GPAT Pharmaceutical Engineering Syllabus

What problem occurs when mixing solids of very different particle size/density, and what is it called?

Segregation (demixing) - the homogeneous mix separates due to differences in size, density or shape, especially on vibration. It limits the achievable degree of mixing.

Name common solid-solid mixers and their mixing mechanism.

Tumbling mixers (double cone, V-cone/twin shell) mix by diffusion/convection during rotation; ribbon/agitator mixers use convective blades; these suit free-flowing powders (tumbling) or cohesive powders (ribbon).

Which mixer is suitable for liquids of low to moderate viscosity and how does it work?

The propeller (or turbine) mixer - a rotating impeller creates axial/radial flow and turbulence; propellers give axial flow for low-viscosity liquids, turbines give radial flow for higher viscosity.

What is a planetary mixer used for in pharmaceutical manufacturing?

For mixing semi-solids and wet masses (ointments, pastes, granulation doughs). The blade rotates on its own axis while orbiting the bowl (planetary motion), reaching all parts without dead spots.

Define crystallisation and the two steps essential to it.

Crystallisation is formation of solid crystals from a homogeneous solution/melt. The two steps are nucleation (formation of new crystal nuclei) and crystal growth (deposition of solute onto existing nuclei).

What is supersaturation and why is it the driving force for crystallisation?

Supersaturation is the state where solute concentration exceeds its equilibrium solubility. The excess concentration is the thermodynamic driving force that causes nucleation and crystal growth.

How do cooling and evaporative crystallisation differ in creating supersaturation?

Cooling crystallisation lowers temperature to reduce solubility (good for solutes whose solubility rises steeply with temperature). Evaporative crystallisation removes solvent at constant temperature (used when solubility changes little with temperature).

How does crystal size relate to the rates of nucleation versus growth?

High nucleation rate (high supersaturation) gives many small crystals; controlled low supersaturation favours growth over nucleation, giving fewer, larger crystals. Size is controlled by managing the supersaturation level.

Define automation and list the basic elements of an automatic control loop.

Automation is operating a process with minimal human intervention using control systems. A feedback control loop comprises a sensor/measuring element, a transmitter, a controller (comparator + control action), and a final control element (e.g., valve).

Differentiate PLC, DCS and SCADA in pharmaceutical process automation.

PLC (Programmable Logic Controller): rugged controller for discrete machine/sequence control. DCS (Distributed Control System): integrated control of continuous plant-wide processes. SCADA: supervisory software for monitoring, data acquisition and control across distributed sites.

What is PAT (Process Analytical Technology) in pharmaceutical manufacturing?

An FDA framework for designing, analysing and controlling manufacturing through timely in-process measurement of critical quality and performance attributes (using tools like NIR, Raman) to ensure final product quality - 'quality by design' rather than end testing.

What does 21 CFR Part 11 govern in automated pharmaceutical systems?

It is the US FDA regulation on electronic records and electronic signatures, requiring controls (audit trails, access control, validation, data integrity) so electronic records are trustworthy and equivalent to paper.

Define 'risk' and name the three steps of risk management per ICH Q9.

Risk = combination of the probability of occurrence of harm and the severity of that harm. ICH Q9 steps: risk assessment (identification, analysis, evaluation), risk control (reduction/acceptance), and risk review/communication.

What do FMEA and HAZOP stand for and how do they differ?

FMEA = Failure Mode and Effects Analysis (identifies failure modes and ranks by Risk Priority Number = Severity x Occurrence x Detection). HAZOP = Hazard and Operability study (uses guide words on process parameters to find deviations). FMEA is failure-focused; HAZOP is deviation-focused.

What is the Risk Priority Number (RPN) in FMEA and how is it calculated?

RPN = Severity x Occurrence x Detection, each rated (typically 1-10). Higher RPN indicates higher risk; it prioritises which failure modes need corrective action first.

What is the purpose of an MSDS/SDS and a fume hood in pharmaceutical safety?

An (M)SDS gives hazard, handling, storage and first-aid information for a chemical. A fume hood is local exhaust ventilation that captures and removes hazardous vapours/dusts to protect workers' breathing zone.

Define evaporation and how it differs from drying.

Evaporation is concentration of a solution by vaporising the solvent (usually water), leaving a concentrated liquid as the product. Drying produces a solid product; evaporation's product remains liquid.

What is 'economy' of an evaporator and how is it improved?

Economy = mass of solvent evaporated per unit mass of steam used. It is improved by multiple-effect evaporation, where vapour from one effect is used as the heating medium for the next, reusing latent heat.

In a multiple-effect evaporator, how do pressure and temperature change across effects?

Each successive effect operates at lower pressure (vacuum) so its boiling point is lower, allowing vapour from the previous effect to act as its heating steam. Pressure and boiling temperature decrease from first to last effect.

What is the chief advantage of a falling-film (or climbing-film) evaporator for pharmaceuticals?

Short liquid residence time and low temperature operation (often under vacuum), giving high heat-transfer rates and making it suitable for heat-sensitive (thermolabile) materials with minimal degradation.

State the basic enthalpy/mass-balance principle used in evaporator design.

Heat supplied by steam = sensible heat to raise feed to boiling point + latent heat to vaporise the solvent (Q = U A delta-T), combined with mass balances on solvent and solute (solute leaves only in concentrated product).

Define distillation and state its governing principle.

Distillation separates liquid mixtures based on differences in volatility (boiling point/vapour pressure). The vapour produced is richer in the more volatile component; condensing it gives a more concentrated distillate.

What is Raoult's law and its role in distillation?

Raoult's law: the partial vapour pressure of a component = its mole fraction in the liquid x its pure-component vapour pressure (p_A = x_A * P_A°). It predicts vapour-liquid equilibrium for ideal mixtures, the basis of distillation design.

Differentiate simple distillation, fractional distillation and steam distillation.

Simple distillation: single vaporisation, for liquids with widely different boiling points. Fractional distillation: uses a column with repeated vaporisation/condensation to separate close-boiling liquids. Steam distillation: passes steam through to distil heat-sensitive, water-immiscible volatile substances below 100 C.

What is an azeotrope and why is it a problem in distillation?

An azeotrope is a mixture that boils at constant temperature with vapour having the same composition as the liquid, so ordinary distillation cannot separate it further (e.g., ethanol-water 95.6%). It requires azeotropic/extractive distillation.

Why is vacuum (reduced-pressure) distillation used in the pharmaceutical industry?

Lowering pressure lowers the boiling point, allowing distillation of high-boiling and thermolabile substances at low temperatures, preventing thermal decomposition.

Distinguish Newtonian from non-Newtonian fluids with examples.

Newtonian fluids have viscosity independent of shear rate (water, glycerin, dilute solutions). Non-Newtonian fluids have shear-dependent viscosity - e.g., pseudoplastic (shear-thinning, like methylcellulose gels), dilatant (shear-thickening), and Bingham plastic (toothpaste).

State Reynolds number, its formula, and the laminar/turbulent transition values for pipe flow.

Re = D v rho / eta (diameter x velocity x density / viscosity); dimensionless ratio of inertial to viscous forces. In pipes: laminar Re < 2000, transitional 2000-4000, turbulent Re > 4000.

State Bernoulli's principle for fluid flow.

For an ideal incompressible fluid in steady flow, the total mechanical energy is conserved: P/rho + v^2/2 + g*z = constant (pressure energy + kinetic energy + potential energy). Where velocity increases, pressure decreases.

Name two devices that measure fluid flow rate based on Bernoulli's principle.

The venturi meter and the orifice meter - both create a constriction; the pressure drop across it is related to flow rate. (A rotameter is a variable-area flow meter; a pitot tube measures velocity.)

What are the three modes of heat transfer, and which dominates in a steam-jacketed kettle heating a liquid?

Conduction, convection and radiation. In a steam-jacketed kettle, conduction through the vessel wall and convection within the liquid dominate (radiation is negligible).

State Fourier's law of heat conduction.

Q = -k A (dT/dx): the rate of heat conduction is proportional to the thermal conductivity k, the area A, and the temperature gradient, and flows from hot to cold (negative sign).

Give the basic equation for heat transfer in an exchanger and define the overall coefficient.

Q = U A delta-T_lm, where U is the overall heat-transfer coefficient, A the heat-transfer area, and delta-T_lm the log mean temperature difference between the two fluids.

Why are heat-sensitive pharmaceutical fluids often heated in plate or scraped-surface exchangers?

They give high heat-transfer coefficients with short residence times and good temperature control; scraped-surface units also handle viscous/fouling products, minimising thermal damage to thermolabile materials.

Define filtration and the two main mechanisms by which a filter retains particles.

Filtration separates suspended solids from a fluid by passing it through a porous medium. Mechanisms: surface (screen/sieve) filtration - particles larger than pores retained on surface; and depth filtration - particles trapped within the tortuous channels of a thick medium.

State the simplified Darcy/filtration principle relating flow rate to pressure.

Filtration rate is directly proportional to the pressure difference and filter area, and inversely proportional to the fluid viscosity and the resistance of the cake plus medium (dV/dt = (delta-P x A) / (eta x R)).

What is centrifugation and the principle behind it?

Centrifugation separates particles from a liquid (or two liquids) using centrifugal force generated by rapid rotation, which greatly increases the effective gravitational settling per Stokes' law, accelerating sedimentation by density difference.

Differentiate a sedimentation centrifuge from a filtration (perforated) centrifuge.

A sedimentation centrifuge has a solid-walled bowl; solids settle against the wall and supernatant decants (for fine particles/clarification). A filtration centrifuge has a perforated basket lined with filter cloth; liquid passes through and solids are retained as a cake (for coarse crystals, e.g., centrifuge for crystal washing).

Define absolute humidity and relative humidity.

Absolute humidity = mass of water vapour per unit mass of dry air. Relative humidity (RH) = ratio of actual water-vapour partial pressure to the saturation vapour pressure at that temperature, expressed as a percentage.

Why is humidity control critical in pharmaceutical manufacturing?

Humidity affects powder flow and caking, tablet/capsule moisture uptake, drug stability (hydrolysis), microbial growth, electrostatic charge, and effervescent/hygroscopic product integrity; controlled RH ensures product quality and reproducibility.

What is dew point and what does it indicate?

Dew point is the temperature to which air must be cooled (at constant pressure) for water vapour to begin condensing (saturation, 100% RH). A lower dew point indicates drier air; it is a key measure in cleanroom and drying-air control.

What instrument measures humidity, and name a method used in pharmaceutical area monitoring.

A hygrometer measures humidity; the psychrometer (wet-and-dry bulb thermometer) determines RH from the wet-bulb depression using a psychrometric chart. Electronic capacitive/dew-point sensors are used for continuous HVAC monitoring.

What is the basic principle of the vapour-compression refrigeration cycle?

A refrigerant is compressed (compressor), condensed releasing heat (condenser), expanded through a throttle valve (pressure/temperature drop), and evaporated absorbing heat from the load (evaporator). It transfers heat from a low- to a high-temperature region using latent heat of the refrigerant.

Define 'ton of refrigeration' and coefficient of performance (COP).

One ton of refrigeration = rate of heat removal to freeze 1 short ton of water at 0 C in 24 h (about 3.517 kW). COP = useful refrigerating effect / work input; a higher COP means a more efficient system.

What are the main functions of an HVAC (air-conditioning) system in a pharmaceutical facility?

It controls temperature, humidity, air cleanliness (filtration), room pressure differentials, and air-change rates to maintain cleanroom classification, prevent cross-contamination, and ensure product/personnel comfort and GMP compliance.

What type of filter is used in pharmaceutical HVAC to achieve cleanroom air quality, and what is its efficiency?

HEPA (High Efficiency Particulate Air) filters, which remove >= 99.97% of particles of 0.3 micrometre, are used in the supply air to clean rooms (ULPA filters give even higher efficiency for critical zones).

How do positive and negative room pressure differentials protect pharmaceutical products?

Positive pressure (room higher than surroundings) keeps contaminants out, protecting sterile/non-hazardous products. Negative pressure (room lower) contains hazardous/cytotoxic or sensitising materials, preventing their escape to adjacent areas.

What is the difference between batch and continuous operation, with a pharmaceutical example of each?

Batch: a fixed quantity is processed through each step then discharged before the next batch (e.g., a fluidised bed dryer load, a reaction in a stirred kettle). Continuous: material flows in and product flows out steadily (e.g., continuous tablet manufacturing line, continuous distillation column).

Why is copper traditionally used for stills and tubing in some pharmaceutical/water systems despite stainless steel's dominance?

Copper has excellent thermal conductivity (good heat transfer) and is easily fabricated; it was traditionally used for stills and heating coils. However, it can contaminate products with copper ions and corrodes, so stainless steel has largely replaced it for product contact.

What is the heat-transfer significance of the log mean temperature difference (LMTD) versus arithmetic mean in exchangers?

Because the temperature difference between the two fluids varies along the exchanger, the LMTD = (delta-T1 - delta-T2)/ln(delta-T1/delta-T2) gives the correct driving force; using a simple arithmetic mean overestimates the driving force and undersizes the exchanger.