Conducting Small-Scale Compounding of Pharmaceutical Products

• LO1. Overview of pharmaceutical analysis

• LO2. Source information on formula

• LO3 Prepare for production process

• LO4. Obtain equipment and supplies

• LO5. Compound products

• LO6. Complete production process

• LO7. Participate in quality control

• LO8. Store and transport released product
Introduction to Small-Scale Compounding

Small-scale compounding involves

the preparation of customized medications in
small batches to meet specific patient needs
when commercial products are unavailable,
unsuitable, or require special formulations.
It is commonly performed in:
• Hospital pharmacies

• Community pharmacies

• Research & development labs

• Veterinary pharmacies
• Key Reasons for Compounding:

• ✔ Unavailable commercial dosage forms (e.g.,

liquid forms for pediatric patients)
✔ Allergen-free formulations (e.g., dye-free or
preservative-free)
✔ Dose adjustments (e.g., lower-strength tablets
for geriatric patients)
✔ Specialized drug delivery systems (e.g.,
transdermal gels, suppositories)
 LO1. Overview of Pharmaceutical Analysis

Pharmaceutical analysis is a branch of

analytical chemistry that involves the
identification, quantification, and purification
of substances used in pharmaceuticals.
It ensures the quality, safety, and efficacy of
drugs by verifying their chemical composition,
purity, and stability.
 Objectives of Pharmaceutical Analysis

• Quality Control (QC) – Ensures that raw

materials, intermediates, and finished products

meet specified standards.

• Quality Assurance (QA) – Monitors processes to

maintain consistency in drug manufacturing.

• Drug Development – Helps in the characterization

of new drug molecules.

• Stability Testing – Determines shelf life and

storage conditions.

• Bioavailability & Bioequivalence Studies –

Assesses drug performance in biological systems.

• Common Techniques in Pharmaceutical
Analysis
• Spectroscopic Methods:

UV-Vis, IR, NMR, Atomic Absorption

Spectroscopy (AAS).
Chromatographic Methods: HPLC,
GC, TLC, UPLC.
• Electrochemical Methods:

Potentiometry, Conductometry.
• Titrimetric Methods:

Acid-base, redox, complexometric titrations.

• Microbiological Assays: Used for antibiotics and
sterility testing
Importance of Pharmaceutical Analysis
• Ensures compliance with regulatory
standards (e.g., USP, BP, ICH, FDA).
• Detects impurities and degradation products.

• Validates manufacturing processes.

• Supports pharmacovigilance and clinical

trials.
 Application of pharmaceutical analysis

Drug Development & Formulation

• Analyzes physicochemical properties (solubility,
stability, polymorphism) of active pharmaceutical
ingredients (APIs).
• Excipient Compatibility Testing: Ensures that inactive
ingredients do not interact with the API.
• Optimization of Dosage Forms: Evaluates tablets,
capsules, injectables, and topical formulations for
consistency.
Quality Control (QC) & Quality Assurance (QA)
• Raw Material Testing: Verifies the purity and
identity of starting materials.
• In-Process Testing: Monitors drug manufacturing
steps to ensure consistency (e.g., blend uniformity,
dissolution testing).
• Finished Product Testing: Confirms that the final
product meets specifications (assay, impurity
profiling, dissolution).
Stability Testing & Shelf-Life Determination
• Accelerated Stability Studies: Predicts drug
degradation under stress conditions (temperature,
humidity, light).
• Real-Time Stability Testing: Determines
expiration dates under recommended storage
conditions.
• Forced Degradation Studies: Identifies potential
Impurity & Degradation Product Analysis
• Identification of Impurities: Detects and
quantifies organic, inorganic, and residual solvent
impurities.
• Genotoxic Impurity Testing: Ensures safety by
analyzing potentially harmful byproducts.
• Degradation Product Profiling: Monitors drug
stability under different environmental conditions.
Pharmacokinetics & Bioanalytical Studies
• Bioavailability & Bioequivalence Testing:
Measures drug absorption in biological fluids
(plasma, urine).
• Therapeutic Drug Monitoring (TDM): Adjusts
drug dosages based on patient blood levels (e.g.,
antibiotics, antiepileptics).
• Metabolite Identification: Studies drug
metabolism using LC-MS/MS and NMR.
Regulatory Compliance & Pharmacopoeial Standards

• Compliance with USP, BP, EP, and ICH

Guidelines: Ensures drugs meet international
quality standards.
• Batch Release Testing: Mandatory testing before
market distribution.
• Documentation for FDA, EMA, and Other
Agencies: Supports drug approval submissions.
Forensic & Anti-Counterfeit Drug Analysis
• Authentication of Drugs: Detects counterfeit or
substandard medicines.
• Doping Control in Sports: Identifies banned
substances in athletes.
• Toxicological Analysis: Detects drug abuse or
poisoning cases.
Microbiological & Sterility Testing
• Sterility Testing: Ensures injectables and implants
are free from microbial contamination.
• Endotoxin Testing (LAL Test): Detects bacterial
endotoxins in parenteral drugs.
• Antimicrobial Effectiveness Testing: Validates
preservative efficacy in liquid formulations.
Environmental & Industrial Applications
• Waste water Analysis: Monitors pharmaceutical
pollutants in the environment.
• Cleaning Validation: Ensures equipment is free from
cross-contamination.
 Pharmaceutical analysis is essential at every stage of drug
development, manufacturing, and post-market surveillance.
It ensures drug safety, efficacy, and compliance with global
regulatory standards.
Qualitative Analysis
• Definition: Identifies the nature (what is present)
of a substance without measuring its exact
quantity.
• Applications in Pharmaceuticals:
• Identification of Active Pharmaceutical Ingredients
(APIs)
• Detection of impurities, degradation products, or
adulterants
• Verification of raw materials and excipients
• Structural elucidation of unknown compounds
Method Principle Example Applications

Thin-Layer Chromatography Screening for impurities,

Separation based on polarity
(TLC) herbal drug identification

Fourier Transform Infrared

Functional group analysis Verification of drug identity
(FTIR) Spectroscopy

Nuclear Magnetic Resonance Molecular structure Confirmation of synthetic

(NMR) Spectroscopy determination compounds

Molecular weight and Detection of counterfeit

Mass Spectrometry (MS)
fragmentation pattern drugs

Preliminary drug screening

Color Tests & Chemical Specific reactions with
(e.g., Marquis test for
Reactions reagents
alkaloids)
Quantitative Analysis
• Definition: Measures the exact amount (how
much is present) of a substance in a sample.
• Applications in Pharmaceuticals:
• Assay of APIs in dosage forms
• Impurity quantification (e.g., related substances,
residual solvents)
• Dissolution testing for tablets and capsules
• Bioavailability & pharmacokinetic studies (drug
concentration in blood)
Method Principle Example Applications

High-Performance Liquid Separation and Assay of drugs, impurity

Chromatography (HPLC) UV/fluorescence detection profiling

Ultraviolet-Visible (UV-Vis) Absorption of light at specific Drug content in

Spectroscopy wavelengths tablets/syrups

Volatile compound
Gas Chromatography (GC) Residual solvent analysis
separation

Titrimetry (Acid-Base, Redox, Volume-based quantitative

Raw material purity testing
Complexometric) reaction

Atomic Absorption Heavy metal testing in herbal

Metal ion quantification
Spectroscopy (AAS) drugs
 Comparison Between Qualitative & Quantitative Analysis
Feature Qualitative Analysis Quantitative Analysis

Purpose Identifies components Measures exact quantity

Concentration (%, mg/mL,

Output Presence/Absence, structure
ppm)

Techniques Used TLC, FTIR, NMR, MS HPLC, UV-Vis, GC, Titration

Drug identification, impurity Batch release, stability

Regulatory Importance
detection studies
• Qualitative analysis answers "What is
it?" (identification).
• Quantitative analysis answers "How much is
there?" (measurement).
• Both are essential for drug development, quality
control, and regulatory compliance.
 LO 2. Sources of Information on Formula

Dosage form selection

• Dosage form selection is a critical step in drug
development and prescribing, as it affects drug
safety, efficacy, patient compliance, and therapeutic
outcomes.
• The choice depends on multiple factors related to
the drug's properties, patient characteristics, and
clinical needs.
 Drug-Related Factors

• Physicochemical Properties: Solubility, stability,

pH sensitivity, and partition coefficient influence
whether a drug is formulated as a solid, liquid, or
semi-solid.
• Absorption & Bioavailability: Some drugs
require specific forms to enhance absorption
• First-pass metabolism: Drugs susceptible to hepatic
metabolism may benefit from alternative routes
 Patient-Related Factors

• Age:
– Pediatrics: Liquids (syrups, suspensions) or orally disintegrating tablets

(ODTs) for ease of swallowing.

– Elderly: Chewable tablets, ODTs, or transdermal patches if swallowing is

difficult.

• Condition & Compliance:

– Dysphagia: Avoid large tablets/capsules; use liquids or patches.

– Psychiatric patients: Long-acting injectables (LAIs) for adherence.

• Convenience: Once-daily extended-release (ER) forms improve

compliance.
 Route of Administration

• Oral (PO): Tablets, capsules, syrups Parenteral (IV/IM/SC): For

rapid action (e.g., IV antibiotics) or drugs with poor oral

bioavailability (e.g., peptides).

• Topical: Creams, ointments Transdermal: Patches (e.g., nicotine,

fentanyl) for sustained delivery.

• Inhalational: Aerosols for asthma/COPD (e.g., salbutamol MDI).

• Buccal/Sublingual: Fast absorption bypassing first-pass (e.g.,

nitroglycerin SL).
 Desired Release Profile

• Immediate-Release (IR): Quick onset (e.g.,

pain relievers like ibuprofen).
• Modified-Release (MR):
– Extended-Release (ER/XR): Reduces dosing
frequency (e.g., metoprolol ER).
– Delayed-Release (DR): Protects drug from
stomach acid (e.g., enteric-coated aspirin).
 Stability & Manufacturing Considerations

• Sterility requirements: Injectables/ophthalmics

need sterile manufacturing.
• Shelf-life: Lyophilized powders for unstable drugs.

• Cost & Market Factors

• Cheaper forms (e.g., tablets) preferred for

widespread use.
• Novel forms (e.g., nanoparticles, liposomes) for
specialty drugs.
 Source of information for master formula

• The Master Formula (also known as the Master

Manufacturing Record, MMR) is a critical
document in pharmaceutical manufacturing that
provides detailed instructions for the production of
a drug product.
• It ensures consistency, quality, and compliance with
regulatory standards (e.g., FDA, EMA, WHO
GMP).
 Sources of Information for Preparing a Master Formula

• Pharmacopoeial Standards

• Regulatory Guidelines

• Drug Development Data

• Manufacturer’s Documentation

• API & Excipient Specifications

• In-House SOPs & Quality Systems

• Literature & Reference Texts

Consolidating and making relevant information
• Definition & Purpose

• What it is: A detailed, approved document

specifying the formulation, manufacturing process,
controls, and packaging of a drug product.
• Why it matters: Ensures batch-to-batch uniformity,
regulatory compliance (GMP), and patient safety.
 Essential Components of a Master Formula

Brand/generic name, dosage form,

1. Product Identification strength (e.g., "Paracetamol 500 mg
Tablets").

Exact quantities of API + excipients (per

2. Composition
unit and batch size).

Step-by-step instructions (e.g., mixing

3. Manufacturing Process
time, granulation parameters).

Critical checks (e.g., weight variation, pH,

4. In-Process Controls (IPC)
hardness).

Container type (blister, bottle), labeling

5. Packaging Details
requirements.

Temperature, humidity, shelf-life (based

6. Storage & Stability
on ICH Q1 studies).

PPE requirements for hazardous materials

7. Safety & Handling
(e.g., cytotoxic drugs).
• Key Components of a Raw Materials List
- Official pharmacopeial
name (USP/EP/BP)
Material Name Amoxicillin Trihydrate (USP)
- Common name (if
applicable)
Role in formulation (API,
2. Function filler, binder, lubricant, API (Active Pharmaceutical Ingredient)
etc.)
Exact amount per dosage
3. Quantity per Unit 500 mg (as amoxicillin)
unit (e.g., tablet, capsule)
Total amount required for
4. Quantity per Batch 50 kg (for 100,000 capsules)
the batch size
- Pharmacopeial grade
(USP/EP/BP)
5. Grade/Specification USP-NF, Ph. Eur.
- In-house specifications
(if custom)
Approved vendor name
6. Supplier/Manufacturer ABC Pharmaceuticals Ltd.
(must be qualified)
Temperature, humidity,
7. Storage Conditions *Store at 15-25°C, protected from moisture*
light sensitivity
- Hazard classification (if
8. Safety & Handling applicable) Wear gloves and mask if handling powder
- PPE requirements
 Equipment required

Material Handling Weighing Balance (GMP) Accurate measurement

of raw materials 0.1 mg–50 kg capacity

Uniform particle size

Sizing/Milling Sieve/Comminuting Mill reduction 40-mesh sieve

Mixing/Blending Bin Blender / V-Mixer Homogeneous blending 100L capacity

of powders

Wet granulation (if 50L Rapid Mixer

Granulation Fluid Bed Dryer / RMG* required) Granulator (RMG)

Encapsulation Automatic Capsule Filler Filling powder into Bosch GKF 2000 (for size
capsules #0 capsules)

Tablet Press (if

Compression applicable) For solid dosage forms Fette 1200i (for tablets)

Applying protective film

Coating Film Coating Machine (if needed) BFC-50 Coater

Blister Machine / Bottle

Packaging Filler Sealing & packaging Uhlmann Blister Packer

Hardness Tester / Pharmatest PTB 311

Quality Control Disintegration Apparatus IPC checks (hardness tester)
 Preparation instructions
- Verify equipment cleanliness (logbook)
Pre-Production Checks
- Confirm raw material dispensed correctly
- Exact quantities (double-checked)
2. Weighing & Dispensing
- Handling precautions (e.g., PPE for hazardous powders)
- Mesh size (e.g., #40 sieve)
3. Sifting/Milling
- Equipment settings (RPM, time)
- Order of addition
4. Mixing/Blending
- Mixing time & speed (e.g., 15 min at 20 RPM)
- Binder solution prep (e.g., PVP in ethanol)
5. Granulation (if applicable)
- Wet massing time, drying parameters
- Machine settings (e.g., tablet hardness, capsule fill weight)
[Link]/Encapsulation
- In-process checks (weight variation)
- Coating solution composition
7. Coating (if applicable)
- Spray rate, pan speed, inlet temperature
- Primary packaging material (blister/bottle)
8. Packaging
- Labeling requirements
- Critical checks (e.g., disintegration time, assay)
9. In-Process Controls (IPC)
- Acceptance criteria
 Storage and stability data
- Temperature (e.g., 15–25°C)
- Humidity (e.g., ≤60% RH)
1. Storage Conditions
- Light protection (e.g., "Store in original
packaging")

- Expiry period (e.g., 24 months from

2. Shelf Life manufacturing)
- Based on ICH Q1A–Q1E stability studies

- Accelerated (40°C/75% RH for 6 months)

3. Stability Studies - Long-term (25°C/60% RH for 24 months)
- Intermediate (30°C/65% RH, if needed)

- Sensitivity to moisture (desiccant required)

4. Special Handling - Cold chain requirements (e.g., 2–8°C for
biologics)

- Primary packaging (e.g., Alu-Alu blisters for

moisture protection)
5. Packaging Requirements
- Secondary packaging (e.g., carton with light
barrier)
 Packaging and label requirements
- Material type (e.g., Alu-Alu blisters, HDPE
bottles)
1. Primary Packaging
- Compatibility with product (e.g.,
moisture/oxygen barrier)

- Carton/box specifications (e.g., light-resistant,

tamper-evident)
2. Secondary Packaging
- Insert requirements (patient leaflet,
desiccant)

- Drug name, strength, dosage form

- Batch number, expiry date, manufacturing
3. Label Content (Regulatory) date
- Storage conditions, handling warnings
- Barcode/QR code (if required)

- FDA 21 CFR Part 210/211 (US)

- EU GMP Annex 9 (Europe)
4. Regulatory Compliance
- Country-specific requirements (e.g., MHRA,
CDSCO)

- Child-resistant caps (for certain drugs)

5. Special Requirements - Braille labeling (EU requirement for blind
patients)
 Confirm suitability of chosen formula and availability of resource

Evaluation Criteria Verification Method Red Flags

• Bioequivalence studies
Therapeutic Efficacy • Dissolution profile • Failed dissolution specs
matching

• Accelerated/long-term
Stability stability data • Degradation > ICH limits
• Compatibility studies

• Pilot batch results • Yield <95%

Manufacturability
• Process validation data • Frequent clumping

• Organoleptic testing • Poor palatability

Patient Acceptability
• Swallowability studies • Size >#00 capsule