Pharmaceutical Sterility, Preservation, Validation, and Specials - Flashcards

A comprehensive set of practice flashcards covering contamination sources, water activity, preservation, sterilisation methods, validation, endotoxin testing, QC, and the use of specials.

What does AW stand for in pharmaceutical microbiology and what does it describe?

Water activity; a ratio describing the amount of free water available for microbial growth, defined as vapour pressure of the solution divided by that of pure water at the same temperature.

Why is water activity (AW) important for microbial growth, and what happens as AW decreases?

Microbial growth requires free water; lowering AW inhibits growth. Growth is unlikely when AW falls below organism-specific thresholds, though some fungi/yeasts tolerate much lower AW.

What are the two main consequences of microbial contamination in pharmaceutical products?

Spoilage (aesthetic/product changes) and health hazards (toxins, infections); endotoxins from Gram-negative bacteria can remain active even after cell death.

Define Sterility Assurance Level (SAL).

The probability of a single viable microorganism remaining after sterilisation; typically required to be ≤10^-6 for sterile-labelled products.

What is Terminal Sterilisation in pharmaceutical manufacturing?

Sterilisation performed in the final container after packaging; preferred approach when feasible.

What is Aseptic Manufacturing?

Sterile ingredients are assembled and filled under sterile conditions, without terminal sterilisation of the final product.

Name two common sterilisation methods and their primary mechanism.

Dry heat sterilisation (oxidation; moisture-free, used for heat-stable items) and Steam sterilisation/autoclaving (moist heat; hydrolysis through saturated steam).

Why is air removal important during autoclaving?

To ensure steam contacts all surfaces; air pockets hinder heat transfer and kill efficiency.

What is ethylene oxide (EO) sterilisation primarily used for, and what are its major risks?

Used for heat-sensitive items; EO is toxic, carcinogenic and explosive at high concentrations; requires aeration to remove residues.

What is Filtration (0.22 μm) sterilisation?

Removal of microbes by filtration; not true sterilisation because some viruses and endotoxins may pass; not suitable for heat-labile viruses/endotoxins in general.

What is a D-value in sterilisation?

Time (or dose for radiation) required to reduce the microbial population by 90% (1 log) under specified conditions.

What is a Z-value?

The temperature change needed to change the D-value by one log; indicates temperature sensitivity of the kill rate.

What is Fo in sterilisation kinetics?

The equivalent exposure time at 121°C; a cycle's lethality expressed as the time at 121°C required to achieve the same kill.

What does a linear survivor curve indicate in kinetics of antimicrobial action?

First-order exponential killing with a straight line on a log survivor plot; indicates predictable kill rate.

What is the difference between process indicators and biological indicators (BIs)?

Process indicators show exposure to the sterilisation process; BIs contain viable microorganisms and prove lethality.

Which organism is commonly used as a BI for moist-heat sterilisation in BP guidelines?

Geobacillus stearothermophilus.

Which organism is used as a BI for dry-heat sterilisation?

Bacillus atrophaeus.

Why is endotoxin testing needed even after a product passes sterility testing?

Sterility tests do not reliably detect endotoxins; endotoxins persist after bacterial death and can cause fever/sepsis.

What is LAL and what are its common methods?

Limulus Amebocyte Lysate assay used to detect endotoxins; methods include gel clot, chromogenic, and turbidimetric (plus recombinant Factor C alternatives).

What is the endotoxin limit (EL) for IV/IM administration for adults?

Typically 5 EU per kg per hour (e.g., ~350 EU for a 70 kg adult over 1 hour).

What is the endotoxin limit for intrathecal administration?

0.2 EU per kg per hour (e.g., ~14 EU for a 70 kg adult over 1 hour).

Why are endotoxin limits route-specific?

Pyrogenic risk and distribution differ by administration route; intrathecal routes have much lower tolerances.

What is the basic principle of Ethylene Oxide (EO) sterilisation process steps?

Air evacuation → Humidification → EO exposure → Aeration to remove residues.

What are the primary advantages and limitations of EO sterilisation?

Advantages: effective for heat-sensitive items; broad-spectrum. Limitations: toxic, carcinogenic, explosive in air, long cycle times, requires aeration.

Why is filtration not considered a true sterilisation method by itself?

Filtration removes but does not kill all microbes; post-filtration aseptic handling is required, and some organisms/viruses may pass through.

What is a common pore size used for sterilising filtration and what is removed?

0.22 μm filters remove bacteria and spores; viruses and endotoxins may pass through.

What are membrane filters vs depth filters in terms of structure and retention?

Membrane filters have uniform pores (0.22 μm) and sieve bacteria; depth filters have irregular pores and entrap particulates; depth filters are typically pre-filters.

What are the three main strategies to preserve pharmaceutical products?

Low temperature storage, pH manipulation, water activity (AW) manipulation, and use of chemical preservatives.

What makes AW manipulation not a universal guarantee of preservation?

Storage conditions, hygroscopicity, and product interactions can alter AW; some fungi can grow at low AW (around 0.65); packaging and protection are often needed.

Which preservative classes are commonly used and what is a key consideration for their use?

Parabens, benzoates, sorbates (acids/esters); alcohols; biguanides (chlorhexidine); heavy metals (thimerosal); phenols; QACs. Consider toxicity, partitioning, and compatibility with formulation.

What does

What is the role of EDTA in preservative efficacy against Pseudomonas aeruginosa?

EDTA chelates divalent cations, destabilizing Gram-negative outer membranes and increasing permeability to preservatives.

What is HACCP and its seven steps in process control?

Hazard Analysis; Critical Control Points (CCPs); Critical limits; Monitoring; Corrective actions; Documentation; Verification.

What does QbD stand for and what is its purpose in manufacturing?

Quality by Design; understanding design space and process linearity to reduce risk and ensure robust processes.

Define Cp and what Cp > 1.0 indicates.

Process capability index; Cp = (USL - LSL) / (6σ). Cp > 1.0 indicates the process spread fits within specification and is well-controlled.

What are the three types of process indicators used in sterilisation monitoring?

Physical indicators (e.g., temperature, pressure), Chemical indicators (color/chemical changes), Biological indicators (viable organisms).

What is the BP recommendation for sterile monitoring organisms for steam (121°C)?

Geobacillus stearothermophilus.

What is a

Why is a positive control needed in sterility testing?

To confirm that microbial growth is detectable under test conditions.

What is the significance of a 12D concept in sterilisation validation?

A standard of achieving a 12-log reduction for spore-forming organisms; relates to D-values and cycle validation.

What is parametric release in sterilisation validation?

Release of a batch based on validated process data rather than end-product sterility testing, assuming compliant kinetics and process controls.

What is Six-Sigma, and what is DMAIC used for in sterile manufacturing?

A quality methodology; DMAIC stands for Define, Measure, Analyze, Improve, Control to reduce defects and variability.

What is the difference between direct inoculation and membrane filtration in sterility testing?

Direct inoculation places product directly into culture; filtration passes product through a sterile filter into culture media; filtration is better for soluble products but can be affected by antimicrobials.

What is an endotoxin unit (EU) and how is it related topg, pg?

1 EU ≈ 100 pg of E. coli LPS; activity is route- and time-dependent. EL values are expressed in EU per dose or per kg.

What is a major ethical advantage of recombinant Factor C (rFC) over traditional LAL tests?

rFC avoids harvesting horseshoe crab blood, addressing conservation and animal welfare concerns.

What is the primary hazard associated with multi-dose ophthalmic products without preservatives?

In-use contamination and risk of infection due to repeated withdrawal. Packaging and preservatives mitigate risk.

What is the main purpose of depyrogenation in sterilisation workflows?

Removal or inactivation of pyrogens (e.g., endotoxins) before or during sterilisation, to prevent fever responses in patients.

Name two important regulatory concerns when using specials in pharmacy.

Ensuring no licensed alternatives exist; obtaining prescriber and patient consent; ensuring appropriate labeling and governance; maintaining records and MHRA compliance.

What information must be included on the labeling of a special medicine?

INN, active ingredients (qualitative/quantitative), route, dosage, warnings, expiry, storage, batch number, manufacturer details, and regulatory notices.

What is a 'special' in clinical practice?

An unlicensed medicine manufactured or obtained to meet a patient’s unique clinical need when no licensed alternative is suitable.

What is a common reason to use a ‘special’ for neonates?

Licensed formulations may contain unsafe excipients (e.g., alcohol); an alcohol-free special may be justified for safety.

What is the main purpose of environmental monitoring in cleanrooms?

To detect contamination and ensure compliance with cleanroom classifications (e.g., Class 100, 10,000, 100,000) and maintain sterility assurance.

Define ‘Lot Tolerance Percent Defective (LTPD)’ in sampling plans.

A predefined level of defective units that, if exceeded, would cause rejection of the lot; used in sampling decision rules.

What is the purpose of conductivity/isotonicity testing in sterile products?

Physical quality attributes to ensure product safety and compatibility with physiological conditions.

What is the difference between a single, double, and sequential sampling plan?

Different schemes for sampling size and acceptance criteria to balance risk of accepting defective lots.

Why might a sterilisation cycle require revalidation every ~6 months?

Changes in procedures, equipment, or materials; ongoing assurance of consistent sterility and performance.

What is the role of