Pharmacopee Internationale

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The In ternational

Pharmacopoeia and

In ternat ional Chem ical

Reference Substances

Rabat 29/11/2007

Quality Assurance and Safety: Medicines

World Health Organization




The Internat ional Pharmacopoeia –

Int.Ph.

1. Introduction

2. Special features

3. Example of a monograph

4. WHO’s strategy in QC

5. WHO’s related activities







WHO Procedure for the preparat ion o f drugQual ity Con trol specif icat ions (1)

…..or why it takes so long….

Preliminary consultation and drafting

Draft Quality Control specifications

Method development + validation: WHO CollaboratingCentres and experts, contracted laboratories

Circulation for comments + testing of samples

Revision process, additional studies, contacts withmanufacturers for queries and additional samples asneeded




WHO Procedu re for the preparat ion o f drug

Qual ity Con trol specif icat ions (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 Testsseries




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…)




Type of monographs

Drug substances

Excipients

Finished dosage forms

General methods and requirements:

oral dosage forms, e.g. tablets

dissolution testing…




Some Figures - 3 rd edi t ion

Volum e 1:

42 General methods and requirements

Volume 2:

88 Active pharmaceutical ingredients

Volume 3:




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Volum e 4:


65 Excipients

25 Oral dosage forms

14 Injectables




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Volume 5:

20 Oral dosage forms



Special section on antimalarial agents, artemisinin derivatives:


8 Oral dosage forms

+ General guidance texts on INNs, graphic formulae,

establishment of RS...



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4 th edi t ion - new

Consolidated in 2 Volumes + CD-ROM:

Vol 1 - pharmaceutical subs tances (A-O)

Vol 2 - pharmaceutical subs tances (P-X) + dosage forms +radiopharmaceut icals + methods o f analysis + reagents

New: Monog raphs on ant i ret rov ia ls

Revis ion of exist ing monographs

Impro ved presentat ion

Improved cro ss-referencing to general methods CD-ROM: impro ved search fun ct ion s



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4 th edi t ion - new

New l is t of impur i t ies sh own to be con tro l led by tests

More to come, first supplement in preparation to cover:

New m onog raphs fo r ARVs, TB and Malar ia medicines,

Revision o f others, e.g. to inc lude disso lut ion tests

For pre-information visit the WHO web site: http: / /www.who.int /medicines/publicat ions/pharmacopoeia/overview/



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New Speci f icat ions adop ted by

40 th WHO Expert Comm ittee 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 HCltablets, - isoniazid + ethambutol HCl tablets, - rifampicin +isoniazid + pyrazinamide tablets



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New Speci f icat ions adopted by

41 s t WHO Expert Comm ittee - 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



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New Specif icat ions adopted by 41 s t WHO Expert Comm ittee –

antimalar ia l medicin es

Doxycycline hyclate capsules (new monograph)

Doxycycline hyclate tablets (revision)

Doxycycline hyclate (revision)

Lumefantrine (new monograph) - subject to further

studies



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New Specif icat ions adopted by 41 s t WHO Expert Comm ittee –

revis ions (disso lut ion )

Metronidazole tablets

Doxycycline tablets

Isoniazid tablets

Chloroquine phosphate tablets

Primaquine diphosphate tablets

Ethambutol hydrochloride tablets

Pyrazinamide tablets

Rifampicin capsules

Rifampicin tablets



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Speci f icat ions dis t r ibu ted for comments

Oral liquids

Artemether and lumefantrine tablets

Lumefantrine

Oseltamivir phosphate

Zinc sulfate

Zinc sulfate oral solution

Zinc sulfate tablets

Magnesium sulfate injection



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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)



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Int . Ph. and l inks w ith o therprogrammes and organizat ions

Establishment of monographs for antiretrovirals

collaboration Ph.Eur. USP, JP, IP, ChinesePharmacopoeia, Brazilian Pharmacopoeia ...

collaboration with manufacturers links with WHO-UNICEF project on

prequalification of suppliers for HIV drugs



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In ternat ional PharmacopoeiaSpec ial features :

1. ….when com plex, techn ically demanding

methods are described (e.g. HPLC),

--> a less technically demanding analyt ical method

(e.g. TLC) proposed as alternative (if possible).

2. …. internat ional validat ion - impurity profile can

vary from country to country!!



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C36H47N5O4,H2O4S

Relative molecular mass. 711.9

Chemical 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 .

Indinavir i su lfas - Ind inavir sulfate



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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.

Requirements

Definition. Indinavir sulfate contains not less than 98.5% and not

more than 101.0% of C36

H47

N5

O4

,H2

O4

S calculated on anhydrous,

ethanol free basis.

Ind inavir i sulfas - Ind inavir sulfate



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Ind inavir i su lfas - Ind inavir su lfate

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 ofdichloromethane R and 2 volumes of 2-propanol as the mobile phase. Applyseparately to the plate 10 μl of each of 2 solutions in methanol containing (A) 5mg of the test substance per ml and (B) 5 mg of indinavir RS per ml. Afterremoving the plate from the chromatographic chamber, allow it to dryexhaustively 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.

http://127.0.0.1:1024/gsdl?sid=X%40QH%5bb%29P7f000001000009c84727684d&a=d&cl=&d=Jb.7.1.14.1







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B. The absorption spectrum of a 0.100 mg/ml solution, whenobserved between 220 nm and 280 nm, exhibits one maximum atabout 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 withtwo 3-ml quantities of water. Dry the washed precipitate for one

hour at 105°C. Using the dried precipitate thus obtained, carry outthe examination as described under "1. 7 Spectrophotometry in theinfrared region". The infrared absorption spectrum is concordantwith the spectrum obtained from indinavir RS or with the referencespectrum of indinavir.

D. A 20 mg/ml solution yields reaction A described under 2.1General identification tests as characteristic of sulfates.

http://127.0.0.1:1024/gsdl?sid=X%40QH%5bb%29P7f000001000009c84727684d&a=d&cl=&d=Jb.7.2.1






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Specific optical rotation. Use a 10.0 mg/ml solution and calculate withreference 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.











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Ethanol content. Determine by 1.14.5 Gas chromatography, usingstatic head-space injection. Use a fused-silica capillary or widebore column 30 m long and 0.32 mm or 0.53 mm in internaldiameter 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 gasat an appropriate pressure and a split ratio 1:5 with a linear velocityof about 35 cm/sec.

Maintain the temperature of the column at 30°C for 7 min, thenraise the temperature at a rate of 35°C per min to 180°C and

maintain for 10 min, maintaining the temperature of the injectionport at 140°C and that of the flame ionization detector at 250°C.






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Test s olut ion. Dissolve 0.200 g of the test substance in purified water and diluteto 20.0 ml with the same solvent. Introduce 5.0 ml of this solution and 1.0 ml ofpurified water into a headspace vial. Prepare two more vials.

Reference so lut ion s. Add 0.200 g of ethanol R to purified water and dilute to200.0 ml with the same solvent. Transfer respectively 2.0 ml, 3.0 ml and 4.0 ml inseparate headspace injection vials and bring the volume to 6.0 ml with purifiedwater.

Blank solut ion. 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 thepeaks obtained from the test solutions is not more than 5%.

Calculate the ethanol content by using the results obtained with the test solutionand with the reference solutions; the ethanol content is not less than 50 mg/g andnot more than 80 mg/g.



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Related substances. Carry out the test as described under 1.14.4 Highperformance liquid chromatography, using a stainless steel column (25 cm x 4.6mm) 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 substanceper ml. For solution (2) dilute a suitable volume of solution (1) to obtain aconcentration equivalent to 2 μg of Indinavir sulfate per ml.

For the system suitability test: prepare solution (3) using 2 ml of solution (1) and2 ml of sulfuric acid (190 g/l), heat carefully in a boiling water bath








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Operate with a flow rate of 1.0 ml per minute. As a detector use an ultravioletspectrophotometer 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 factorbetween the two major peaks, with a retention time between 15 and 20 min, isnot 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 thanthe principal peak, is not greater than the area of the principal peak obtained withsolution (2) (0.1 %). The sum of the areas of all peaks, other than the principalpeak, 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 areaof the principal peak in the chromatogram obtained with solution (2) (0.05%).



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Assay. Dissolve 0.300 g, accurately weighed, in 50 ml ofwater 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 C36

H47

N5

O4

,H2

O4

S; calculate with reference to the

anhydrous and ethanol free substance



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Int . Ph. and l inks w ith o therprogrammes and organizat ions

Monographs for antimalarials, anti-TB drugs(different clusters in WHO)

General requirements for products derived fromplant materials (WHO Traditional Medicines

Programme) Monographs for radiopharmaceuticals (with

International Atomic Energy Agency - IAEA)

Monographs for excipients (with PharmacopoeialDiscussion Group - PDG)



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In ternat ional Chem ical Reference

Subs tances (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.



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Internat ional Chem ical Reference Substances (ICRS)

For ordering information, please visithttp://www.apl.apoteket.se/who.

http://www.apl.apoteket.se/who

http://www.apl.apoteket.se/who



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Internat ional In fra-red Reference Spectra

WHO COLLABORATING CENTRE FOR CHEMICAL REFERENCESUBSTANCES 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

80

90

100,0

cm-1

%T

W105232T

IR-spectrum of lamivudine

I t ti l Ch i l R f S b t



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International Chemical Reference Substances

Establishment of 4-ETC ICRS

I t t i l Ch i l R f S b t



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Internat ional Chem ical Reference Substances

4- ETC CoA of Manu factu rer




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4-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 hasto be replaced. The monograph for Tetracycline hydrochloride in The InternationalPharmacopoeia, Fourth Edition, requires a reference substance of 4-epitetracycline hydrochloride to be used in the thin-layer chromatographic test forrelated substances.

Material

About 15 g of the sample (manufacturer ́s batch no 10) were received at the WHOCentre in September 2006. The material is being stored in tightly closedcontainers at + 5 °C, protected from light.




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4-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

60

70

80

90

100,0

cm-1

%T

W306098

Internat ional Chem ical Reference S bstances



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4-ETC

UV-spectrum

A UV-spectrum in 10 mM hydrochloric acid was recorded




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4-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




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4-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 withexternal 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.




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4-ETC




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4-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.



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What needs to be kept in m ind !!

1. Quality cannot be tested into theproduct!



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2. Specifications in national and regionalpharmacopoeias are:

- based on manufacturers' specifications

- specific for the product(s) marketed in

its legislative territory



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3. Specifications should be used in acomprehensive 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!

The In ternat ional Pharmacopoeia's



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The In ternat ional Pharmacopoeia sadvantages

1. Specifications validated internationally, through anindependent scientific process

2. Input from WHO Collaborating Centres, nationalDrug Quality Control laboratories

3. Collaboration with manufacturers around theworld, especially for new projects

4. Close collaboration with WHO Member States,Drug Regulatory Authorities



Further questions ??????

http:www.who.int/medicines

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