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QUALITY ASSURANCE/QUALITY CONTROL Quality Characteristic built into the product during production to satisfy the needs of the

consumers QA Broad concept, involves variation Ensures products will be consistently of the quality required by their intended use QC Good Manufacturing Practices/GMP RMQC, IMQC, FPQC Sampling, specifications and testing Documentation and release QC testing of pharml dosage forms = sum of all process that ensure safety and efficacy Accuracy Closeness of test results to true value Precision Degree of agreement among individual test results when the method is applied repeatedly to multiple sampling of the homogeneous sample Specificity Ability to assess unequivocably the analyte in the presence of components that may be expected to be present such as impurities, degradation products, matrix composition Robustness Measure of capacity to remain unaffected by small but deliberate variations in method, parameter and provides an indication of its reliability during normal range Monograph Document that specifies tests, procedure, references, expected results for materials or products Certificate of Analysis Document that specifies results of tests that show compliance/noncompliance with established standards/specifications QUALITY CONTROL I. Raw Materials QC A. ID Tests 1. Chemical Methods o General indications/+ reaction: Precipitation Evolution of gas Color change o E.g. sulfonamides diazo-coupling reaction (production of dyes, pH indicators)

Sulfonamide + naphthol dye (orange) Instrumental Methods a. Infrared Spectroscopy o Principle: the energy is not enough to cause excitation of the molecule only vibration o Forms: stretching, bending o Use for functional group determination o IRsx = IR std b. UV-Vis Spectroscopy o Principle: UV-Vis absorbed excitation from ground state to excited state/highest energy level light is transmitted upon return to ground state o Instrument measures the amount of absorbed and transmitted light o The evaluation of the absorption peaks can be correlated with the types of bonds present in a given molecule o UV-Vis sx = UV-Vis std c. High Performance Liquid Chormatography/HPLC o Retention factor used to compare the migration rates of solutes on columns Rf = tr to to tr =retention time to =dead time/void time (no retention) tm=time spent by the solute in the mobile phase ts=time spent by the solute in the stationary phase o Rf sx = Rf std d. Nuclear Magnetic Resonance/NMR o Measures the amount of electromagnetic energy absorbed by the magnetic nucleus of the molecule o NMR structure elucidation - determines the type of C, H and connectivity present in the sample o NMR sx = NMR std B. Test for Purity o Monograph (Assay) Titration Instrumental Method Direct % P = NV x MW f x 1000 x 100% sx wt 2.

Residual % P = N1V1- N2V2 x MW f x 1000 x 100% sx wt Residual with Blank % P = N2 (Vb -V2) x MW f x 1000 x 100% sx wt C. Limit Tests 1. Gross impurities dirt, insoluble matter 2. Chemical impurities trace metals, ions Limit Tests for: Use: Chlorides AgNO3 (AgCl) Sulfates BaCl2 (BaSO4) Arsenic Diethyldithiocarbamate UV-Vis spec 535-545 nm Heavy metals H2S (black) except Zn white Cd yellow Sb orange Mn pink Iron NH4SCN (blood red complex) 3.

Biological impurities microorganisms, degradation products D. Physical Tests When there are no available chemical tests 1. Specific Gravity o Pycnometer o Westphal Balance SG = wt sx wt std 2. Solubility Test o Dissolution of a compound in a suitable solvent Descriptive Terms Parts of solvent per 1 part solute Very soluble <1 Freely soluble 1 10 Soluble 10 30 Sparingly soluble 30 100 Slightly soluble 100 1,000 Very slightly soluble 1,000 10,000 Practically insoluble >10,000 3. Refractive Index o Refractometer (Abbe) o E.g. volatile oils, sugars o Ratio of the velocity of light in air to the velocity of light in the sample

II.

=C Vp o C = velocity in vacuum/air o Vp = phase/sx velocity 4. Optical Activity o Polarimeter measures the angle of optical reflection of plane polarizes light passing through the substance o Chiral C - determines optical activity, has 4 different functional group attached, non-superimposable 5. Boiling Point and Melting Point o Purity determination 9C = 5F 160 E. Special Tests 1. Paracetamol (INN)/Acetaminophen (USAN) INN International nonproprietary name USAN US adopted name o Test for the presence of pcholoracetanidlide, p-aminophenol o Chemical name: APAP/Nacetyparaaminophenol o Max dose: 4 g/day SE: liver toxicity 2. Quinine Sulfate o Tests for the presence of dihydroquinone sulfagte o Crystalline alkaloid with antimalarial, analgesic, anti-inflammatory and antipyretic properties o Source: Cinchona succirubra/Cinchona tree Intermediate Products QC Tests performed during production A. Granules/Powders 1. Uniformity of Mixture o Coning and quartering

2.

3.

sample batch assay: compute for the % active ingredient Primary Moisture Content o Acceptable limit: 31 35% o Accounts for the moisture due to the starch used as binder o 2 methods: Gravimetric weigh oven weigh Ohaus-Moisture Balance digital Adequacy of Wetness o We granulation o

o o

4.

5.

Simple qualitative test during mixing Make a ball press with thumb Crumble not enough Divided into 2 smooth portions enough Final Moisture Content o Granules prior to compression o Acceptable limit: 0.55 1.0% o Problems with high moisture Sticking adhesion to the die wall Picking removal of the surface of the tablet and adhesion to the punch o Problems with low moisture Capping complete/partial separation of the top or bottom part of the tablet Chipping separation of small portions Lamination separation of the tablet into 2 or more distinct layers Particle Size Determination o Sieve analysis o Mesh # - number of square opening per linear inch o mesh # - size openings 20 40 60 80 CP 20 Coarse 40 Good CP Fines o Good particle size distribution: 85% good <10% fines Angle of Repose o Measure of flowability tan = h r = arctan h R o Note: r = d o - pile up, spread o Methods Fixed funnel Fixed height o Procedure

Seal Powder Scrape Release Target: tip-to-top

Angle (oC) <25 Excellent 25 30 Good 30 40 Fair >40 Poor 7. Bulk/Tap Density o Procedure Add powder to grad cylinder Measure initial volume Tap Measure final volume Bulk density = wt sx Vi Tapped density = wt sx Vf 8. Compressibility Index CI = Bulk vol Tap vol x 100 Bulk vol o CI good compressibility Easier transportation, cheaper expenses 9. Hausners Ratio HR = Vi Vf B. Tablets 1. Hardness o Crushing strength o Equipment Stokes-Monsanto Hardness Tester spring Strong-Cobb application of force: air pump Pfizer pliers Erweka suspended weights Schleuniger motorized test jaws Acceptance Criteria Ordinary compressed 4 10 kg Buccal 7 10 kg Chewable/SL 2 3 kg 2. Friability o Ability to resist breakage during packaging and transport Instrument Friabilator Setting 25 rpm, 4 mins (100 cycles)

6.

No of samples

>= 650 mg: 6 6.5 g dedusted sample < 650 mg: 20 tablets

procedure Dedust Take weight Load into friabilator Unload and remove loose particles Take weight Compute % friability % Friability = Wti Wtf x 100% Wti Acceptance Criteria Stage/Sample Limit 1 (10/20) Nmt 1% 2 (20/40) Nmt 1% New formulation Nmt 0.8% No capping and chipping 3. Tablet thickness o Micrometer caliper o Acceptance Criteria: <=5% of relative standard deviation Tablets/Capsules 1. Disintegration Equipment Basket rack assembly 6 cylinder tubes: 10-mesh wire cloth Temp 37 +- 2oC o Procedure Load 1 tab or cap in each tube under specified conditions Use sinker or 10-mesh wire cloth as specified Acceptance Criteria Medium Disintegration time Plain Distilled water 30 mins (uncoated), sugar coated tablets, capsules Enteric coated Distilled Should not water(soaking disintegrate 5 mins) Simulated Should not gastric juice pH disintegrate 2.5 (soaking 1 hr) Simulated 1 hour intestinal juice Buccal tablets Distilled water 4 hours Sublingual Distilled water 3 minutes

C.

tablets (e.g. Isordil, Catapres) Chewable X X Passed if non remained except impalpable core If 1 or 2 did not disintegrate, perform 2 more trials Nmt 2 of the 18 samples tested failed to disintegrate 2. Dissolution Equipment Vessels: Type 1 basket (capsule) Type 2 paddle (tablet) Media Simulated gastric juice TS Simulated intestinal juice TS As specified in monograph Temp 37 +- 0.5oC o Procedure Sample Assay Measure amount of active component dissolved in the medium Acceptance Criteria Stage Sample AC 1 6 units All units should have nlt Q + 5% Q = tolerance specified in the monograph (Q = 90% - nlt 95%) 2 +6 units Ave of 12 units nlt Q No unit < Q-15% 3 +12 Aver of 24 units nlt Q units Nmt 2 units < q 15% No unit < Q 25% 3. Weight Variation o Wt of active component > 50 mg o Procedure Get 20 units Weigh individual tablets Get average weight Upper and lower limits Weight (mg) Limits <130 +- 10% 130 324 +- 7.5% >324 +- 5% Comparison of the individual unit from the limit o Acceptance criteria: no unit outside the limits o E.g. 150 mg 7.5% UL: 150 + (150 x 0.075) LL: 150 - (150 x 0.075) Content Uniformity o Wt of active component <= 50 mg

4.

Ensures potency of samples Procedure Get 30 samples assay 10 samples individually o USP limit: 85-115% D. Parenterals 1. Test for Pyrogens o Pyrogens fever producing substances a. Bacterial Endotoxin Test/Limulus Amebocyte Lysate (LAL) Test Horseshoe crab Limulus polyphemus (+) coagulation pyrogens b. Rabbit test Dose: 10 mL/kg Dilutent: NSS Sample: 37 +- 0.2oC Procedure initial/basal temp (rectal) injection (veins of the ear) after 1 hr, measure temp Acceptance Criteria Stage Sample AC 1 3 Individual temp rise nmt 0.5oC 2 +5 Nmt 3/8 should have individual rise of >0.5oC Total temp rise nmt 3.3oC 2. Limit Test for Particulate Matter o Microscopy o Light obscuration particle counter using principle of light blockage USP Limits >= 10 um >=25 um SVP (<100 mL) MM 3000 300 LO 6000 600 LVP (>100 mL) MM 12 2 LO 25 3

o o

Agar/TSA or broth

count

for 48 72 hrs

III.

Final Products QC A. Non-Sterile Oral/Topical Products 1. Microbial Limit Test Medium Use Potato Dextrose total yeast and Agar/PDA molds Tryptone Soya total aerobic

Incubation 20 25oC for 5 7 days 30 35oC

B. Sterile Products Parenteral Ophthalmic (vs otic) 1. Direct Transfer o Procedure Get aliquot Transfer to the medium (agar, broth( Incubate Results 2. Membrane Filtration o Procedure Filter using membrane filter Transfer membrane filter into the medium Incubate Results o Indication of growth: turbidity o Expected results: no growth Medium Use Fluid Thioglycolate Enterococci Clostridium sp Soybean Casein Enterococci Digest Agar Clostridium sp Tryptone Soya Streptococci Broth Membrane filters o Bubble Point Test (Efficiency) Clean Room o Has Laminar Air Flow Environment High Efficiency Particulate Air Filter o Dioctylphthalate (Efficiency Test) Leakers Test o Ampoules o 1% methylene blut o To test for proper sealing C. Liquid Dosage Forms 1. Solutions a. Appearance visual inspection for the presence of impurities and floating matter b. Physical characteristics determination of stability in terms of: Viscosity viscometer Color spectrophotometrically at a particular wavelength Clarity appropriate eqpt Taste and odor taste panel, subjective evaluation

Chemical characteristics detection of the presence of degradation products, determination of pH and % potency 2. Emulsion Type of Test External Emulsion a.Dye Solubility Test Amaranth green Green Water o/w (water soluble) Sudan red (oil soluble) Red Oil w/o b.Dilution Test dilution with water Miscible Water o/w Immiscible Oil w/o c.Conductivity use of electricity Conduction Water o/w (+) electricity d.CoCl2 filter paper test Pink Water o/w Filter paper CoCl2 pink = wet NVR/blue Oil w/o (oven) blue =dry e.UV Absorption (+)UV absorption Oil w/o f.Direction of Creaming Upward water o/w Oil< water Downward Oil w/o Oil>water 3. Suspensions a. Sedimentation Volume VS = Vf Vi VS < 1 VS near 1 or Vf ~ Vi suspension is ideal b. Redispersibility force necessary to redisperse particles, no sediment should be present at the base of the container after shaking c. Particle Size microscope or micrometer eyepiece d. Flow Properties/Rheological Properties determination of viscosity e. pH determines particle size, acidity and basicity influence particle formation D. Microbial Assay of Antibiotics 1. Cylinder plate o Agar plate + bacteria o Cylinder + Abx o (+) zone of inhibition Z - Efficacy 2. Turbidimetric or Tube Assay o Liquid medium/broth + bacteria + Abx

c.

E. -

F.

(-) turbidity turbidity growth Efficacy Drugs Microorganisms tested against Ampicillin/Clindamycin/ Micrococcus luteus Erythromycin Chloramphenicol E. coli Penicillins, PRPs S.aureus (Oxacilli, Cloxacillin), Tetracyclines Rifampicin B.subtilis Streptomycin Klebsiella pneumonia Biological Assays use of animals in testing drugs Drugs Animal Employed Digitalis Pigeon Oxytocin injection Chicken Parathyroid Dog Glucagon injection Cat Insulin injection HPLC (rabbit) Tubocurarine injection Metocurine injection Rat: Vasopressin Male Chorionic gonadotropin Female Same (of either sex) Corticotropin Spectrophotometer Cod liver oil Rachitic Heparin Sheep blood plasma Protamine sulfate Assay Methods for Selected Drugs
Drugs Oil soluble vitamins Vitamin A Vitamin D Vitamin E Vitamin K (menadione) Water soluble vitamins Vitamin B1 (thiamine) Vitamin B2 (riboflavin) Vitamin B3 (niacin) Animal Employed Spectrophotometry HPLC GC Spectro (635nm) Fluorometry Spectro (450nm) Microbiological Lactobacillus plantarum Microbiological Lactobacillus plantarum HPLC Spectro (361, RM) Microbiological Lactobacillus lechmannii Spectro (535 nm) GC HPLC/Hydroxylamine Rabbit blood sugar method

Vitamin B5 (pantothenic acid) Vitamin B6 (pyridoxine) Vitamin B9( (folic acid) Vitamin B12 (cyanocobalamin) Steroids Barbiturates Pens/Cephs Insulin

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