturing — Aligned with Annex 9: Contamination Control Strategy (CCS): In place to prevent microbiological and particulate contamination, including zoning, closed systems, gowning, and cleaning validation. Clean-in-Place (CIP) Systems: CIP procedures validated for tanks, pipework, and processing equipment, with design features to avoid dead legs or microbial accumulation. Material and Equipment Design: Use of 316L stainless steel for product-contact surfaces. Avoid glass or fragile apparatus in production areas to prevent breakage and particulate contamination. Water System and Sanitisation Control: Purified Water (PW) quality monitored routinely. Effective flushing protocol post-sanitisation to remove residues of cleaning or sanitising agents. Goods-In and Material Quality Checks: Starting materials undergo identity testing and CoA verification. Qualified supplier process and storage conditions checked on receipt. Product Transfer and Pipework Verification: Pipelines must be clearly labelled and dedicated or validated for intended product use to avoid cross-contamination or misrouting. Control of Particle Shedding Risks: Avoid particle-generating materials (e.g. wooden pallets, fibreboard) in production areas. Homogeneity Sampling: In-process checks for uniformity of active content using samples from the beginning, middle, and end of mixing, as per Annex 9. Defined Holding Times: Maximum holding times between processing and filling are specified, validated, and routinely monitored to prevent degradation or contamination.

Answer 32

“The source of a raw material is critical because it affects both product quality and manufacturing performance. It can influence CQAs such as dissolution, assay, microbial load, and physical properties like pH or viscosity. All sources must be qualified, GMP-compliant, and subject to ongoing oversight.”

Answer 33

he Preservative Efficacy Test (PET) — also called the Antimicrobial Preservative Effectiveness Test — is a compendial microbiological test described in British Pharmacopoeia / Ph. Eur. 5.1.3. Its purpose is to demonstrate that the antimicrobial preservative system in a multi-dose pharmaceutical product is effective in controlling microbial contamination throughout the product’s shelf life. Key Elements of the Test: 1. Applicability: Required for multi-dose products such as creams, ointments, nasal drops, eye drops, and oral liquids. Ensures product remains microbiologically safe after opening and during use. 2. Test Procedure: The product is artificially inoculated with a known number of standard microbial strains. Microbial survival is monitored at defined time intervals (e.g. Day 0, 7, 14, 28). Acceptance criteria are based on log reduction (e.g. 3-log reduction in bacteria within 14 days, with no increase after that). 3. Microorganisms Used (per Ph. Eur. 5.1.3) Organism Category-Why included Staphylococcus aureus-Gram-positive bacterium -Skin flora / human contaminant Pseudomonas aeruginosa-Gram-negative bacterium-Waterborne / opportunistic pathogen Escherichia coli (Oral)-Gram-negative bacterium-Hygiene indicator Candida albicans-Yeast-Common fungal contaminant Aspergillus brasiliensis (formerly A. niger)-Mould Zygosaccharomyces Rouxii (High sugar product) 4. Media and Conditions: Growth media: Tryptone Soya Agar (TSA) and Sabouraud Dextrose Agar (SDA) for fungi Incubation: Typically 20–25°C for fungi, 30–35°C for bacteria Neutralisers are used to inactivate preservatives during enumeration. 5. Interpretation: Results must meet the acceptance criteria defined in the pharmacopoeia, based on product category (e.g. topical, oral, parenteral). The test must be validated for the product matrix and preservative system. Viva-ready summary: “PET is used to assess the antimicrobial preservative system in multi-dose products, ensuring protection over the shelf life. It involves deliberate inoculation with specified strains like S. aureus, P. aeruginosa, C. albicans, and A. brasiliensis. The product must show defined log reductions over time, in accordance with BP/Ph. Eur. 5.1.3.”

Answer 34

“Non-sterile oral liquids do not require a classified cleanroom like Grade D. However, manufacturing should take place in a controlled environment with appropriate cleaning, ventilation, and segregation. If the product has higher microbiological risk, a Grade D area may be considered, based on a risk assessment.”

Answer 35

The 2022 revision of Annex 1 introduces a more structured, risk-based approach to sterile manufacturing, with greater emphasis on contamination control and the pharmaceutical quality system (PQS). Key changes include: 1. Contamination Control Strategy (CCS) – New Requirement All manufacturers of sterile products must implement a formal, documented CCS. CCS must integrate facility, equipment, utilities, personnel, and materials. It must be reviewed regularly and updated based on data and performance trends. 2. Enhanced Role of Pharmaceutical Quality System (PQS) Stronger integration of QRM and PQS across all sterile manufacturing processes. Emphasis on management responsibility, CAPA, and continuous improvement. 3. Container Closure Integrity (CCI) Detailed expectations for Container Closure Integrity Testing (CCIT), especially for blow–fill–seal (BFS) and closed system fills. CCIT is now expected, not optional, especially in lieu of sterility testing in some cases. 4. Water for Injection (WFI) Production Reverse osmosis (RO) is now accepted as a method for WFI production (if appropriately validated and monitored), aligning with EMA guidance from 2017. 5. Isolators and Restricted Access Barrier Systems (RABS) Greater clarity on the use and qualification of gassing isolators and RABS. Focus on aseptic transfer, decontamination cycles, integrity testing, and routine maintenance. 6. Filter Integrity Testing Mandatory pre- and post-use integrity testing of sterilising grade filters (e.g. bubble point, diffusive flow). Tests must be documented, and post-use failure triggers batch investigation. 7. Cleanroom Classification Updates 5.0 μm particle limit has been removed for Grade A and B “at rest” classification, but still expected to be controlled. Real-time non-viable monitoring in Grade A areas during aseptic processing is now required, not just recommended. 8. Personnel Gowning Requirements More detailed gowning expectations: Sterile goggles and sterile socks now required for Grade A/B areas. Gowning practices must be validated and risk assessed. 9. Particle Monitoring System Design Clearer guidance on particle counter tubing: Specifies maximum tubing length (e.g. <1 metre) Limit bends/angles to prevent particle loss and ensure accuracy. Viva-ready summary: “Annex 1 (2022) introduced major changes including the requirement for a formal CCS, stricter PQS integration, and enhanced expectations for CCIT, filter integrity testing, and use of isolators. Cleanroom classification has been clarified, and gowning requirements expanded, including sterile goggles and socks. The revision promotes a risk-based, science-driven approach to sterility assurance.”

Answer 36

1. Initiate Change Control Open a formal change control within the Pharmaceutical Quality System (PQS) Perform impact assessment covering: Licence scope Quality systems Facilities, equipment, personnel, and utilities Contamination risks and process validation requirements 2. Submit a Manufacturer’s Licence Variation (MIA) to MHRA Check whether the existing MIA or MIA(IMP) covers the new sterile dosage form or activity. If not, submit a licence variation using the MHRA MLX form, including: Updated Site Master File (SMF) New or revised floorplans List of manufacturing activities and dosage forms to be added Description of cleanroom design, HVAC system, and barrier technology (e.g. isolator or RABS) Contamination Control Strategy (CCS) update MHRA inspection will typically be scheduled before approval. GMP certificate will be issued upon successful inspection, reflecting the new activity in EudraGMDP. 3. Facility and Equipment Qualification Perform DQ/IQ/OQ/PQ for: Cleanrooms and HVAC (per ISO 14644) Barrier systems (isolator/RABS) Critical utilities (WFI, clean steam, compressed air) Sterilisation systems (autoclaves, VHP, filters) 4. Contamination Control Strategy (CCS) and PQS Updates Update the CCS to reflect new risks and controls related to sterile processing. Review and revise SOPs, risk assessments, training, and documentation systems. 5. Environmental Monitoring Programme Conduct risk assessment to define: Monitoring locations for viable and non-viable particles Sampling frequency, alert/action limits, and trending procedures Establish limits based on cleanroom qualification data, with 3-sigma trending applied between average and action limits (Annex 1). 6. Aseptic Process Simulation (Media Fills) Validate the new aseptic process through at least three consecutive successful media fills Include interventions, changeovers, and worst-case scenarios Conduct under routine operating conditions with qualified personnel 7. Personnel Qualification and Training Ensure personnel are trained and qualified in aseptic technique, gowning, and environmental monitoring Include gowning qualification, EM competency, and ongoing requalification plans Viva-ready summary: “To introduce a new sterile manufacturing process at an existing site, I would raise a change control and submit a variation to our MIA using the MHRA MLX form. This requires an impact assessment on the licence, facility, and PQS. An MHRA inspection is usually required, and a GMP certificate will be issued if successful. I would ensure full facility and equipment qualification, CCS update, EM programme setup, operator qualification, and aseptic process validation through media fills — all in line with Annex 1, Annex 15, and ISO 14644.”

Answer 37

A sterility test failure in a sterile ophthalmic product is a critical event requiring immediate containment, formal investigation, and risk assessment. I would take the following steps: 1. Immediate Containment Quarantine the affected batch and any other potentially impacted batches (e.g. those manufactured in the same session or with shared equipment). Suspend aseptic operations on the line until initial investigation determines if a systemic issue exists. 2. Initiate Formal OOS Investigation Follow the OOS SOP in accordance with MHRA guidance and Annex 1. Confirm if this is a true OOS or laboratory error: Review media integrity, sampling method, incubation conditions, and analyst technique. Send sample for microbial identification to determine likely contamination source. 3. If Confirmed True OOS – Escalate to Deviation Raise a manufacturing deviation and conduct impact assessment: MA: Batch is OOS for sterility, not compliant with product specification. GMP: Indicates potential failure in sterility assurance; CCS robustness is questioned. Patient safety: Eye drops are high-risk, as contamination can lead to serious ocular infections. 4. Root Cause Investigation (Ishikawa / Fishbone Analysis) QMS Review recent deviations, OOS/OOT, CC, and PQR for similar trends. Personnel Review operator aseptic process simulation (APS) performance Check gowning qualification, hand hygiene, training records, recent staff changes Review CCTV footage if available for operator technique and interventions Facility/Equipment Check cleaning/disinfection records, PPM, and HEPA filter integrity Any recent maintenance? EM excursions? Documentation Review batch manufacturing records (BMRs) for anomalies, unrecorded interventions, near misses Review sterility test records – which unit failed, what container, from which part of the batch? Process Was this a filtered product? If so: Review filter integrity testing, pre/post-use Was filling performed in an isolator or Grade A with Grade B background? Review APS trends, pre-/post-session EM and personnel monitoring results Materials/Suppliers Check Goods In checks for sterile components, API, excipients, and packaging Any issues flagged with sterile container-closure system? Review supplier audit reports and CoAs Audit/Inspection Findings Any recent self-inspection or MHRA observations related to aseptic controls? 5. Product Disposition and Risk Assessment If sterility cannot be assured, the affected batch must be rejected. If any batch was released to the market, initiate a recall assessment (likely Class 1 or 2) and notify the MHRA/DMRC. Document decision with QP justification. 6. Corrective and Preventive Actions (CAPA) Based on root cause, implement appropriate CAPA: Operator retraining Enhanced cleaning frequency Improved gowning practices or equipment upgrade Consider changing cleaning/disinfection agents or revalidating sanitisation Update the CCS and relevant SOPs as required Perform CAPA effectiveness checks and requalify the line before resuming manufacturing 7. Media Fill and APS (if applicable) If the root cause involved aseptic technique or facility failure: Requalify operators via APS Conduct media fills under simulated worst-case conditions (Annex 1)

Answer 38

To manufacture an ATMP in the UK, the site must hold a: • Manufacturer’s Authorisation (MIA or MIA(IMP)), depending on whether the product is for commercial or clinical trial use. • HTA License under The Human Tissue (Quality and Safety for Human Application) Regulations 2007 (SI 2007/1523), if handling human tissues/cells such as leukapheresis material. • The site must also be GMP-compliant and inspected by the MHRA, with an up-to-date GMP certificate. Additionally, clinical sites (hospitals administering the product) must be HTA-approved to receive, store, and handle human-derived materials.

Answer 39

Model Answer: Key GMP controls include: • Grade A isolators operated under positive pressure with a Grade D background. • Use of validated closed systems (e.g., CliniMACS Prodigy) to minimise contamination risks. • Validated disinfection and decontamination cycles (e.g., vaporised hydrogen peroxide for isolator gassing). • Single-use systems to avoid cross-contamination between patients (as these are autologous products). • In-process critical process parameters (CPPs) such as controlled time from leukapheresis to processing (e.g., max 96 hours), and controlled-rate freezing (e.g., 1°C/min) for cryopreservation.

Answer 40

Model Answer: Under the 2007 HTA Regulations (SI 2007/1523), donor material must be screened for: • HIV 1/2 • Hepatitis B and C • Syphilis • HTLV I/II • Other risk-based markers depending on donor risk assessment. Testing must occur within 30 days before leukapheresis. If the patient has an active infection, leukapheresis must be postponed until resolved, to avoid impacting cell viability and manufacturing outcomes.

Answer 41

Model Answer: For clinical trial ATMPs, if a batch is OOS for non-safety-related parameters (e.g., potency), a clinical justification can be made. The QP can certify that the batch was manufactured in accordance with the approved CTA and GMP, but final use is a clinical decision. The investigator must: • Conduct a risk-benefit assessment, • Obtain informed consent from the patient, • Seek regulatory approval (e.g., via the MHRA clinical trials unit), if required. However, OOS for sterility, endotoxin, mycoplasma, or identity cannot be released due to patient safety concerns

Answer 42

Model Answer: Key QC tests include: • Sterility • Endotoxin • Mycoplasma • Viability (e.g., flow cytometry) • Identity (e.g., CD3+, CD4/CD8 phenotype) • Vector copy number (must be <5 to avoid oncogenic risks) • Potency: e.g., impedance-based cytotoxicity assay to measure cancer cell killing capability. Due to the short shelf-life (e.g., 6 months), release may be done on partial results (e.g., interim sterility) with full results available post-release, based on risk assessment and control strategy.

Answer 43

Model Answer: No. CAR-T products are ATMPs, and unlike vaccines and plasma-derived products, they are not subject to official batch release testing by NIBSC. Under Directive 2001/83/EC Article 114 and UK regulations, official batch release applies to: • Immunological medicinal products (e.g., vaccines), • Blood/plasma-derived products. ATMPs are excluded from NIBSC batch release but still require QP certification before use.

Answer 44

Model Answer: A key CPP is the holding time from leukapheresis to start of manufacturing, as prolonged storage reduces cell viability. • Initial limit: 72 hours. • Updated based on data: reduced to 26 hours. • Controlled by: • Time-stamped transport logs. • Acceptance criteria at goods-in (viability testing, temperature logs). • Deviations raised and investigated if exceeded. Another example is controlled-rate freezing: 1°C/min to preserve cell integrity.

Answer 45

Model Answer: • Autologous: Cells are collected from the patient and returned to the same patient. Each batch is unique. • Risk: patient-specific variability, limited material, identity mix-ups. • Allogeneic: Cells are from a healthy donor and used to treat other patients. • Risk: immune rejection, need for HLA matching. CAR-T is usually autologous, which poses traceability and batch segregation challenges that the QP must oversee.

Answer 46

Model Answer: The QP must ensure: • Unique identifiers (e.g., barcodes, patient ID codes) are applied at collection, maintained through manufacture, testing, and release. • Chain of custody and chain of identity documentation is robust. • Cross-checking during goods-in, batch processing, and final labelling. • Segregation of material at all stages. • Staff training on patient-specific handling procedures. Failure in traceability could result in administering the wrong product — a critical patient safety risk.

Answer 47

API, suspending agent, vehicle (water or alcohol-based), flavouring agent, colouring agent, buffering agent (for pH), flocculating agent, preservative, and viscosity enhancers.

Answer 48

A: A cream is typically an emulsion made up of two phases—aqueous phase (water-based) and oil phase (lipid-based). Common ingredients include: • Aqueous phase: Purified water, humectants (e.g. glycerol, propylene glycol), buffering agents • Oil phase: White soft paraffin, liquid paraffin, cetostearyl alcohol, isopropyl myristate • Emulsifiers: To stabilise the emulsion (e.g. polysorbates, cetomacrogol, sodium lauryl sulfate) • Preservatives: To prevent microbial growth (e.g. methylparaben, propylparaben, phenoxyethanol) • Antioxidants: To prevent oxidation of oils (e.g. vitamin E [tocopherol], butylated hydroxytoluene [BHT]) • Thickening agents/viscosity enhancers: e.g. carbomers, xanthan gum • Active pharmaceutical ingredient (API): Incorporated depending on the intended therapeutic effect

Answer 49

Tablets contain various excipients that serve specific functions in the formulation. A helpful mnemonic is A–I: • A = Active Pharmaceutical Ingredient (API): The medicinal substance. • B = Binder: Helps hold ingredients together (e.g. starch paste, povidone, hydroxypropyl cellulose). • C = Coating agent: Improves appearance, taste masking, and stability (e.g. hydroxypropyl methylcellulose, PEG, Eudragit). • D = Disintegrant: Aids tablet breakup in GI tract (e.g. crospovidone, sodium starch glycolate, croscarmellose sodium). • E = — (Not typically assigned). • F = Filler (Diluent): Adds bulk to tablets (e.g. lactose, microcrystalline cellulose, dibasic calcium phosphate). • G = Glidant: Improves powder flow (e.g. colloidal silicon dioxide, talc). • H = Anti-adherent: Prevents sticking to equipment (e.g. talc, magnesium stearate). • I = Lubricant: Reduces friction during compression (e.g. magnesium stearate, stearic acid).

Answer 50

A: No, infectious disease marker testing is not part of the final QC testing for the finished ATMP or gene therapy product. These tests are performed early in the process to assess the suitability of the starting material, particularly when the starting material (e.g., peripheral blood for leukapheresis) is of human origin. In autologous ATMPs like CAR-T, these markers — HIV 1 and 2, Hepatitis B and C, HTLV-I, and Syphilis — are part of donor (or patient) eligibility screening. This testing falls under the Human Tissue Authority (HTA) in the UK, in line with the Human Tissue (Quality and Safety for Human Application) Regulations 2007, which implement EU Directive 2004/23/EC and Commission Directive 2006/17/EC. The primary purpose is to ensure biological safety, traceability, and compliance with donor suitability criteria. In contrast, final GMP QC tests for ATMPs include sterility, endotoxin, mycoplasma, vector copy number, potency, identity, and viability. These are performed under GMP and are essential for QP certification and batch release.

Answer 51

In contrast, Final QC testing for ATMPs includes: • Sterility • Endotoxin • Mycoplasma • Vector copy number • Potency • Cell identity and viability

Answer 52

Because the starting material is patient-specific and cannot be replaced with a banked cell line due to the autologous nature of the therapy.

Answer 53

1. Active pharmaceutical ingredient (API) – the drug, usually insoluble in water. 2. Suspending agent – helps keep solid particles dispersed (e.g. xanthan gum, methylcellulose). 3. Wetting agent / Surfactant – reduces surface tension to allow proper wetting of solid particles (e.g. polysorbates like Tween 80, sodium lauryl sulfate). 4. Vehicle – usually purified water or a mix of water and other solvents. 5. Buffering agents – to maintain pH. 6. Preservatives – to prevent microbial growth (e.g. parabens, benzyl alcohol). 7. Flavouring and sweetening agents – for oral suspensions, to improve palatability. 8. Colorants – optional, for appearance. Note: Oil is only included in emulsion-based suspensions or oil-based vehicles, but most suspensions are aqueous.

Answer 54

Steps: 1. Blending – uniform mix of API and excipients. 2. Binder addition – e.g., purified water (CPP: quality must meet Ph. Eur). 3. Wet Massing – forming a granulated mass. 4. Drying – controls on temperature and time (CPPs). 5. Milling/Sieving – controls on screen size (CPP). 6. Blending with lubricant – e.g., magnesium stearate to reduce sticking. 7. Compression – tablet formation (CPP: compression force, speed). 8. Coating (if required) – for stability/appearance. CQAs Identified: • Granule particle size • Powder flow • Tablet weight uniformity • Appearance (shape, color) • Density • Disintegration time CPPs Identified: • Mixing time and speed • Binder solution quality and quantity • Drying temperature/time • Milling screen size • Compression force

Answer 55

Potency is assessed using an impedance-based cytotoxicity assay where the CAR-T product is incubated with CD19⁺ target cells derived from a qualified cell bank. The system measures real-time killing of target cells by monitoring electrical impedance. This method provides a functional readout of the CAR-T cells’ ability to recognize and eliminate antigen-positive targets. The assay uses reference cancer cell lines to ensure consistency across batches. In an impedance-based assay (e.g. xCELLigence system): • Cancer target cells are seeded onto a special plate with gold microelectrodes at the bottom. • These adherent cells attach and spread, generating a baseline electrical impedance. • When CAR-T cells kill the cancer cells, the dead cells detach from the plate. • As cells detach, the impedance drops — and this change is detected in real-time.

Answer 56

1. Formulation • Selection of excipients (e.g. bulking agents, cryoprotectants). • Solution preparation and sterile filtration (if aseptic). 2. Filling • Aseptically fill drug solution into vials/trays. • Partial stoppering of vials in Grade A environment. 3. Loading into Freeze Dryer • Load into pre-cooled shelf in lyophiliser under aseptic conditions. 4. Freezing • Controlled nucleation or uncontrolled freezing to form solid ice matrix. • Typical temp: –40 to –50°C. 5. Primary Drying (Sublimation) • Chamber pressure reduced (vacuum), shelf temp raised to allow sublimation. • Ice → Vapour; most of water removed here. 6. Secondary Drying (Desorption) • Shelf temp increased further (e.g. 20–40°C) to remove bound water. 7. Stoppering under Vacuum or Inert Gas • Stopper vials while under vacuum or inert gas atmosphere. 8. Unloading • Unload from lyophiliser into Grade A or B area. 9. Capping and Final Packaging • Fully stopper and cap, then label and store under appropriate conditions.

Answer 57

CQA Justification Residual Moisture - Affects product stability and shelf life Appearance (cake structure)- Collapsed/particulate indicates poor drying or contamination Reconstitution Time- Impacts usability and delivery Potency/Assay- Ensures therapeutic efficacy pH after reconstitution- Critical for drug stability Sterility- Essential for parenteral products Endotoxin level- Particularly for injectables Container Closure Integrity- Prevents microbial ingress, ensures sterility

Answer 58

CPP Impact Freezing rate and shelf temperature-Affects ice crystal size, cake porosity, and sublimation efficiency Chamber pressure during primary drying P-Affects sublimation rate and product temperature Shelf temperature during primary and secondary drying- Impacts residual moisture, cake collapse Duration of drying phases-Ensures complete water removal without degradation Stoppering pressure and timing- Impacts container closure integrity Vacuum leak rate- Affects process efficiency and sterility assurance

Answer 59

Buzz words: 1. Impeller Speed: • What it is: The rotation speed (RPM) of the impeller, the main mixing blade in the granulator. • Purpose: Controls the mixing intensity and powder movement. Helps distribute the granulating liquid throughout the powder bed to start forming granules. • Impact: • Too high → over-granulation (large, wet lumps). • Too low → poor mixing, uneven granules. ⸻ 2. Chopper Speed: • What it is: The rotation speed (RPM) of the chopper blade in the granulator. • Purpose: Breaks down larger wet lumps of granules into smaller, uniform particles. It prevents agglomeration and controls granule size distribution. • Impact: • Too high → overly fine granules (poor flow). • Too low → large, uneven granules. ⸻ 3. Granulation Time: • What it is: The total duration (minutes) of the granulation process — how long the impeller and chopper run with the granulating liquid. • Purpose: Controls how long the powders are mixed and granulated to form granules of the desired size and consistency. • Impact: • Too long → over-wet or overworked granules (dense, possibly sticky). • Too short → incomplete granulation (powders not binding properly). • Flowability → about how well powder/granules move. • Compressibility → about how well they compress into a solid form. Inlet Air Temperature: • This is the temperature of the air entering the fluid bed dryer (or any drying system). • It’s the hot air that dries the wet granules by evaporating moisture. Outlet Air Temperature: • This is the temperature of the air leaving the drying chamber after it has picked up moisture from the granules. • It reflects how much moisture has been removed—higher outlet temp = less moisture remaining. Fluidisation (or fluidization): • It refers to the process of suspending solid particles (like granules or powders) in an upward flow of air or gas, making them behave like a fluid. • This happens in a fluid bed dryer, where hot air is blown from the bottom to lift and mix the granules, ensuring even drying. Think of it like popping popcorn—the hot air moves the kernels around so they heat evenly. In drying, the air lifts the granules, allowing uniform heat and moisture removal. Turret Speed (in a tablet press): • The turret is the rotating part of the tablet compression machine that holds the dies and punches. • Turret speed refers to how fast the turret rotates—usually measured in revolutions per minute (RPM). As the turret rotates: • Powder is filled into each die. • The punches compress the powder into tablets. • The tablet is ejected, and the process repeats. ⸻ Why is turret speed important? It’s a CPP (Critical Process Parameter) in tablet compression. • Too fast turret speed: • Less time for powder filling → can cause weight variation. • Less dwell time (time under compression) → may lead to weak tablets (low hardness, friability issues). • Too slow turret speed: • Reduces productivity. • Might not affect quality, but inefficient. 1. Weighing and Dispensing • Purpose: Ensure correct quantities of raw materials. • CPPs: Accuracy of weighing. • CQAs: Material identity, potency, and purity. ⸻ 2. Wet Granulation • Purpose: Mix powders with a granulating liquid to form granules, improving flowability and compressibility. • CPPs: • Impeller speed. • Chopper speed. • Granulation time. • Temperature (if heated). • CQAs: • Granule size distribution. • Bulk/tapped density. ⸻ 3. Drying (e.g., Fluid Bed Dryer) • Purpose: Remove moisture from granules. • CPPs: • Inlet/outlet air temperature. • Fluidisation air velocity. • Drying time. • CQAs: • Loss on drying (LOD). • Granule moisture content. ⸻ 4. Milling/Sieving • Purpose: Reduce granule size to uniform distribution. • CPPs: • Mill speed. • Sieve size. • CQAs: • Granule size distribution. ⸻ 5. Blending (Including Lubrication) • Purpose: Mix dried granules with additional excipients (e.g., lubricants like magnesium stearate). • CPPs: • Blender speed. • Mixing time. • CQAs: • Blend uniformity (assessed by sampling top, middle, bottom). ⸻ 6. Compression (Tablet Press) • Purpose: Compress the blended powder into tablets. • CPPs: • Turret speed. • Fill depth. • Pre-compression and main compression force. • Dwell time. • CQAs: • Tablet weight. • Hardness. • Friability. • Disintegration time. • Uniformity of dosage units (content uniformity). ⸻ 7. Coating (Optional) • Purpose: Apply a coating for taste masking, protection, or controlled release. • CPPs: • Pan speed. • Spray rate. • Atomization pressure. • Bed temperature. • Distance between spray gun and tablet bed. • CQAs: • Coating uniformity. • Weight gain. • Appearance (e.g., color, gloss). ⸻ 8. Packaging • Purpose: Protect the tablets from environmental factors (moisture, light). • CPPs: • Packaging line speed. • Seal integrity (e.g., blister packs). • CQAs: • Pack integrity. • Labeling accuracy.

Answer 60

Simple Process Flow: 1. Powder blending → 2. Roller compaction → 3. Ribbon formation → 4. Milling (to granules) → 5. Lubrication blending → 6. Tablet compression. Words: Dwell Time (in tablet compression): • Definition: Dwell time is the amount of time the tablet punches remain in contact with the powder under compression force (i.e., how long the powder is compressed before the punches move apart). • It’s the time duration during which the upper and lower punches maintain pressure on the powder within the die cavity. • Measured in milliseconds (ms). ⸻ Why is dwell time important? • Longer dwell time allows better consolidation of the powder, leading to: • Stronger tablets (higher hardness). • Reduced risk of capping/lamination (tablet defects). • Better binding of particles. • Short dwell time (due to high turret speed or small punch size) can cause: • Weak tablets. • Poor mechanical strength. ⸻ How is it controlled? • CPPs affecting dwell time: • Turret speed: Faster turret = shorter dwell time. • Punch head flat length: Longer head flat = longer dwell time. (Some presses use extended dwell time punches for this reason.) Fill Depth (in tablet compression): • Definition: Fill depth is the depth of powder filled into the die cavity during tablet compression. • It determines how much powder gets into each die cavity before compression happens, which directly affects: • Tablet weight. • Tablet thickness. ⸻ Why is fill depth important? • It’s a CPP (Critical Process Parameter) because: • Too much fill depth → tablets could be overweight or too thick. • Too little fill depth → tablets could be underweight or too thin. • It ensures uniform dosing (critical for content uniformity) and consistent tablet dimensions. ⸻ How is fill depth controlled? • By adjusting the lower punch position during the filling stage: • The lower punch controls how deep the powder fills. • Changing the fill cam setting alters the fill depth. • CPPs influencing fill depth: • Filling speed. • Powder flowability. • Turret speed (indirectly, faster speed = less time to fill). What is Ribbon Density? • Ribbon density refers to the density of the compacted sheet or “ribbon” formed during roller compaction in dry granulation. • It’s a CQA (Critical Quality Attribute) because it indicates how well the powder has been compacted between the rollers. ⸻ Why is Ribbon Density Important? • It directly affects: • Granule properties after milling (size, strength, flowability). • Compressibility of the granules (how well they form tablets later). • Content uniformity and tablet weight variation downstream. ⸻ How is it calculated? • Usually measured as: \text{Ribbon Density} = \frac{\text{Mass of ribbon sample}}{\text{Volume of the ribbon sample}} (can be expressed in g/cm³) • Some companies use in-line sensors or off-line tests on ribbon segments to assess density. ⸻ Controlled By Which CPPs? • Ribbon density is influenced by key roller compaction CPPs: • Roller pressure / compaction force • Roller gap width • Roller speed • Feed screw speed Dry Granulation Process (Roller Compaction) 1. Weighing and Dispensing • Purpose: Accurate measurement of raw materials. • CPPs: Weighing accuracy. • CQAs: Material identity, potency, purity. ⸻ 2. Blending (Pre-Mixing) • Purpose: Homogeneously mix powders (API + excipients). • CPPs: • Blender speed. • Mixing time. • CQAs: • Blend uniformity. ⸻ 3. Roller Compaction (Granulation Step) • Purpose: Compress powder mixture between two rollers to form ribbons or flakes (no liquid used). • CPPs: • Roller pressure/compaction force. • Roller speed. • Gap width between rollers. • CQAs: • Ribbon density (affects downstream flowability and compressibility). • Granule size distribution (after milling). • Bulk/tapped density. ⸻ 4. Milling/Sieving (Post-Compaction) • Purpose: Mill the compacted ribbons into granules of desired size. • CPPs: • Mill speed. • Sieve size. • CQAs: • Granule size distribution. • Flowability. ⸻ 5. Lubrication (Final Blending) • Purpose: Add lubricants (e.g., magnesium stearate) to granules. • CPPs: • Blender speed. • Mixing time. • CQAs: • Blend uniformity (including lubricant distribution). ⸻ 6. Compression (Tablet Press) • Purpose: Compress granules into tablets. • CPPs: • Turret speed. • Fill depth. • Compression force. • Dwell time. • CQAs: • Tablet weight. • Hardness. • Friability. • Disintegration time. • Content uniformity. ⸻ 7. Coating (if applicable) • Same as wet granulation (optional).

Answer 61

1. Manufacturing Steps Solutions (e.g., Paracetamol oral solution) • Step 1: Dispense and weigh raw materials (API, excipients, purified water). • Step 2: Prepare purified water according to EP/BP specifications. • Step 3: Dissolve excipients (e.g., preservatives, sweeteners) in water under stirring. • Step 4: Add API gradually while maintaining agitation to ensure complete dissolution. • Step 5: Adjust final volume with purified water. • Step 6: Filter (e.g., 0.45 µm) to remove particulates. • Step 7: Fill into containers under non-sterile, GMP-controlled conditions. Suspensions (e.g., Amoxicillin suspension) • Step 1: Dispense and weigh raw materials. • Step 2: Prepare dispersion medium (water + suspending agents + preservatives). • Step 3: Wet the API (to prevent clumping) and add to dispersion medium. • Step 4: Homogenize to achieve uniform distribution of suspended particles. • Step 5: Adjust final volume, mix thoroughly. • Step 6: Fill into containers with gentle agitation to maintain uniformity. Emulsions (e.g., oil-in-water) • Step 1: Prepare aqueous phase (water + hydrophilic excipients). • Step 2: Prepare oil phase (API + lipophilic excipients). • Step 3: Heat both phases (often ~60-70°C) to match temperatures. • Step 4: Slowly add the oil phase into the aqueous phase under high-shear mixing. • Step 5: Homogenize to achieve fine droplet size and stable emulsion. • Step 6: Cool to ambient temperature and fill. Syrups (e.g., simple syrup or medicated syrup) • Step 1: Prepare concentrated sugar solution (heat water, dissolve sugar). • Step 2: Prepare a separate solution of excipients/API in water. • Step 3: Combine the sugar solution and excipient/API solution while mixing. • Step 4: Adjust final volume, mix thoroughly. • Step 5: Filter and fill. ⸻ 2. Critical Process Parameters (CPPs) • Mixer speed: Ensures uniform mixing; too high may introduce air, too low may cause non-uniformity. • Homogenizer speed/height: Controls particle/droplet size distribution, especially for suspensions/emulsions. • Addition rate of APIs/excipients: Too fast may cause clumping or incomplete dissolution. • Temperature: Crucial during dissolution or emulsification (e.g., heating phases in emulsions). • Mixing time: Sufficient to ensure uniformity but avoid degradation or over-shearing. ⸻ 3. Critical Quality Attributes (CQAs) • Appearance: Clear for solutions, uniformity for suspensions/emulsions, absence of phase separation. • pH: Ensures stability, solubility, and preservative efficacy (typically specified range). • Preservative content: To prevent microbial contamination in multi-dose containers. • Related substances: Impurity profile must be within limits. • Viscosity: Especially critical for suspensions and emulsions for dose uniformity and pourability. • Microbial limits: Typically ≤100 CFU/mL (BP/EP) for non-sterile liquids. • Assay: API content within specified limits.

Answer 62

1. Cell Banking * Steps: o Create Master Cell Bank (MCB) and Working Cell Bank (WCB). o Store in liquid nitrogen. * CPPs: o Thawing temperature/time. o Cryopreservation conditions (liquid nitrogen, ≤ -150°C). * CQAs: o Cell identity (genetic stability). o Cell viability. o Sterility, mycoplasma, virus-free status. ________________________________________ 2. Upstream Processing (Cell Culture) * Steps: o Thaw WCB → expand cells in shake flasks → transfer to seed bioreactors → large-scale production bioreactor. * CPPs: o Temperature (e.g., 37°C for mammalian cells). o pH, dissolved oxygen (DO), CO₂ levels. o Agitation speed (ensures mixing without damaging cells). o Nutrient feed rates (glucose, amino acids). * CQAs: o Cell viability, growth rate. o Product titre (concentration). o Metabolite levels (e.g., lactate, ammonia). ________________________________________ 3. Harvest / Clarification * Steps: o Remove cells/debris from culture medium (centrifugation or depth filtration). * CPPs: o Centrifuge speed, flow rate, filter pore size. * CQAs: o Product yield. o Host Cell Protein (HCP) and DNA content (impurities). ________________________________________ 4. Downstream Processing (Purification) * Steps: o Capture step (e.g., Protein A chromatography for mAbs). o Polishing steps (e.g., ion exchange, viral filtration). * CPPs: o Flow rate of chromatography columns. o pH, buffer composition, conductivity. o Filtration parameters (pressure, pore size). * CQAs: o Purity (removal of HCP, DNA). o Potency (bioactivity). o Viral clearance (critical for safety). ________________________________________ 5. Formulation * Steps: o Buffer exchange (e.g., diafiltration), addition of stabilisers/excipients. * CPPs: o Mixing speed, temperature. o Sterile filtration (0.22 µm). * CQAs: o Concentration, stability. o pH, osmolality. ________________________________________ 6. Fill & Finish (Sterile Filling) * Steps: o Aseptic filling into vials/syringes under Grade A (isolator) with Grade B background. * CPPs: o Filling volume, stopper placement, capping torque. o Sterile filtration (final 0.22 µm filter). * CQAs: o Sterility, endotoxin levels. o Particulate matter. o Container Closure Integrity (CCI). ________________________________________ 7. Storage and Distribution * Steps: o Store under controlled conditions (e.g., 2-8°C). * CPPs: o Temperature control (validated cold chain). o Humidity (if applicable). * CQAs: o Product stability, integrity (no degradation). ________________________________________ Regulatory References: * EU GMP Annex 2 (Biological medicinal substances and products). * Part II (ICH Q7 for APIs). * EU GMP Annex 1 (for sterile processes, Fill/Finish). * ICH Q5C (Stability of Biotech products). * ICH Q5D (Cell substrate characterization).

Pharmaceutical formulation and processing Flashcards

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