36 terms

establishing specifications for drug product quality

3 stages of acetaminophen tablets
raw material, tablets, finished product
need what for all 3 stages of acetaminophen tablets--- this is part of what guideline
specifications and quality testing at all stages of drug manufacturing to assure quality of drug product---part of GMP
what are specification (to ensure what?)
- standard and acceptable limits for quality
- assure safety and efficacy
- extend from raw material to finished product
- tests for pharm quality (in terms of identity, appearance, purity, potency etc.)
what is the definition of specifications***
a detailed description of a drug, the material used in a drug or the packaging material for a drug including
1. state of all properties and qualities of the drug, raw material or packaging material that are relevant to manufacture, packaging and use of the drug including identity, potency, purity of the drug, raw material and or packaging material
2. a detailed description of methods used for testing and examining the drug, raw material, or packaging material
3. a statement of tolerances for the properties and qualities of the drug, raw material or packaging material
what is a pharmacopoeia
sets official standards and specifications for many drug products
all drugs can be found in the pharmacopoeia
false. new drugs not listed
Acetaminophen USP raw material (3 things to ensure it's good)
1. assay the potency of the drug substance (what % is acetaminophen)
2. identify the drug substance (is this material acetaminophen?)
3. determine level of impurity (water, inorganic impurity, heavy metals, p0aminophenol, p-chloroacetanilide etc)
using UV spec to assay the acetaminophen raw material
at wavelength of 244nm
what is the USP range of acetaminophen
98-101 % acetaminophen (from calibration curve)
how is the calibration curve of acetaminophen constructured
by measuring the UV abs of solutions of aceetainophen USP reference standard solution (purchased)
what is a reference standard
extremely pure (100%) standards of a drug which are kept in a secure controlled area under stable long term storage cnoditions
what is primary vs. secondary reference
primary standards are very expensive
secondary standards are in house materials that have been shown to be calibrated against the primary standard and are used for routine testing (but cannot be used for confirmation of AI)
specifications for new drugs
1. new drugs are not listed in USP
2. pharm companies have to establish the specfication for new drugs- in house standards
3. specficiations have to follow general accepted principles and be acceptable to health canada or US FDA
- companies have to synthesize highly pure in house reference standards for the drug and keep these in secure location under highly stable conditions
drug raw material identity tests can be done against secondary standards
false. only against primary standard
what are some drug raw material identity tests (specific techniques/methods) done for acetaminophen (3)
1. IR spec
2. uv vis spec
3. melting point determination
what are some drug raw material purity assays and tests (5 big categories)
4. Capillary electrophoresis
5. isoelectric focusing
acetaminophen impurity test
1. p-aminophenol (measure absorbance at 710nm) limit is <0.005%
2. p-chloroacetanilide (TLC limit test <0.001%)
these 2 impurities are unique to this drug
we always worry about heavy metals in general
using a standard and measuring UV abs at 710nm and if the abs of our material is greater than the standard, then batch fails
tests for raw material identity test
proton and C-NMR
2. mass spec
3. IR
4. Melting point
5. colour tests for functional groups
6. UV vis spec
7. chromatographic parameters (eg. retention time in HPLC, mw determination in SE-HPLC)
8. amino acid analysis
9. electrophoretic properties by SDS page and western blot
acetaminophen raw material specification (7)
1. purity (98-101% of acetaminophen, UV spec at 244nm)
2. identification (IR, UV, TLC, MP)
3. water content <0.5%
4. residue on ignition test <0.1%
5. heavy metals <0.001%
6. free p-aminophenol <0.005% using UV vis
7. free p-chloroacetanilide <0.001%)- TLC
USP vs. ACS raw materials
should always use USP grade chemicals and reagents for drug manufacturing b/c these meet high quality standards.

ACS= american chemical society
acetaminophen tablet USP (3)
1. potency: tablet contain 90-110% of labelled amt of acetaminophen. measured by HPLC
2. identification: retention time from HPLC, Rf in TLC
3. dissolution: not less than 80% of drug dissolved in pH 5.8 phosphate buffer in 30 min
finished product assay
assay for potency (expected amt of active drug substance and other key components)
general tests in USP apply to drugs in what way
apply to drugs in a similar class or similar product category
what are examples of general tests in USP
sterility test, pyrogen test, bacterial endotoxin test, spec identification test, TLC, limit tests for impurities, antibiotic microbial assays, disintegration tests, dissolution
tests for minor impurities (what are some things to test for and how to test for them, not regarding acetaminophen)
1. residual solvents (measured by GC)
2. inorganic compounds (measured by residue on ignition)
3. heavy metal (reaction with thioacetamide glycerin Test solution, compare with standard solution colour formed with this time)
why is it important to measure water content in drugs
b/c drug products are often lyophilized(freeze dried) to improve their stability and extend their expiry. so it's imp to measure the residual amt of water present by karl fisher titration
sterile product must be tested for what?
ph range (ideally 7.4)
clear, no particulate matter
sterile (absence of viable bacteria or fungi or other microorganisms)
apyrogenic- doesn't cause fever in patients
very low bacterial endotoxin level
pacakged in way to maintain these properties
what is USP sterility test detecting for and how do they do it?
detecting for presence of viable fungi/bacteria
- 14 day incubation on 2 media (soybean casein medium, fluid thioglycholate broth)
- injectables are terminally sterilized (aseptic filtration through 0.22um filter or autoclaving

no growth is acceptable!!
what is USP pyrogen test
detects all types of pyrogens (rabbit is more sensitive than humans)
- inject 3 rabbits with scaled dose (4x human dose on mg/kg basis)
"Measure rectal temperature every 0.5 h for 3 h. If no rabbit has an increase in temperature of 0.5 oC or more the product is considered to be absent of pyrogens. If one rabbit has an increase in temperature of 0.5 oC or more an additional five rabbits are tested."
USP bacterial endotoxins test tests for gram + bacterial endotoxin
false! official test for gram - bacterial endotoxin
what does in vitro bacterial endotoxin test rely on? (what condition is incubation?)
formation of a clot in test tube when a sample of the drug product (solution) is incubated with the lysate from blood cells of horseshoe crab for 37 deg for 1 hour (if clot formation occurs, it's a fail b/c it takes alot of endotoxin to form a clot)
how is packaging material monitored
- must not decrease drug quality (adsorption, contamination, physicochemcial degradation, bacterial contamination)
- changing packaging material can greatly decrease the stability of the drug
3 phases of drug development
phase 1: clinical trial of the safety and toxicity of a new drug in a small cohort of healthy volunteers except for anti-neoplastics which are tested in cancer patients
phase 2: clinical trial of optimal and safe dose of drug in large cohort (50-100 ppl) of patients with the disease drug is intended to treat
phase 3: randomized clinical trial of the drug in a large cohort (200-300) patients who are to receive the new drug or the standard treatment of a disease
stringency of quality control through out the development phases are kept the same
false. stringency of control increases as moves from preclinical to phase ii and finally to new drug submission
do drugs expire after expiry date?
not necessarily, just means it hasn't been tested beyond that time. expiry times are short in phase I but are extended once long term stability data is available
testing of stability must be done under standard conditions (Room Temp, 2-4 deg)
no. can be done under extreme conditions (eg. freezing or high temp)