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SK | 21 April 20232 |
The International Pharmacopoeia and International Chemical Reference Substances
Rabat 29/11/2007
Quality Assurance and Safety: Medicines
World Health Organization
SK | 21 April 20233 |
The International Pharmacopoeia – Int.Ph.
1. Introduction
2. Special features
3. Example of a monograph
4. WHO’s strategy in QC
5. WHO’s related activities
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SK | 21 April 20235 |
WHO Procedure for the preparation of drug Quality Control specifications (1)
…..or why it takes so long….
Preliminary consultation and drafting
Draft Quality Control specifications
Method development + validation: WHO Collaborating Centres and experts, contracted laboratories
Circulation for comments + testing of samples
Revision process, additional studies, contacts with manufacturers for queries and additional samples as needed
SK | 21 April 20236 |
WHO Procedure for the preparation of drug Quality Control specifications (2)
Adoption by WHO Expert Committee on Specifications for Pharmaceutical Preparations
Presentation to WHO Governing Bodies
Recommendation to governments for implementation
publication in Technical Reports and
The International Pharmacopoeia and Basic Tests series
SK | 21 April 20237 |
WHO does the work … with Partners
National and regional authorities
International organizations (UNAIDS, UNICEF, World Bank, etc.)
International professional and other associations, NGOs (including consumer associations, industry)
WHO Expert Panels (official nomination process)
Specialists from all areas, regulatory, university, industry………
WHO Collaborating Centres (official nomination process)
Pharmacopoeia Commissions and Secretariats, national institutions and institutes ..
Regional and interregional groups (ICH…)
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Type of monographs
Drug substances
Excipients
Finished dosage forms
General methods and requirements:
oral dosage forms, e.g. tablets
dissolution testing…
SK | 21 April 20239 |
Some Figures - 3rd edition
Volume 1:
42 General methods and requirementsVolume 2:
88 Active pharmaceutical ingredientsVolume 3:
100 Active pharmaceutical ingredients
SK | 21 April 202310 |
Some Figures - 3rd edition
Volume 4:
23 Active pharmaceutical ingredients
65 Excipients
25 Oral dosage forms
14 Injectables
11 General methods and requirements
SK | 21 April 202311 |
Some Figures - 3rd edition
Volume 5:
20 Oral dosage forms
39 Active pharmaceutical ingredients
9 General methods and requirements
Special section on antimalarial agents, artemisinin derivatives:antimalarial agents, artemisinin derivatives:
5 Active pharmaceutical ingredients
8 Oral dosage forms
+ General guidance texts on INNs, graphic formulae, establishment of RS...
SK | 21 April 202312 |
4th edition - new
Consolidated in 2 Volumes + CD-ROM:Vol 1 - pharmaceutical substances (A-O)Vol 2 - pharmaceutical substances (P-X) + dosage forms
+ radiopharmaceuticals + methods of analysis + reagentsNew: Monographs on antiretrovials Revision of existing monographsImproved presentationImproved cross-referencing to general methodsCD-ROM: improved search functions
SK | 21 April 202313 |
4th edition - new
New list of impurities shown to be controlled by tests
More to come, first supplement in preparation to cover: New monographs for ARVs, TB and Malaria medicines, Revision of others, e.g. to include dissolution testsFor pre-information visit the WHO web site:http://www.who.int/medicines/publications/pharmacopoeia/overview/
SK | 21 April 202314 |
New Specifications adopted by 40th WHO Expert Committee
ARVs/APIs: - abacavir sulfate, - efavirenz, - lamivudine, - stavudine, - zidovudine;
ARVs/finished products: - nelfinavir mesilate tablets, - nelfinavir mesilate oral powder, and - saquinavir mesilate capsules
fixed-dose antituberculosis medicines: - rifampicin tablets, - rifampicin capsules, - rifampicin + isoniazid tablets, - rifampicin + isoniazid + pyrazinamide + ethambutol HCl tablets, - isoniazid + ethambutol HCl tablets, - rifampicin + isoniazid + pyrazinamide tablets
SK | 21 April 202315 |
New Specifications adopted by 41st WHO Expert Committee - ARVs
– Abacavir oral solution– Abacavir sulfate tablets– Didanosine tablets– Didanosine oral solution (adult formulation)– Lamivudine oral solution– Lamivudine tablets– Stavudine capsules– Zidovudine capsules– Zidovudine IV injection– Zidovudine oral solution– Zidovudine and Lamivudine tablets– Zidovudine, Lamivudine and Abacavir tablets
SK | 21 April 202316 |
New Specifications adopted by 41st WHO Expert Committee – antimalarial medicines
Doxycycline hyclate capsules (new monograph)
Doxycycline hyclate tablets (revision)
Doxycycline hyclate (revision)
Lumefantrine (new monograph) - subject to further studies
SK | 21 April 202317 |
New Specifications adopted by 41st WHO Expert Committee –
revisions (dissolution)
Metronidazole tablets
Doxycycline tablets
Isoniazid tablets
Chloroquine phosphate tablets
Primaquine diphosphate tablets
Ethambutol hydrochloride tablets
Pyrazinamide tablets
Rifampicin capsules
Rifampicin tablets
SK | 21 April 202318 |
Specifications distributed for comments
Oral liquids
Artemether and lumefantrine tablets
Lumefantrine
Oseltamivir phosphate
Zinc sulfate
Zinc sulfate oral solution
Zinc sulfate tablets
Magnesium sulfate injection
SK | 21 April 202319 |
WHO’s strategy for quality control
Step-wise approach:
Basic tests (identification) Screening tests (TLC) The International Pharmacopoeia International reference materials
(ICRS and IR reference spectra)
SK | 21 April 202320 |
Int. Ph. and links with other programmes and organizations
Establishment of monographs for antiretrovirals
collaboration Ph.Eur. USP, JP, IP, Chinese Pharmacopoeia, Brazilian Pharmacopoeia ...
collaboration with manufacturers links with WHO-UNICEF project on
prequalification of suppliers for HIV drugs
SK | 21 April 202321 |
International Pharmacopoeia Special features:
1. ….when complex, technically demanding methods are described (e.g. HPLC),
--> a less technically demanding analytical method (e.g. TLC) proposed as alternative (if possible).
2. …. international validation - impurity profile can vary from country to country!!
SK | 21 April 202322 |
C36H47N5O4,H2O4SRelative molecular mass. 711.9Chemical name. (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-N-(1,1-dimethylethyl)-4-(pyridin-3-ylmethyl)
piperazine-2-carboxamide sulfate; CAS Reg. No. 157810-81-6.
C36H47N5O4,H2O4SRelative molecular mass. 711.9Chemical name. (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-N-(1,1-dimethylethyl)-4-(pyridin-3-ylmethyl)
piperazine-2-carboxamide sulfate; CAS Reg. No. 157810-81-6.
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
SK | 21 April 202323 |
Description. A white or almost white powder.Solubility. Freely soluble in water, soluble in methanol.Category. Antiretroviral (protease inhibitor).Storage. Indinavir sulfate should be kept in a tightly closed container, protected from light.Additional information. Indinavir sulfate occurs as the monoethanolate which is hygroscopic. It converts to the hydrate upon loss of ethanol and exposure to moist air.RequirementsDefinition. Indinavir sulfate contains not less than 98.5% and not more than 101.0% of C36H47N5O4,H2O4S calculated on anhydrous, ethanol free basis.
Description. A white or almost white powder.Solubility. Freely soluble in water, soluble in methanol.Category. Antiretroviral (protease inhibitor).Storage. Indinavir sulfate should be kept in a tightly closed container, protected from light.Additional information. Indinavir sulfate occurs as the monoethanolate which is hygroscopic. It converts to the hydrate upon loss of ethanol and exposure to moist air.RequirementsDefinition. Indinavir sulfate contains not less than 98.5% and not more than 101.0% of C36H47N5O4,H2O4S calculated on anhydrous, ethanol free basis.
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
SK | 21 April 202324 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Identity tests
• Either tests A, B and D, or tests C and D may be applied.
A. Carry out test A.1. or, where UV detection is not available, test A.2.
A.1. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-propanol as the mobile phase. Apply separately to the plate 10 μl of each of 2 solutions in methanol containing (A) 5 mg of the test substance per ml and (B) 5 mg of indinavir RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in a current of cool air. Examine the chromatogram in ultraviolet light (254 nm).
The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.
SK | 21 April 202325 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
B. The absorption spectrum of a 0.100 mg/ml solution, when observed between 220 nm and 280 nm, exhibits one maximum at about 260 nm; the specific absorbance is between 56 and 65.
C. Dissolve 0.1 g in 10 ml of water, add 2 ml of sodium hydroxide (~80g/l)TS and shake. Filter the resulting precipitate and wash with two 3-ml quantities of water. Dry the washed precipitate for one hour at 105°C. Using the dried precipitate thus obtained, carry out the examination as described under "1. 7 Spectrophotometry in the infrared region". The infrared absorption spectrum is concordant with the spectrum obtained from indinavir RS or with the reference spectrum of indinavir.
D. A 20 mg/ml solution yields reaction A described under 2.1 General identification tests as characteristic of sulfates.
SK | 21 April 202326 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Specific optical rotation. Use a 10.0 mg/ml solution and calculate with reference to the anhydrous and ethanol free substance: +27° to +31°.
Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 1; determine the heavy metals content according to Method A; not more than 10 μg/g.
Sulfated ash. Not more than 1.0 mg/g.
Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 0.5 g of the substance; the water content is not more than 15 mg/g.
pH value. pH of a 10 mg/ml solution in carbon-dioxide-free water R: 2.8-3.2.
SK | 21 April 202327 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Ethanol content. Determine by 1.14.5 Gas chromatography, using static head-space injection. Use a fused-silica capillary or wide bore column 30 m long and 0.32 mm or 0.53 mm in internal diameter coated with macrogol 20M R (film thickness: 0.25 μm).
As detector use a flame ionization detector.
Use nitrogen for chromatography R or helium R as the carrier gas at an appropriate pressure and a split ratio 1:5 with a linear velocity of about 35 cm/sec.
Maintain the temperature of the column at 30°C for 7 min, then raise the temperature at a rate of 35°C per min to 180°C and maintain for 10 min, maintaining the temperature of the injection port at 140°C and that of the flame ionization detector at 250°C.
SK | 21 April 202328 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Test solution. Dissolve 0.200 g of the test substance in purified water and dilute to 20.0 ml with the same solvent. Introduce 5.0 ml of this solution and 1.0 ml of purified water into a headspace vial. Prepare two more vials.
Reference solutions. Add 0.200 g of ethanol R to purified water and dilute to 200.0 ml with the same solvent. Transfer respectively 2.0 ml, 3.0 ml and 4.0 ml in separate headspace injection vials and bring the volume to 6.0 ml with purified water.
Blank solution. Introduce 6.0 ml of purified water into a headspace vial.
The test is not valid unless the relative standard deviation on the areas of the peaks obtained from the test solutions is not more than 5%.
Calculate the ethanol content by using the results obtained with the test solution and with the reference solutions; the ethanol content is not less than 50 mg/g and not more than 80 mg/g.
SK | 21 April 202329 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Related substances. Carry out the test as described under 1.14.4 High performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography R (5μm).
Use the following conditions for gradient elution:
Mobile phase A: 30 volumes of acetonitrile R, 5 volumes of phosphate buffer pH 7.5 and 65 volumes of purified water.
Mobile phase B: 70 volumes of acetonitrile R, 5 volumes of phosphate buffer pH 7.5 and 25 volumes of purified water.
Prepare the following solutions. For solution (1) use 2.0 mg of the test substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 2 μg of Indinavir sulfate per ml.
For the system suitability test: prepare solution (3) using 2 ml of solution (1) and 2 ml of sulfuric acid (190 g/l), heat carefully in a boiling water bath
SK | 21 April 202330 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 220 nm.
Maintain the column temperature at 40°C.
Inject 20 μl of solution (3). The test is not valid unless the resolution factor between the two major peaks, with a retention time between 15 and 20 min, is not less than 3.5. If necessary adjust the amount of acetonitrile in mobile phase A, or adjust the gradient program.
Inject alternatively 20 μl each of solutions (1) and (2).
In the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is not greater than the area of the principal peak obtained with solution (2) (0.1 %). The sum of the areas of all peaks, other than the principal peak, is not greater than five times the area of the principal peak obtained with solution (2) (0.5 %). Disregard any peak with an area less than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).
SK | 21 April 202331 |
Indinaviri sulfas - Indinavir sulfateIndinaviri sulfas - Indinavir sulfate
Assay. Dissolve 0.300 g, accurately weighed, in 50 ml of water and titrate with sodium hydroxide (0.1 mol/l) VS, determine the end point potentiometrically. Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 35.59 mg of C36H47N5O4,H2O4S; calculate with reference to the anhydrous and ethanol free substance
SK | 21 April 202332 |
Int. Ph. and links with other programmes and organizations
Monographs for antimalarials, anti-TB drugs (different clusters in WHO)
General requirements for products derived from plant materials (WHO Traditional Medicines Programme)
Monographs for radiopharmaceuticals (with International Atomic Energy Agency - IAEA)
Monographs for excipients (with Pharmacopoeial Discussion Group - PDG)
SK | 21 April 202333 |
International Chemical Reference Substances (ICRS)
202 ICRS + 12 melting point reference substances Established by WHO COLLABORATING CENTRE FOR CHEMICAL
REFERENCE SUBSTANCES in Sweden Primary reference standard Linked to Ph.Int. Price for ICRS US$ 70 Includes: - Directions for use and - Certificate of analysis Monitoring and on-going stability testing Can be used for tests and analysis not included in Ph.Int.
SK | 21 April 202334 |
SK | 21 April 202335 |
International Chemical Reference Substances (ICRS)International Chemical Reference Substances (ICRS)
For ordering information, please visit http://www.apl.apoteket.se/who.
SK | 21 April 202336 |
International Infra-red Reference Spectra
WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCE SUBSTANCES in Sweden
69 International Infrared Reference Spectra
Linked to Ph.Int.
Price for ICRS US$ 5
Publication under review..
4000,0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400,0
0,0
10
20
30
40
50
60
70
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100,0
cm-1
%T
W105232T
IR-spectrum of lamivudineIR-spectrum of lamivudine
SK | 21 April 202337 |
International Chemical Reference SubstancesEstablishment of 4-ETC ICRS
International Chemical Reference SubstancesEstablishment of 4-ETC ICRS
SK | 21 April 202338 |
International Chemical Reference Substances4- ETC CoA of Manufacturer
International Chemical Reference Substances4- ETC CoA of Manufacturer
SK | 21 April 202339 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
Analysis by WHO Collaborating Centre Sweden
Intended use
The stock of the current batch of the International Chemical Reference Substance (ICRS) for 4-epitetracycline hydrochloride Control No 293098 is depleted and has to be replaced. The monograph for Tetracycline hydrochloride in The International Pharmacopoeia, Fourth Edition, requires a reference substance of 4-epitetracycline hydrochloride to be used in the thin-layer chromatographic test for related substances.
Material
About 15 g of the sample (manufacturer´s batch no 10) were received at the WHO Centre in September 2006. The material is being stored in tightly closed containers at + 5 °C, protected from light.
SK | 21 April 202340 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
Infrared spectrum
4000,0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400,0
0,0
10
20
30
40
50
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80
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100,0
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%T
W306098
SK | 21 April 202341 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
UV-spectrum
A UV-spectrum in 10 mM hydrochloric acid was recorded
SK | 21 April 202342 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
Thin-layer chromatography
Two secondary spots were detected. They were identified as tetracycline hydrochloride and 4-epianhydro-tetracycline hydrochloride and estimated to about 0.1% and 0.3%, respectively
SK | 21 April 202343 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
High performance liquid chromatography
The purity was estimated to 99.6% (w/w). Two impurities above the limit of quantification were detected. They were identified as tetracycline hydrochloride and 4-epianhydrotetracycline hydrochloride and estimated with external standards to 0.1% and 0.3% (w/w), respectively (n=6, RSD=0.01% for the main peak, RSD=9.5% for tetracycline, RSD=3.6% for 4-epianhydrotetracycline.
SK | 21 April 202344 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
SK | 21 April 202345 |
International Chemical Reference Substances4-ETC
International Chemical Reference Substances4-ETC
Stability
No special stability studies have been performed. Regular re-examinations of this ICRS when stored in the dry state will be performed.
Conclusion
4-Epitetracycline hydrochloride, Control No 306098, can be considered suitable as International Chemical Reference Substance for the intended purpose.
SK | 21 April 202346 |
What needs to be kept in mind!!What needs to be kept in mind!!
1. Quality cannot be tested into the product!
SK | 21 April 202347 |
What needs to be kept in mind!!What needs to be kept in mind!!
2. Specifications in national and regional pharmacopoeias are:
- based on manufacturers' specifications
- specific for the product(s) marketed in its legislative territory
SK | 21 April 202348 |
What needs to be kept in mind!!What needs to be kept in mind!!
3. Specifications should be used in a comprehensive way, i.e. including all tests listed
4. Specifications should be used intelligently, there is no guarantee that all (possible and impossible) impurities and alterations are covered!
SK | 21 April 202349 |
The International Pharmacopoeia's advantages
The International Pharmacopoeia's advantages
1. Specifications validated internationally, through an independent scientific process
2. Input from WHO Collaborating Centres, national Drug Quality Control laboratories
3. Collaboration with manufacturers around the world, especially for new projects
4. Close collaboration with WHO Member States, Drug Regulatory Authorities
SK | 21 April 202350 |
Further questions ??????http:www.who.int/medicines
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