Drug Manufacturing for Clinical Trials

Investigational Medicinal Product (IMP)

The product used in clinical studies. The dosage form used depends on the clinical stage of development and is often different in early stages (FIH/Phase 1) compared to later stages (Phase 2/3).

First-in-Human (FIH) studies

The 'bulk in a bottle approach' - small amounts of API are weighed into a bottle in a clean room, and a diluent is added at the clinical center to dissolve or suspend the API.

NIMPs

Non-Investigational Medicinal Products - products used to create a response (e.g., histamine to create an allergic reaction when developing an anti-allergy drug).

Rescue medication

A drug that is available if something goes wrong with the initial drug (e.g., for severe adverse reactions).

Five basic steps in drug manufacture for clinical trials

1) Dispensing, 2) Mixing, 3) In-process control testing, 4) Production of the finished dosage form, and 5) Storage of the finished dosage form.

Bill of materials (BoM)

A list of all materials necessary to complete a batch, including API, excipients, solvents, packaging materials, etc.

Mixing stage processes

Dry blending, wet granulation followed by drying, lubrication to aid flow, sterile solution/suspension preparation, cream/gel formation, milling, or pellet formation.

Examples of in-process controls (IPCs)

Potency and blend homogeneity testing, moisture content measurement, weight variability checks, disintegration testing, and sampling for microbiological control.

Production of finished dosage form

Filling into vials/ampoules, encapsulation, tableting, coating of tablets, filling tablets into capsules for blinding purposes, and creating matching placebos.

Common terminal sterilization techniques for sterile IMPs

Moist heat (autoclave), dry heat, radiation (e.g., gamma radiation), and ethylene oxide.

Aseptic techniques necessity

When IMPs will not survive or are incompatible with terminal sterilization techniques.

Final step for liquids before filling into containers in aseptic processing

Filtration using 0.22 micron membrane filters.

Quality attributes for injectable IMPs

They must be sterile, pyrogen-free, and free of visible and sub-visible particles.

Different grades of manufacturing areas in aseptic processing

Grade A (high-risk operations), Grade B (background for Grade A), and Grades C & D (less critical stages).

Grade A zone in aseptic manufacturing

A local zone for high-risk operations where the product is open to the atmosphere, usually achieved via laminar flow systems, closed isolators, or glove boxes.

Purpose of settle plates in aseptic manufacturing

They are standard petri dishes containing culture media that are exposed to the air and subsequently incubated to allow visible colonies to develop and be counted.

Importance of controlling sterility and endotoxin levels

Not specified in the notes.

Pyrogens/Endotoxins

Substances that can cause fever if injected, which may remain even after sterilization of bacteria.

HEPA filter

High Efficiency Particulate Air filter designed to remove 99.97% of dust, pollen, mold, bacteria, and airborne particles with a size of 0.3μm.

Aseptic pharmacy

Aseptic manufacturing within a hospital environment where expert pharmacists provide ready-to-administer treatments specific to a patient.

Good Manufacturing Practice (GMP)

The part of quality assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use.

Introduction of GMP

Led by a history of poor practices resulting in patient injuries and deaths due to cross-contamination, fraudulent data, and defective products.

5 P's of GMP

Products, Processes, Procedures, Premises, and People.

GMP compliance in drug development

"Full compliance" cannot be achieved in early development, but requirements increase as the drug development process moves through various stages.

Global GMP requirements

USA: Code of Federal Regulations (21CFR), EU: Council Directive 2003/94/EC, ICH: Q7 GMPs for Active Pharmaceutical Ingredients.

GMP guidelines in developing countries

World Health Organisation (WHO) guidelines are generally adopted, although some Central and South American countries adopt USA regulations.

Products with additional GMP requirements

Biologics, sterile products, and blood products.

Packaging decisions

Driven by product properties such as moisture sensitivity, light sensitivity, and contact material compatibility.

Study design impact on packaging

Factors include clinic or home dosing, number of visits, blinding requirements, and tamper evidence.

Identical packs in blinded studies

Necessary to maintain blinding so that neither patients nor researchers can identify which treatment is being administered.

Labeling purpose on clinical trial medications

To provide contact information for emergencies, enable unblinding in emergencies, and identify the product and its proper use.

Information on packaging labels

Should include contact information, dosage form, batch number, trial reference code, subject ID number, investigator name, usage directions, expiry date, and safety warnings.

"Tear-off" or "peelable" sections

Used for placing on the patient's clinical records when the primary container is too small for all required information.

Labeling for international studies

Multi-language labels are required as labels must use the language(s) of the country where the study is carried out.