1
Q
What are the three pre‑requisites before pre‑formulation studies begin?
A
Synthesis of the drug with suitable purity (e.g., ~100 mg at ≥99% purity); demonstration of pharmacological activity in animal or cell models; and completion of toxicology studies determining safety.
2
Q
What four development criteria must a pharmaceutical dosage form satisfy during pre‑formulation?
A
1) Effective therapeutic activity, 2) suitable for administration to the patient, 3) chemically and physically stable, and 4) suitable for large‑scale manufacturing.
3
Q
What is the purpose of analytical techniques developed during pre‑formulation?
A
To determine drug identity, quantify (assay) the drug, evaluate purity, and identify potential contaminants or degradation products.
4
Q
Give examples of traditional analytical techniques used in pre‑formulation.
A
Thin Layer Chromatography (TLC), UV/Visible spectroscopy, and basic High Performance Liquid Chromatography (HPLC).
5
Q
Give examples of modern analytical techniques used in drug pre‑formulation.
A
HPLC‑MS, UPLC‑MS, and GC‑MS/MS.
HPLC-MS uses standard high-pressure liquid chromatography for soluble compounds, UPLC-MS offers superior speed and resolution through ultra-high-pressure liquid chromatography, and GC-MS/MS utilizes gas chromatography for volatile, thermally stable compounds, employing tandem mass spectrometry for enhanced sensitivity and structural confirmation
6
Q
What three key characteristics must analytical methods used in pre‑formulation possess?
A
Sensitivity (detect low concentrations), selectivity (distinguish analyte from contaminants), and reproducibility (consistent results across repeated tests).
7
Q
How does particle size influence pharmaceutical formulation?
A
It affects solubility, dissolution rate, bioavailability, sedimentation rate in suspensions, powder flow characteristics, and content uniformity of the final dosage form.
8
Q
Why can irregular crystal shapes complicate pharmaceutical formulation?
A
Uneven crystal shapes reduce powder flowability and make mixing and processing difficult, leading to poor content uniformity in dosage forms.
9
Q
How can crystal shape uniformity be improved during formulation?
A
By particle engineering processes such as crushing or wet granulation.
10
Q
What techniques are commonly used to determine melting point during pre‑formulation?
A
Capillary melting point apparatus, hot stage microscopy, and differential scanning calorimetry (DSC).
11
Q
Why is aqueous solubility an important parameter in pre‑formulation studies?
A
It strongly influences drug dissolution, absorption, and bioavailability after administration.
12
Q
What level of aqueous solubility generally indicates good oral bioabsorption?
A
Aqueous solubility greater than 10 mg/mL across the pH range 1–7.
13
Q
What is intrinsic solubility (Co) and at what temperatures is it commonly measured?
A
The solubility of the neutral form of a drug in water; commonly measured at 4°C and 37°C.
14
Q
How can solubility testing help determine whether a drug is a weak acid or weak base?
A
If a drug is soluble in acidic solution but not in water it is likely a weak base; if soluble in alkaline solution but poorly soluble in water it is likely a weak acid.
15
Q
What does aqueous solubility of a free acid/base below 1 mg/mL indicate?
A
It suggests that a salt form may be required to improve solubility and bioavailability.
16
Q
Why can formation of a salt improve drug formulation?
A
Salt formation can increase aqueous solubility, improve dissolution rate, and enhance oral bioavailability.
17
Q
What is polymorphism and why is it important in pharmaceutical formulation?
A
Polymorphism is the ability of a compound to exist in multiple crystalline forms with different physical properties (e.g., solubility, stability, melting point) that influence drug performance.
18
Q
How does pKa influence drug dissolution in the gastrointestinal tract?
A
Weak bases dissolve better in acidic environments such as the stomach, while weak acids dissolve better in more alkaline environments such as the intestine.
19
Q
What is Log P and why is it relevant in pre‑formulation?
A
Log P is the partition coefficient between octanol and water, representing drug lipophilicity and influencing membrane permeability and absorption.
20
Q
What is the typical acceptable potency for a commercial drug product during shelf life?
A
At least 95% of labeled potency at recommended storage conditions.
21
Q
Why is forced drug stability testing performed during pre‑formulation?
A
To identify degradation pathways and inform formulation strategy, excipient selection, protective additives, and packaging requirements.
22
Q
What three key criteria must excipients meet in a formulation?
A
They must be suitable for the dosage form, used at appropriate concentrations, and compatible with the drug substance.
23
Q
Give an example of a dosage‑form incompatibility involving excipients.
A
Liquid paraffin cannot be used in intravenous formulations due to safety and incompatibility concerns.
24
Q
What is an example of a chemical incompatibility involving preservatives and surfactants?
A
Methyl paraben can interact with non‑ionic surfactants such as Tween 80, reducing antimicrobial activity.
25
What is the Maillard reaction in pharmaceutical formulation?
A condensation reaction between reducing sugars (e.g., lactose) and primary amine drugs that can lead to degradation or discoloration.
26
Name four common oral dosage forms.
Tablets, capsules, oral solutions, oral suspensions, and syrups.
27
What are common diluents or fillers used in oral formulations?
Lactose and starch.
28
What are common binders used in tablet formulations?
Gelatin and povidone.
29
What excipient is commonly used as a disintegrant in oral tablets?
Microcrystalline cellulose (Avicel).
30
What excipient is commonly used as a lubricant in tablet manufacturing?
Magnesium stearate.
31
Give examples of excipients used to improve organoleptic properties.
Sweeteners (saccharin, sorbitol), fruit extracts (citrus), natural colorants (β‑carotene), and artificial flavours or dyes.
32
What does GRAS mean in relation to excipients?
Generally Recognized As Safe — a regulatory designation indicating substances considered safe for use in food or pharmaceutical products.
33
Name common topical dosage forms.
Creams, ointments, gels, and lotions.
34
Give examples of oily bases used in topical formulations.
White soft paraffin (WSP), hard paraffin, liquid paraffin, lanolin, and wool alcohol.
35
Name examples of gelling agents used in aqueous topical formulations.
Carbomer, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose (SCMC), xanthan gum, and poloxamer.
36
What is the role of antioxidants in topical formulations?
They prevent oxidation of active ingredients and excipients, improving product stability.
37
Give examples of antioxidants used in topical formulations.
Vitamin E, ascorbic acid, propyl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA).
38
Name examples of skin penetration enhancers used in topical formulations.
Ethanol, propylene glycol, glycofurol, transcutol, and crodamol GTCC.
39
What are two advantages of topical drug delivery?
Ease of application for patients and relatively simple large‑scale manufacturing.
40
What are two disadvantages of topical drug delivery?
Limited systemic absorption for many drugs and difficulty controlling precise dosage.
41
What are the two main types of emulsions used in creams and their HLB ranges?
Oil‑in‑water emulsions (HLB 8–16) and water‑in‑oil emulsions (HLB 3–6).
42
What key requirements must ophthalmic formulations meet?
They must be sterile, isotonic, and formulated with suitable buffers and preservatives.
43
What solvent is typically used in ophthalmic solutions?
Purified water.
44
Name three common routes of parenteral administration.
Intravenous (IV), intramuscular (IM), and subcutaneous (SC).
45
What defines small volume parenterals (SVP)?
Injections typically between 0.1 mL and 1.5 mL administered as single bolus doses.
46
What defines large volume parenterals (LVP)?
Infusion products typically greater than 100 mL administered intravenously over time.
47
What are the key requirements for parenteral formulations?
They must be sterile, isotonic, and free of pyrogens.
48
Why is particle size critical in intramuscular depot injections?
Particles must be smaller than ~5 µm to allow controlled dissolution and absorption without causing tissue damage.
49
What is the normal physiological pH of blood?
Approximately pH 7.4.
50
What is the typical blood osmolality range?
280–303 milliosmoles.
51
Give examples of tonicity modifiers used in parenteral formulations.
Sodium chloride, dextrose, and mannitol.
52
What particle size is required for pulmonary drug delivery to reach the lungs?
Particles smaller than 5 µm in diameter.
53
Name three inhalation delivery devices.
Nebulisers, Metered Dose Inhalers (MDIs), and Dry Powder Inhalers (DPIs).
54
What propellants are commonly used in MDIs?
Fluorinated hydrocarbons such as HFA‑134a and HFA‑227.
55
What is the typical carrier particle used in dry powder inhalers?
Lactose particles with sizes between 50–250 µm.
56
What are two major advantages of rectal drug administration?
It can be used when oral administration is impossible and can bypass first‑pass metabolism.
57
What is the typical vaginal pH and why is it relevant to formulation?
Approximately pH 4; formulations must remain stable and effective under acidic conditions.
58
What is the purpose of a medicines recall?
To protect patient safety when a medicinal product is defective, substandard, or potentially harmful.
59
Which UK body oversees medicines recalls?
The MHRA (Medicines and Healthcare products Regulatory Agency).
60
What is the Yellow Card Scheme used for?
Post-marketing surveillance and reporting of suspected medicine defects or adverse reactions.
61
What defines a Class 1 medicines recall?
Life-threatening or serious risk requiring immediate action.
62
What defines a Class 2 medicines recall?
Could cause harm; action required within 48 hours.
63
What defines a Class 3 medicines recall?
Unlikely to cause harm; action required within 5 days.
64
What defines a Class 4 medicines recall?
Caution in use; no physical recall required.
65
Which recall class is most urgent?
Class 1.
66
What defect triggered the Zomorph® Class 1 recall example?
Homogeneity failure causing variable morphine dose.
67
Why are opioids particularly high risk in recalls?
They have a narrow therapeutic index and overdose risk.
68
What is the pharmacist’s first action during a recall?
Immediate stock checking.
69
Where must stock be checked during a recall?
Dispensary, CD cabinets, fridges, robots, off-site storage.
70
What does quarantining stock involve?
Removing, segregating, labelling, and preventing dispensing.
71
How long must recall documentation be retained?
5 years.
72
What are the pharmacist’s two main roles during a recall?
Operational compliance and clinical patient safety.
73
Define drug stability (full definition).
The ability of a pharmaceutical product to maintain its chemical, physical, microbiological, toxicological, and therapeutic integrity over time.
74
List 5 common signs that a product has become unstable.
Loss of potency (API loss), toxic degradants, changes in appearance/physical state, changes in solubility/precipitation, changes in pH/colour/odour.
75
Why does poor stability create a patient safety risk even if the product ‘looks fine’?
Potency can fall below therapeutic levels and/or harmful degradation products may form without obvious visual change.
76
What is the main purpose of stability testing?
To establish shelf-life (expiry), storage conditions, and suitable packaging by assessing effects of temperature, humidity, light, oxygen, etc.
77
What is the formal shelf-life threshold for API content?
Shelf-life ends when API content falls below 90% of the original (t90 concept).
78
What are the 3 main shelf-life ‘failure’ criteria besides API <90%?
Degradants exceed limits, physical changes make product unusable, microbial/preservative failure (as relevant).
79
State the Q10 rule.
Reaction rate approximately doubles for every 10°C increase in temperature.
80
What does the Arrhenius equation model in stability science?
The exponential relationship between temperature and degradation rate constant (k).
81
Write the Arrhenius equation (symbol form).
k = A · e^(−Ea/RT)
82
In the Arrhenius equation, what does k represent?
The degradation rate constant.
83
In the Arrhenius equation, what does A represent?
The pre-exponential (frequency) factor—constant for a given reaction.
84
In the Arrhenius equation, what does Ea represent?
Activation energy for the reaction.
85
In the Arrhenius equation, what does R represent?
The ideal gas constant.
86
In the Arrhenius equation, what does T represent?
Absolute temperature in Kelvin.
87
Why can Arrhenius-based shelf-life extrapolation be imprecise?
High temperatures can change mechanisms, create secondary degradants, alter oxygen solubility (liquids), alter moisture availability (solids), and melt semi-solids (invalidating kinetics).
88
List 4 ways high temperature can destabilise medicines.
Faster reaction rates; promotes hydrolysis/oxidation/polymerisation; can denature proteins; may trigger polymorphic transitions/precipitation (esp. temperature cycling).
89
Give 2 examples of drugs that degrade significantly at >40°C (from notes).
Lorazepam and diazepam can degrade substantially (>40°C).
90
Give an example of a biologic destabilised by temperature/mechanical stress.
Insulin can denature/aggregate.
91
Give an example of an API with potency loss between 25–55°C (from notes).
Paclitaxel shows potency drop across ~25–55°C.
92
What pH range are most drugs relatively stable in?
Approximately pH 4–8.
93
Give 2 examples of acid-labile drugs (from notes).
Erythromycin and penicillin (also paclitaxel listed as acid-labile).
94
Give an example of a base-labile drug (from notes).
Indomethacin.
95
Why do extreme pH values accelerate hydrolysis?
Acid/base catalysis increases rate of cleavage of susceptible functional groups (e.g., esters, amides, lactams).
96
Example pH trap: Procaine hydrolysis is rapid at what pH (from notes)?
Procaine hydrolyses rapidly at pH 4.
97
Example pH trap: Penicillin G degrades how fast in acid (from notes)?
Penicillin G can degrade within minutes in acidic conditions.
98
Example pH trap: What does low pH do to tetracycline (from notes)?
Low pH can lead to formation of epitetracycline/epimerisation-related products.
99
List 3 oxidation mechanisms mentioned in the notes.
Autoxidation (free-radical chain), photo-oxidation, and metal-catalysed oxidation.
100
Name 3 drug/classes especially susceptible to oxidation (from notes).
Catecholamines (dopamine/adrenaline), phenothiazines, retinoids (also morphine, unsaturated lipids).
101
Name 3 metal contaminants that can catalyse oxidation (from notes).
Copper (Cu), iron (Fe), nickel (Ni).
102
Oxidation exam trap: what visible/organoleptic changes often suggest oxidation?
Colour change and/or odour formation (oxidation can produce coloured/odorous products).
103
What happens to sulphur-containing proteins during oxidation (from notes)?
Thiol (–SH) groups can oxidise to form disulphide bonds.
104
List 3 photolysis outcomes caused by UV/visible light.
Bond cleavage, isomerisation, and oxidation.
105
Give 4 examples of photosensitive substances from the notes.
Retinoids (e.g., isotretinoin), prednisolone, hydrocortisone, nifedipine (also riboflavin/folate, benzodiazepines).
106
What packaging strategy is first-line for photolabile drugs?
Opaque or light-resistant packaging (e.g., amber containers).
107
What is the most common chemical degradation pathway in pharmaceuticals?
Hydrolysis.
108
List 6 functional groups susceptible to hydrolysis (from notes).
Esters, amides, lactams, lactones, carbamates, anhydrides.
109
What does water activity (Aw) represent?
The availability of water for reactions (not just total water content).
110
At what Aw is hydrolysis very slow (from notes)?
Aw < 0.25 → very slow hydrolysis.
111
What does Aw = 1 correspond to (from notes)?
Equivalent to ~20% water content (as stated in the notes).
112
Aspirin hydrolysis produces which products?
Salicylate and acetate.
113
How can damaged packaging accelerate tablet degradation?
Moisture ingress increases hydrolysis and other reactions.
114
Besides hydrolysis, what other risk does moisture increase?
Microbial growth (especially in aqueous preparations).
115
Why must drugs be tested alone AND with excipients during stress testing?
Excipients may change pH/water activity or introduce trace metals that initiate/accelerate degradation (especially oxidation).
116
Give an example of an excipient/buffer that accelerates degradation (from notes).
Sodium phosphate buffer can increase codeine hydrolysis ~20-fold.
117
How can metal ions in excipients affect stability?
They can catalyse oxidation reactions.
118
What is a common strategy to reduce metal-catalysed oxidation?
Add chelating agents to bind trace metals (e.g., EDTA).
119
Name two antioxidants listed in the notes.
BHT and EDTA (EDTA also acts as a chelator).
120
Name 2 storage strategies to reduce hydrolysis.
Moisture-barrier packaging and using water binders / controlling water activity (e.g., PEG noted; plus optimal pH buffering).
121
Name 3 storage strategies to reduce photodegradation.
Amber/opaque packaging, light-protective outer cartons, avoid sunlight exposure.
122
Name 3 storage strategies to reduce oxidation.
Oxygen-barrier packaging, antioxidants, and chelators (plus limiting headspace oxygen).
123
How can mechanical stress destabilise protein drugs?
Agitation can cause denaturation, aggregation, and precipitation.
124
Give an example of a mechanical-stress sensitive product (from notes).
Insulin (also antibodies/biologics).
125
Define solvolysis in the context of stability.
Degradation via solvent-mediated nucleophilic attack (often in aqueous systems).
126
Give an example of a drug susceptible to nucleophilic attack/solvolysis (from notes).
Midazolam (also alprazolam, fluocinolone listed).
127
List 5 types of isomerisation/structural transformations in degradation.
Racemisation, epimerisation, tautomerisation, cis–trans isomerisation, structural rearrangements.
128
Give an example of racemisation from the notes.
Atropine/Hyoscyamine racemisation.
129
Give an example of tautomerisation from the notes.
Tetracycline tautomerisation.
130
Give an example of cis–trans isomerisation from the notes.
Cisplatin converting to transplatin.
131
Which types of molecules commonly polymerise (from notes)?
Peptides, amino-penicillins (e.g., ampicillin), catecholamines, nucleotides.
132
Why is polymerisation clinically relevant?
It can reduce potency and may create immunogenic/toxic aggregates (esp. proteins/peptides).
133
Give an example of a nephrotoxic degradant from the notes.
Tetracycline → anhydro-4-epi-tetracycline (nephrotoxic).
134
Give an example of a potentially hepatotoxic degradant from the notes.
Paracetamol → p-aminophenol (hepatotoxic at high levels).
135
Why must degradants be monitored even if API remains >90%?
Degradants may exceed safety limits before API drops below 90%.
136
What packaging is recommended for oxygen-sensitive drugs (from notes)?
Amber glass (also oxygen-resistant containers).
137
What is the purpose of moisture-barrier materials?
Prevent water ingress to slow hydrolysis and microbial growth.
138
Why might packaging redesign be needed after photostability testing?
If drug degrades even in final pack, stronger light protection is required (e.g., chlorpromazine example in notes).
139
Which method is used for trace moisture content testing (from notes)?
Karl Fischer coulometric titration.
140
What is the principle of Karl Fischer titration (one line)?
Iodine-based redox reaction quantifies water content at trace levels.
141
What are the two main phases of stability testing described?
Pre-formulation stress testing (short-term) and long-term stability testing (shelf-life determination).
142
What is the goal of pre-formulation (stress) testing?
Determine intrinsic stability and guide formulation/excipient/packaging decisions.
143
List 4 stress tests used in pre-formulation.
Hydrolysis (water/acid/base), oxidation (±oxygen), photostability (UV/visible), and excipient compatibility testing.
144
What is the goal of long-term stability testing?
Define real-world shelf-life once formulation and packaging are finalised.
145
What is a typical ‘survey/initial’ stability testing duration (from notes)?
About 6 months.
146
What is the minimum long-term stability testing duration (from notes)?
At least 12 months.
147
What is the ideal long-term stability testing duration (from notes)?
24–36 months.
148
State the commonly used accelerated stability condition from the notes.
40°C / 75% RH.
149
SAQ trap: Why are 40°C / 75% RH conditions selected?
They represent severe tropical ‘worst-case’ conditions, accelerating heat-driven reactions and humidity-driven hydrolysis to assess global suitability and predict shelf-life faster.
150
What does increased humidity mainly accelerate?
Hydrolysis (and can increase microbial risk in aqueous systems).
151
What does increased temperature mainly accelerate?
Most chemical reaction rates (hydrolysis, oxidation, polymerisation) via Arrhenius behavior.
152
What are WHO climatic zones based on?
Mean annual temperature (MAT) and mean annual water vapour pressure (MAWVP).
153
Climatic Zone I: describe and give example locations.
Temperate: 21°C + 2°C / 45% RH + 5%
UK, USA, Northern Europe.
154
Climatic Zone I long-term test setup (from notes table).
21°C / 45% RH.
155
Climatic Zone II: describe and give example locations.
Subtropical/Mediterranean: Japan, Southern Europe.
156
Climatic Zone II long-term test setup (from notes table).
25°C / 60% RH.
157
Climatic Zone III: describe and give example locations.
Hot/dry: Iraq, India.
158
Climatic Zone III long-term test setup (from notes table).
30°C / 35% RH.
159
Climatic Zone IVa: describe and give example locations.
Hot/humid: Iran, Egypt.
160
Climatic Zone IVa long-term test setup (from notes table).
30°C / 65% RH.
161
Climatic Zone IVb: describe and give example locations.
Very hot/very humid: Brazil, Singapore.
162
Climatic Zone IVb long-term test setup (from notes table).
30°C / 75% RH.
163
What additional stability conditions may be used for cold-chain products?
Refrigerated (~5°C) and frozen (~−15°C) conditions when applicable.
164
Which degradation pathway is a major issue for isotretinoin (from notes list)?
Photo-oxidation to 4-oxo-tretinoin (photosensitivity).
165
Which degradation pathway affects chlorhexidine (from notes list)?
Ion hydrolysis.
166
Which pathway is highlighted for cephalosporins in the notes list?
Isomerism-related degradation.
167
Which pathway can produce an ocular toxin in ethambutol (from notes list)?
Isomerisation from (S,S) to (R,R) isomer (ocular toxin).
168
Paracetamol degrades by which mechanism (from notes list)?
Acid/base hydrolysis.
169
Folic acid is degraded by which conditions (from notes list)?
Acid and UV hydrolysis.
170
Cisplatin is unstable under what conditions (from notes list)?
pH > 6 and light (bond cleavage).
171
Indomethacin degrades via what mechanism (from notes list)?
OH⁻-ion based hydrolysis.
172
Doxorubicin degrades via which mechanisms (from notes list)?
Acid/base hydrolysis and oxidation.
173
Give 3 possible ‘indicator’ changes that suggest degradation to a patient/pharmacist.
Colour change, unusual odour, precipitation/cloudiness (in liquids), tablet softening/crumbling.
174
What is a classic indicator of paracetamol degradation mentioned in the notes?
Acetic odour indicating breakdown.
175
Why should pharmacists consider preservative stability during shelf-life studies?
Preservatives can lose potency too, increasing microbial risk even if API is acceptable.
176
Challenges to effective action in sustainable pharm
Recycling “rate” is poor Health and safety concerns Restrictive regulation – involves a complex process of re-testing Collection costs Recycling costs Manufacturing capacity Environmental impact – low priority
177
What is the aim of sustainable medicine manufacturing?
To improve global pharmaceutical manufacturing using cleaner synthesis and reduced environmental impact.
178
What does sustainable manufacturing require across the supply chain?
Collaboration across organisations + adherence to Green Chemistry, Waste Prevention, and Circular Economy principles.
179
What are the 3 pillars of sustainable manufacturing?
Green Chemistry; Waste Prevention; Circular Economy.
180
Define atom economy.
Maximising incorporation of reactant atoms into the final product to reduce waste.
181
What is cleaner synthesis?
Routes minimising waste, hazards, energy, and environmental impact.
182
Why is hazard-reduction synthesis important?
Reduces worker, patient, and environmental risk by using safer reagents.
183
What is safer chemical design?
Assess hazards before use; design chemicals that are inherently safer.
184
Examples of unsafe/common laboratory solvents.
Benzene; toluene; xylene; methanol; acetone; ethyl acetate.
185
What is meant by 'design with degradation in mind'?
Designing chemicals that degrade into non-toxic, non-persistent by-products.
186
What is real-time pollution prevention?
Monitoring and preventing waste/emissions during synthesis.
187
Why is catalysis important in green chemistry?
Increases selectivity, reduces energy, decreases waste.
188
What does waste prevention favour?
Preventative action over reparative waste management.
189
Why minimise derivatives/by-products?
They reduce atom economy and increase process waste.
190
Define circular economy.
Keeping products/materials in circulation as long as possible.
191
Processes enabling circularity.
Maintenance; reuse; refurbishment; remanufacture; recycling; composting.
192
Define resource efficiency.
Achieving more output using fewer resources and lower environmental impact.
193
What are the 2 core enablers of sustainable pharma?
Regulation; Measurement/Standards/Data.
194
Examples of regulatory bodies/treaties.
UN SDGs; COP30; EPA.
195
Define carbovigilance.
Awareness/monitoring of carbon footprint.
196
What % of UK carbon footprint is from Healthcare?
5–7%.
197
What % of Healthcare carbon footprint is from pharmaceuticals?
16–25%.
198
What % of MSW is pharmaceutical waste?
2–3%.
199
What % of pharma’s carbon footprint is from manufacturing?
0.7
200
Breakdown of manufacturing footprint.
Formulation 5–11%; Processing 45–70%; Other 25–45%.
201
% from API/excipient synthesis.
0.18
202
% from packaging.
3–7%.
203
Why is mixed plastic waste difficult to recycle?
It contains incompatible polymers.
204
Examples of hazardous pharmaceutical waste.
Chlorinated hydrocarbons; dioxins; electroplating waste; leachate; refinery sludges; spent solvents.
205
Why are wastewater sludges/tars/activated carbon residues hazardous?
They contain acute toxins like arsenic and organo-arsenic compounds.
206
CO₂ eq produced per £1M spent by pharma vs automotive.
Pharma 50 t CO₂-eq; Automotive 30 t CO₂-eq.
207
Define GWP-100.
Climate warming potential over 100 years (CO₂ = 1 reference).
208
GHG with the highest GWP.
SF₆ (up to 22,800).
209
GWP ranges for medical anaesthetic gases.
130–2540.
210
GWP ranges for HFCs.
124–14800.
211
GWP for PFCs.
7390–12200.
212
Why do MDIs contribute to GHG emissions?
They use HFC propellants.
213
Agreements regulating inhaler propellants.
Montreal 1987; FDA 2009; Paris 2016; Kigali 2016.
214
Propellants currently used in MDIs.
HFC-134a; HFC-227ea.
215
Why are halides concerning in pharma?
Strong GHGs + toxic incineration by-products.
216
Examples of halogenated packaging polymers.
CPE; PVC; PVdC; PVF; PVdF; PCTFE; PTFE.
217
Incineration by-products of halogenated plastics.
CxHyClz or CxHyFz gases.
218
Why does aluminium smelting generate fluorinated waste?
It uses cryolite (Na₃AlF₆).
219
GHG shares of total pollution.
CO₂ 80%; CH₄ 10%; NOx 7%; others 3%.
220
Which gas causes most radiative forcing impact?
NOx (~89.2% due to high GWP).
221
Which healthcare activity produces the most carbon?
Hospitals (40%).
222
Biggest contributor to pharma carbon footprint?
Manufacturing (70%).
223
Environmental drawback of blister packaging?
High carbon footprint; halogenated plastic use.
224
Which GHG has the longest atmospheric lifetime?
PFCs (up to 50,000 years).
225
Data definition
Information (stats, quantities, images, characters) used as a basis for reasoning, discussion, or calculation; stored electronically.
226
Key stages benefiting from ML in drug discovery
Pre-discovery, discovery, molecule development, medicine development, clinical trials, licensing, manufacturing, supply.
227
Total timeline for making a new medicine
Typically 10–15 years.
228
Why data is important in drug development
Data is generated at every stage; informs safety, dosing, efficacy, formulation, manufacturing and regulatory decisions.
229
Examples of data types in drug development
Safety data, dose data, adverse effects, physicochemical data, clinical data.
230
Big data – key characteristics
Volume, velocity, variety, veracity (truthfulness).
231
Future scale of data growth
Zettabytes (10^21).
232
Common sources of big data
Wireless sensors, mobile devices, remote sensing, RFID, IoT devices, clinical trial data.
233
Key issues in big data management
Security, privacy, sensitivity, ethics.
234
Pharma modelling cycle
Design → Make → Test → Analyse.
235
High-throughput screening definition
Rapid automated testing of large numbers of compounds to identify activity.
236
Main challenges in pharmaceutical development
High costs, high IND failure rate, limited surveillance insight, need for modelling.
237
Data literacy definition
Ability to read, write, manage and communicate data in context; understanding data sources and handling techniques.
238
Disciplines within data literacy
Statistics, computing, visualisation, algorithms.
239
Why high data literacy matters
Improves decisions, increases productivity and innovation.
240
Core components of DL framework
Data collection, management, evaluation, application, communication.
241
Data mining definition
Sorting through large datasets to identify patterns and relationships useful for solving problems.
242
Machine learning definition
Algorithms that learn patterns from large datasets to enable prediction and pattern extraction.
243
AI layered structure
Inner layer: infrastructure; Middle layer: ML algorithms; Outer layer: service delivery.
244
Most common AI techniques in drug development
ML (28%) and deep learning (17%).
245
Most common use of AI in drug discovery
Drug molecule discovery (76%).
246
Example AI system in drug design
AtomNet – structure-based deep learning model.
247
Purpose of process modelling
Represent and analyse physical, chemical, and manufacturing processes (energy, mass, heat flows).
248
What PFD stands for
Process Flow Diagram.
249
Use of swim-lane diagrams
Shows tasks divided by role or department (e.g. A, B, C).
250
Drug development pipeline steps
Target ID → Screening → Chemistry → Animal studies (PK/PD) → Phase I → Phase II → Phase III → Phase IV → Launch.
251
Academic vs industry modelling focus
Academic: systems biology & computational modelling; Industry: cost, safety, timelines.
252
CADD definition
Computer-aided drug design including modelling, docking, virtual screening, QSAR, pharmacophores.
253
Structure-based drug design definition
Uses 3D protein structures to design molecules that bind optimally.
254
Ligand-based drug design definition
Uses activity of known ligands to derive pharmacophore/QSAR models.
255
Molecular docking definition
Predicting ligand binding orientation and affinity in a target protein.
256
QSAR definition
Quantitative Structure–Activity Relationship; mathematical modelling linking molecular features to biological activity.
257
Pharmacophore definition
Abstract arrangement of features necessary for molecular recognition.
258
Examples of drugs developed using CADD
Erdafitinib (FGFR inhibitor, 2019), Dacomitinib (EGFR inhibitor, 2018).
259
Protein–protein interaction modelling purpose
Understanding surfaces and binding interfaces (e.g., APC–Asef interaction).
260
Molecular input architecture
Encoder → compressed code → decoder producing reconstructed molecular structures.
261
Role of simulation in CADD
Molecular dynamics to observe ligand–protein interactions over time.
262
Key topics covered in lecture
Pathway to new therapeutics, big data, data literacy, ML, AI, process modelling, CADD.
263
Purpose of Quality Testing
Ensures medicines are safe, effective, consistent, stable, and produced according to GMP.
264
What Quality Testing Applies To
Raw materials, intermediates, final dosage forms, and packaging components.
265
Regulatory Standards
Defined by BP, EP, USP, and ICH Q guidelines.
266
Role of GMP in Quality Testing
GMP provides environment, personnel training, equipment, and documentation standards that ensure quality.
267
GMP – Premises
Designed to minimise contamination and mix-ups; require environmental controls (airflow, humidity, dust).
268
GMP – Personnel
Must be properly trained and wear protective apparel.
269
GMP – Equipment
Must be properly designed, calibrated, maintained, cleaned, and validated.
270
GMP – Documentation
Includes SOPs, batch records, QC logs, cleaning validation.
271
QC Requirements
Verify raw material identity, purity, API content, impurities, degradation products, finished product quality, packaging integrity.
272
Gravimetric Analysis
Quantification by precise mass measurement; used for moisture content, inorganic impurities (ash).
273
Gravimetric Pros/Cons
Advantage: very accurate; disadvantage: slow and labour-intensive.
274
Volumetric (Titrimetric) Analysis
Uses titrations (acid–base, redox, complexometric); measures API assay, preservatives, acidity, ion content.
275
Acid–Base Titration
Determines acidic or basic substances; used for vitamin C, aspirin, NaOH quantification.
276
Karl Fischer Titration
Measures water content using reaction: I₂ + SO₂ + H₂O → 2 HI + SO₃; extremely sensitive.
277
Karl Fischer Applications
Lactose, sorbitol, gelatin, powders, lyophilised products.
278
Chromatography Purpose
Separates mixture components for identification and quantification.
279
Chromatography Principle
Mobile phase carries analyte; stationary phase interacts; differences cause separation.
280
Gas Chromatography (GC)
Used for volatile compounds and residual solvent detection; often headspace GC.
281
GC Applications
Solvent screening, impurity profiling, volatile degradant detection.
282
HPLC / Liquid Chromatography
Most widely used QC method for APIs, impurities, degradants, stability testing, complex mixtures.
283
Reverse-Phase LC
Uses non-polar stationary phase (C18); polar mobile phase.
284
Normal-Phase LC
Uses polar stationary phase; non-polar mobile phase.
285
Polarity Order (Low → High)
Alkyl < aromatic < halides < sulfides < ethers < nitro < esters/aldehydes/ketones < alcohols/amines < amides < carboxylic acids < water.
286
Size Exclusion Chromatography
Separates by molecular size; large molecules elute first, small molecules later.
287
SEC Applications
Protein analysis, polymer sizing, monoclonal antibody QC.
288
LC-MS
Combination of LC separation with MS mass identification.
289
LC-MS Uses
Impurity ID, metabolite analysis, structural elucidation, trace analysis.
290
Chromatogram Output
Plot of detector response vs retention time.
291
Retention Time (tR)
Time analyte takes to elute; used for qualitative ID.
292
Peak Area / Height
Proportional to analyte concentration; used for quantification.
293
Peak Shape & Resolution
Good chromatography shows sharp, symmetrical, well-resolved peaks with baseline separation.
294
Poor Resolution Indicates
Method issues, column degradation, or poor mobile phase selection.
295
Validated Analytical Method Criteria
Must be accurate, precise, specific, sensitive, robust, reproducible; validated under ICH Q2.
296
Foundational Techniques to Revise
UV–Vis, IR spectroscopy, TLC (from PY413).
297
QC Testing Summary
Understand GMP’s role, QC tests for raw materials and finished products, main analytical techniques, chromatography interpretation, LC-MS value.
298
Good Manufacturing Practice (GMP)
Regulatory framework ensuring medicines are consistently produced and controlled to quality standards appropriate for their intended use.
299
GXP
General term for “Good Practices” including GCP, GLP, GMP, GDP, etc., forming a framework for quality and compliance.
300
Good Clinical Practice (GCP)
Standards for designing, conducting, recording, and reporting clinical trials to ensure credibility and participant protection.
301
Good Laboratory Practice (GLP)
Quality system concerning the organisational process and conditions under which non-clinical health and environmental studies are conducted.
302
Good Manufacturing Practice (GMP)
Regulations ensuring products are consistently high quality, safe, and effective.
303
Good Automated Manufacturing Practice (GAMP)
Framework for computerised systems in pharmaceutical manufacturing.
304
Good Validation Practice (GVP)
Standards ensuring processes consistently produce expected results.
305
Good Distribution Practice (GDP)
Standards ensuring quality is maintained throughout the distribution/supply chain of medicinal products.
306
cGMP (Current GMP)
Modern GMP framework emphasising state-of-the-art systems, continual improvement, updated standards.
307
Key cGMP Component: Trained Personnel
Staff must be appropriately educated, trained, and qualified to perform GMP roles.
308
Key cGMP Component: Premises & Equipment
Facilities must be appropriately designed, maintained, and validated to prevent contamination and mix-ups.
309
Key cGMP Component: QP Approved Procedures
All manufacturing steps must follow procedures authorised by the Qualified Person (QP).
310
Key cGMP Component: Suitable Storage & Logistics
Materials and products must be stored and transported in conditions that maintain quality.
311
Key cGMP Component: Batch Recall Procedures
Systems must enable rapid, effective recall of any defective batch.
312
Key cGMP Component: Detailed Records
Documentation must ensure traceability, data integrity, and compliance.
313
MI2 Cycle (Sarker 2008)
Model describing manufacturing improvement and investigation cycles (exact detail not provided).
314
Quality by Design (QbD)
Systematic approach to development beginning with predefined objectives, emphasising understanding processes and controlling variability.
315
QbD Equation
QbD = QA × (Good Practice “GCP + GMP + GLP”).
316
Quality Management System (QMS)
Overall system integrating policies, processes, and procedures across R&D, QA, and product lifecycle to ensure quality.
317
Three Golden Rules of Good Practice
Honesty, rigour, and sound scientific basis.
318
Total Quality
Philosophy where the entire organisation contributes to continual quality improvement.
319
Suitability for Release Criteria
Finished product must meet specification, licence, purity, consistency, and quality standards.
320
QSE
Quality, Safety, Efficacy—core criteria for medicinal product acceptability.
321
Clean Room Production
Controlled environments for sterile production, based on particulate classification (e.g., Class 100, 10,000, 100,000).
322
Clean Room Particulates
Particles in 0.5–5 µm range must remain below class-specific concentration thresholds.
323
Risk Zones for Sterile Products
Spatial classifications based on contamination risk (higher risk → stricter controls).
324
Qualified Person (QP)
Registered professional responsible for certifying that each batch meets regulatory and quality standards.
325
QP Requirements
Degree + professional registration + postgraduate qualification or equivalent experience.
326
QP Responsibilities
Ensure product quality, protect patient safety, uphold professional/ethical standards, and ensure organisational compliance.
327
MCQ Example – Grünenthal Drug
Thalidomide.
328
Difference Between QA and QC
QA = systems/processes to ensure quality; QC = analytical testing of materials/products to confirm quality specifications.
329
Quality Assurance (QA)
Systems ensuring processes are designed to achieve consistent quality, including SOPs and validation.
330
Quality Control (QC)
Testing activities confirming product quality (e.g., assays, purity, microbiological tests).
331
Patents Importance
Protect innovation, allow recovery of R&D costs, support market exclusivity, incentivise development of new medicines.
332
333
Primary packaging definition
Directly encloses and protects the drug (e.g., blister, bottle, ampoule).
334
Secondary packaging definition
Carton/box that protects primary packaging and groups multiple units for warehousing.
335
Tertiary packaging definition
Outer transport packaging such as pallets, hoppers, and overwraps used for bulk handling and shipping.
336
Main goals of pharmaceutical packaging
Contains, protects, preserves, transports, informs, and sells the product.
337
Physical protection examples
Sunlight, mechanical shock, vibration, electrostatic discharge, compression, temperature.
338
Barrier protection role
Prevents ingress/egress of oxygen, CO₂, water vapour, microbes, and enzymatic contamination.
339
Common packaging additives
Oxygen scavengers, plasticisers, handling agents, preservatives, pigments.
340
Function of oxygen scavengers
Remove oxygen to reduce oxidation of sensitive drug products.
341
Examples of smart materials
Nanoparticles that indicate mechanical injury, temperature abuse, or tampering.
342
Role of plasticisers
Increase flexibility of plastics and improve thermoforming.
343
Examples of handling aids
Slip agents that reduce friction and improve processing.
344
Common pigments in packaging
Titanium dioxide, anthraquinones, azo dyes, carbon black, aluminium, iron oxides.
345
Polypropylene film properties
No plasticisers, non-toxic, recyclable, moderate oxygen/water vapour barrier, thermoformable.
346
Aluminium foil properties
Excellent barrier to air, water vapour, and light; used for sensitive products.
347
PET film properties
Good heat resistance, stable.
348
LDPE film properties
Cheap, versatile, commonly used for shrink applications.
349
HDPE film properties
High moisture barrier, rigid.
350
PVC film properties
High clarity and stiffness, low–medium O₂/WV barrier, toxic on incineration, needs plasticisers.
351
Laminated paper properties
Cheap with some water resistance.
352
Factors in container selection
Cost, volume, robustness, properties, environmental impact, utility, patient compliance.
353
Cheapest packaging materials
PE, PP, PET, PVC (~£0.5/kg).
354
Most expensive packaging materials
Laminate films (£3.0–5.4/kg), aluminium (£3.1/kg), PS/PC/PA (~£2.6/kg).
355
Most commonly used packaging materials
Polyethylene (largest globally), paperboard (for cartons).
356
Basic chemical formula of polyethylene
(C₂H₄)ₙH₂.
357
General properties of polyethylene
Strong, resilient, acid/base resistant, oxidation-resistant, impermeable (especially cross-linked).
358
Classification of PE
By molecular weight and density.
359
HMWHDPE uses
Ultra-high MW; used in hip joints, bulletproof vests, machine parts.
360
HDPE uses
Bottles, skips, drums; density >0.941 g/cm³.
361
MDPE uses
Bottle closures, pack films; density 0.926–0.94 g/cm³.
362
LLDPE uses
Bags requiring puncture resistance; density 0.915–0.925 g/cm³.
363
LDPE uses
Bags, shrink-wrap; density 0.91–0.94 g/cm³.
364
VLDPE uses
Stretch-wrap, cling-film, bubble-wrap.
365
CPE (chlorinated PE) properties
Oxygen and solvent resistance.
366
PEX/XPE properties
Cross-linked; used for corrosives and high chemical resistance; thermoset polymer.
367
Paper and cardboard composition
95% cellulose, 5% lignin.
368
Cellulose structure
β(1→4) D-glucose polymer, 10–100k monomers.
369
Packaging test categories
DSC, gas transmission (WVTR, CO₂/O₂), thickness, mechanical strength, tensile, Young’s modulus, hardness/impact, burst pressure, density/porosity.
370
Definition of WVTR
Water Vapour Transmission Rate.
371
Definition of OTR
Oxygen Transmission Rate.
372
Highest moisture barrier materials
Aluminium, glass (WVTR = 0).
373
Lowest moisture barrier examples
LDPE (1.7–2.5), PVC (2.4–4.0).
374
Examples of excellent oxygen barriers
Aluminium, glass (OTR = 0).
375
Examples of poor oxygen barriers
LDPE (241), PS (127), PC (114).
376
High density polymer characteristics
Efficient chain packing → high strength, high melting point.
377
Low density polymer characteristics
More branching → weaker packing, lower melting point, more flexible.
378
Essential QC tests for packaging
Visual, identity, dimensional, physical (e.g., Tm/Tg), chemical (plasticisers/impurities), microbiological contamination.
379
Cause of haze in polymers
Presence of crystallites/spherulites that scatter light.
380
Definition of blister pack
Pharmaceutical “push-through pack” (PTP).
381
Blister pack webbing
Polymer laminates or copolymers forming the formed cavities.
382
Blister pack backing
Aluminium or coated aluminium.
383
Main purposes of pharmaceutical packaging
Protection (physical, chemical, microbiological), opacity (UV protection), leakage prevention.
384
Risk of extractables/leachables
Plasticisers or impurities migrating into the drug.
385
Common oxygen scavenger antioxidants
BHT, propyl gallate.
386
Examples of common plasticisers
DEHP, DIOP, DBP, DEHA.
387
Examples of falsified medicine contaminants
No/wrong API, incorrect dose, starches, chalk, pesticides, solvents, brick dust, paint, floor wax, bacteria.
388
Types of packaging (summary)
Primary, secondary, tertiary.
389
Key reasons for container selection
Cost, robustness, chemical compatibility, environmental impact, patient compliance.
390
Most abundant plastic globally
Polyethylene.
391
Major use of medical plastics
40–50% used once.
392
Paperboard main use
Cartons and secondary packaging.
393
Difference between thermoplastic and thermoset
Most plastics are thermoplastics; cross-linked PE (PEX) is thermoset and cannot be remelted.
394
Role of laminated films
Increase barrier properties and mechanical strength.
395
Importance of opacity in packaging
Prevents photodegradation of light-sensitive drugs.
396
Why PVC is problematic
Difficult to recycle, toxic when incinerated, requires plasticisers.
397
Why aluminium is used in pharma
Perfect moisture/oxygen barrier, protects from light.
398
Environmental concerns in packaging
Renewability, extraction/synthesis impacts, disposal/recycling.
399
Examples of renewable materials
Paper, some bioplastics.
400
Reasons plastics dominate packaging
Cheap, strong, versatile, good barrier properties, easily manufacturable.
401
WVTR meaning in dosage storage
Indicates moisture barrier performance—critical for hygroscopic drugs.
402
Why HDPE is common for bottles
Strong, high moisture barrier, chemically resistant.
403
Why PET is used for drinks/heat applications
Excellent stability and heat resistance.
404
Purpose of shrink wrap (LDPE)
Package collation and tamper evidence.
405
What are extractables?
Compounds that can be removed from packaging under aggressive conditions (solvents, high heat).
406
What are leachables?
Compounds that migrate into the drug during normal storage conditions.
407
Examples of leachables
Plasticisers such as DEHP, DEHA.
408
Examples of manufacturing issues prevented by packaging
Oxygen exposure, moisture ingress, microbial contamination, physical damage.
409
Purpose of anti-counterfeiting measures
Prevent falsified or tampered medicines entering supply chain.
410
Smart packaging example
Nano-inks indicating temperature excursions.
411
Example of a handling aid
Slip agents reducing friction in packaging films.
412
PVC-PVdC barrier properties
Low WVTR and OTR due to PVdC coating; used for high-barrier blister packs.
413
Aclar film properties
Very high barrier, extremely low WVTR (0.08–0.3), premium blister film.
414
Examples of plastic failure mechanisms
Crazing, cracking, stress whitening, deformation.
415
Effect of crystallinity on polymer properties
Higher crystallinity → stronger, less flexible, more opaque.
416
Why blister packs are common
Easy visual identification, individual dose protection, tamper evidence.
417
Definition of tensile strength
The maximum stress material withstands before breaking.
418
Definition of Young’s modulus
Stiffness of a material (stress/strain in elastic region).
419
Key legislation considerations
Packaging must meet storage, sterility, quality control, and stability requirements.
420
Film additive: titanium dioxide
Provides white opacity; improves UV protection.
421
Film additive: carbon black
Provides black coloration and increases UV resistance.
422
Film additive: azo dyes
Provide red–yellow coloration.
423
Film additive: anthraquinones
Provide blue and green pigments.
424
Role of pigments in packaging
Identification, UV protection, branding, opacity.
425
Why counterfeit meds are dangerous
May contain toxic chemicals, wrong active ingredient, wrong dosage, or bacterial contamination.
426
Red flags for falsified products
Unusual packaging quality, spelling errors, colour differences, lack of safety seals.
427
Drug development duration
Discovery 2–4 yrs → Clinical trials 3–6 yrs → Regulatory 1–3 yrs.
428
Drug development cost
> $1 billion total; clinical trials = 70–80% of cost.
429
Drug development sectors
Research → Pharma development → Production → Regulatory affairs → Medical information.
430
Research stage
Identify disease mechanisms & targets; preclinical testing for suitability.
431
Pharmaceutical development
Create dosage form; ensure stability, bioavailability, packaging, reproducibility.
432
Production
GMP-compliant scale-up; strict quality control.
433
Regulatory affairs
Ensure compliance (EMA, FDA, MHRA); submit dossiers; obtain approvals.
434
Medical information
Provide safety/scientific information to clinicians & public.
435
Drug product definition
Final dosage form containing API designed to deliver drug safely & effectively.
436
Drug product examples
Tablets, capsules, injectables, topicals, inhalers, modified-release forms.
437
Drug product requirements
Stable, bioavailable, effective release, appropriate for disease & patient population.
438
Preclinical studies
In vitro + animal toxicology, PK, PD; determine safe starting dose in humans.
439
Stakeholders in clinical trials
Patients, clinicians, pharma industry, regulators, ethics boards, insurers, investors.
440
Stakeholder priorities
Safety, efficacy, cost-effectiveness, innovation, market success.
441
General problems in trials
High cost, recruitment issues, ethics limits, long timelines, high failure risk, limited generalisability.
442
Failure rates
30% fail: lack of efficacy/poor trial design; 25% fail: safety issues despite preclinical data.
443
Definition of clinical trials
Systematic human studies assessing safety, efficacy, PK, PD, side effects, comparison with SOC/placebo.
444
Interventions tested
Drugs, biologics, devices, surgery, behavioural changes, diagnostics, preventive methods, combinations.
445
Why perform clinical trials?
Determine safety, efficacy, optimal dose, compare to existing therapy, identify side effects, meet regulatory requirements.
446
Clinical trial key questions
Safety? Efficacy? Improved QoL? Does it cure or improve disease?
447
Basic requirements for a clinical trial
Scientific rationale, preclinical evidence, ethics approval, informed consent, funding, infrastructure, qualified investigators, detailed protocol.
448
ICH requirement: risk-benefit
Benefits must outweigh risks.
449
ICH: participant rights
Participant interest > science; informed consent required; subjects can withdraw anytime.
450
ICH: confidentiality
Must be protected at all times.
451
ICH: scientific quality
Trials must be scientifically sound, ethics-approved, protocol-defined; dosing supported by preclinical data.
452
ICH: qualified staff
Only medically qualified personnel manage subjects.
453
ICH: data standards
Data must follow GLP, GCP, GMP.
454
Phases overview
Phase I: safety (20–80). Phase II: efficacy/dose (100–300). Phase III: large confirmatory (1000+). Phase IV: post-marketing (10,000+).
455
Phase I purpose
Safety, dose tolerance, PK, early side effects; usually healthy volunteers (except cancer drugs).
456
Phase I designs
SAD, MAD, food–drug interaction, PK profiling.
457
Phase I outcomes
Safety profile, MTD, recommended Phase II dose, PK (Cmax, Tmax, AUC).
458
Phase IIa
Small, exploratory; early efficacy signals; guidance for dose; short-term safety.
459
Phase IIb
Larger, statistically powered; randomised, double-blind; test vs comparator vs placebo; optimise dose.
460
Phase II outcomes
Supports go/no-go; provides regulatory data; confirms doses for Phase III.
461
Phase III purpose
Large-scale, multicentre; definitive evidence of efficacy & safety; required for marketing approval.
462
Phase IV purpose
Post-marketing surveillance; detect rare/long-term ADRs; real-world effectiveness; observational.
463
Placebo definition
Inactive comparator; reduces bias; distinguishes true drug effect from psychological/background response.
464
Trial participants Phase I
Mostly healthy young males; special populations added only if needed.
465
Trial participants Phase II
Always patients with target disease.
466
Trials in children/pregnancy
Rare; ethical concerns; often extrapolated from adult data except essential cases.
467
Challenges in clinical trials
Toxicity, insufficient efficacy, poor delivery, long-term toxicity (e.g., thalidomide), risk-benefit changes.
468
Commercial success note
Even successful trials do NOT guarantee commercial success.
469
Key takeaways
Clinical trials essential, costly, regulated; safety is priority; each phase has distinct goals; regulatory bodies require robust data.
470
What is not the main purpose of Phase I clinical trial?
a. To determine safety profile of the drug
b. To determine dose tolerance
c. To establish drug efficacy
d. To establish pharmacokinetic profile for the drug
e. To investigate for any unwanted side-effects
not main purpose = establish efficacy.
471
SAQ safety profile determination
Start with Phase I healthy volunteers; very low doses; SAD/MAD escalation; monitor vitals, labs, ECG, AEs; collect PK to link exposure-toxicity; identify MTD; refine in Phase II/III.
472
Drug development overview
A multi-stage, highly regulated process transforming an idea/compound into a safe, effective, approved therapeutic by identifying disease mechanisms, selecting targets, discovering/optimising compounds, and completing clinical & regulatory phases.
473
Major stages of drug development
Discovery → Preclinical → Clinical Phases I–III → Regulatory approval → Post-marketing (Phase IV).
474
Learning outcome: drug discovery phases
Describe: Target ID → Target validation → Hit discovery → Hit-to-lead → Lead optimisation → Preclinical → Clinical → Approval.
475
Learning outcome: therapeutic types
Understand small molecules, biopharmaceuticals, gene therapy, cell therapy, electroceuticals, and protein-degradation technologies.
476
Learning outcome: emerging developments
Aware of advances such as CRISPR, regenerative medicine, PROTACs, molecular glues, electroceuticals.
477
Disease trends
Ageing populations + lifestyle changes → rise in chronic + neurodegenerative diseases → demand for personalised therapy.
478
Nature of disease
Modern diseases involve dysregulated signalling, gene expression, protein misfolding, immune dysfunction, environmental exposures.
479
Therapeutic aims
Directed toward individuals, families, and society.
480
Small-molecule drugs
Chemically synthesised; ~90% of drugs; typically target receptors or enzymes.
481
Biopharmaceuticals
Monoclonal antibodies, peptides, recombinant proteins; used for inflammation, cancer, vaccines.
482
Gene therapy
Introduces, removes, or edits genes to treat or cure disease.
483
Cell therapy & regenerative medicine
Uses cells, stem cells, engineered tissues to repair damaged tissues.
484
Electroceuticals
Use electrical stimulation devices to modulate physiological circuits.
485
Novel degradation technologies
Include PROTACs & molecular glues that target proteins for ubiquitination + degradation.
486
Drug discovery→prescription overview
Target ID → Screening → Lead optimisation → Preclinical → Clinical → Approval → Phase IV monitoring.
487
Discovery phase
Identify disease mechanisms, select targets, screen compounds, identify hits.
488
Preclinical testing
Test toxicity, safety, pharmacokinetics, basic efficacy in vitro and in vivo.
489
Clinical Phase I
Safety, tolerability, PK in humans.
490
Clinical Phase II
Efficacy testing, dose-finding in patients.
491
Clinical Phase III
Large-scale confirmation of safety and efficacy.
492
Phase IV
Post-marketing surveillance for long-term risks & rare adverse effects.
493
Target identification
Choose a biologically relevant, measurable, modifiable target.
494
Target validation
Confirm that altering the target modifies disease phenotype.
495
Target validation methods
Knockouts, RNAi, CRISPR, gene profiling, pharmacological activation/inhibition.
496
Differential gene expression in target ID
Identifies up- or downregulated disease genes → potential targets.
497
Transcriptomics role
Reveals actionable disease pathways and prioritises high-evidence targets.
498
HTS definition
Automated screening of large compound libraries to find active hits.
499
HTS library size
Typically 5,000–250,000 compounds.
500
HTS assay types
Enzyme assays, binding assays, cell-based assays.
501
HTS equipment
Robotic liquid handlers, microplate readers, automated imaging, compound libraries, LIMS.
502
HTS magic triangle
Speed, cost, quality.
503
Drug design
Rational design using structure-based/ligand-based tools, virtual screening, in silico models.
504
Lead optimisation
Improves potency, selectivity, ADME, toxicity, stability of hit compounds.
505
QSAR
Quantitative structure–activity modelling predicting how chemical changes affect biological activity.
506
Biotechnological lead optimisation
Antibody humanisation, protein engineering, peptide stabilisation, expression optimisation.
507
In silico models
Low cost, ethically favourable, high translational potential with human data.
508
In vitro testing
Cell lines, enzyme/reporter assays; high throughput but low physiological relevance.
509
Ex vivo testing
Tissue slices, organ baths; intermediate relevance.
510
In vivo testing
Whole-animal PK, toxicity, efficacy; high relevance but species-limited and costly.
511
Receptor-binding assays
Measure affinity of compounds for receptors.
512
Functional efficacy assays
Measure biological responses (agonism/antagonism).
513
2D vs 3D culture
3D mimics real tissue better → better prediction of penetration, metabolism, toxicity.
514
Organ-on-chip
Advanced microfluidic human cell systems with high physiological relevance.
515
Throughput trend
In vitro > ex vivo > in vivo (highest → lowest).
516
Predictive power trend
Molecular assays < cell-based < whole animal < disease models.
517
3D culture advantages
Improved modelling of absorption, penetration, toxicity, metabolic activity.
518
Organ-on-chip limitation
Lack full vasculature → limits systemic, long-term modelling.
519
Reasons drugs fail
Lack of efficacy, toxicity, poor bioavailability, off-target effects, immunogenicity, commercial failure.
520
Natural product drugs
Penicillin, morphine, paclitaxel; extracted from microorganisms/plants/animals.
521
Synthetic drugs
Chemically synthesised; majority of drugs since 1950; huge chemical space.
522
Biopharmaceutical approvals
~30–35% of new drug approvals (2012–2023).
523
Small molecule advantages
Chemical diversity, oral availability, established manufacturing, familiar to clinicians.
524
Small molecule disadvantages
Toxicity unpredictable, lower selectivity, poor absorption, rapid metabolism.
525
Biopharmaceutical advantages
Lower unexpected toxicity, rapid discovery, avoids pathogen contamination.
526
Biopharmaceutical disadvantages
Expensive, non-oral, do not cross BBB, species-specific activity complicates animal testing.
527
Precision medicine
Tailors treatment to molecular characteristics of individual patients.
528
Molecular glues mechanism
Small molecules inducing new PPI between target + E3 ligase → ubiquitination → degradation.
529
PROTAC mechanism
Bifunctional molecule linking target protein + E3 ligase via a linker → ubiquitination → degradation.
530
Molecular glue vs PROTAC
Glues = monovalent, small, serendipitous; PROTACs = bivalent, large, rational design with linker.
531
Regenerative medicine
Stem cells, engineered tissues, scaffolds for organ/tissue repair.
532
Regenerative medicine examples
Cardiac repair, skin regeneration, neuroregeneration.
533
Casgevy
First CRISPR therapy; edits bone marrow stem cells to restore haemoglobin; treats sickle cell & beta-thalassemia.
534
Electroceutical examples
Vagus nerve stimulation, implantable neuromodulators, wearable stimulation devices.
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Electroceutical rationale
Many physiological processes are electrically regulated → modulation treats inflammation, arrhythmias, neurological disorders.
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Modern drug discovery shifts
Regenerative medicine, gene therapy, electroceuticals, PROTACs, molecular glues.
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MCQ: Objective of hit-to-lead phase
A. Consolidate on a few compounds of high promise
B. Develop in silico models to find promising new compounds
C. Improve on the most promising compounds
D. Screen a wide range of compounds
E. Test the safety and efficacy of compounds
A. Consolidate on a few compounds of high promise
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SAQ: What are PROTACs?
Heterobifunctional molecules linking a target protein to an E3 ubiquitin ligase, inducing ubiquitination and proteasomal degradation.
