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The International Pharmacopoeia Quality standards for TB medicines. Caroline Mendy - Technical Officer - Quality Assurance and Safety: Medicines. Tutorial workshop, Beijing, March 2010. Quality standards for TB medicines – an issue?.

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The International Pharmacopoeia

Quality standards for TB medicines

Caroline Mendy - Technical Officer - Quality Assurance and Safety: Medicines

Tutorial workshop, Beijing, March 2010

quality standards for tb medicines an issue
QualitystandardsforTBmedicines – an issue?
  • "[…] reliable quality of medicines is absolutely essential for effective TB programmes" TB Alliance
  • "[…] low quality drugs damage patient recovery and increase the likelihood of drug-resistant strains of TB Stop-TB partnership

Several WHO studies carried out or on-going to monitor the quality of marketed TB medicines

quality standards for tb medicines
QualitystandardsforTBmedicines
  • Monographs available in Ph.Int.
  • Monographs, requirements and identity tests
  • Assay and related substances
    • method development
  • Dissolution / disintegration specifications
    • Isoniazid and Ethambutol hydrochloride tablets

Focus: TB FDC tablets

ph int tb monographs
Ph.Int. TB monographs

Priorities for inclusion of new specifications for TB medicines:

  • WHO Essential medicines lists
  • WHO specific disease programmes (e.g. Stop-TB, Prequalification)

Specifications for first-line and second-line TB drugs available (APIs and FPP)

ph int tb monographs5
Ph.Int. TB monographs

Amikacin (revision) - Oct 2009

Amikacin sulfate (revision) - Oct 2009

Amikacin injection - Oct 2009

kanamycin monosulfate - Oct 2009

kanamycin acid sulfate - Oct 2009

Kanamycin injection - Oct 2009

  • Isoniazid
  • Isoniazid tablets
  • Pyrazinamide
  • Pyrazinamide tablets
  • Rifampicin
  • Streptomycin sulfate
  • Streptomycin sulfate powder for injection
  • Thioacetazone
  • Cycloserine
  • Cycloserine capsules
  • Ethambutol HCl (revision)
ph int tb monographs to come
Ph.Int. TB monographs – to come…

Capreomycin - draft in progress

Capreomycin injection - draft in progress

Ethionamide tablets*

Protionamide tablets*

Terizidone*

Ofloxacin tablets*

Levofloxacin tablets*

p-aminosalicylic acid granules/tablets*

*on 2010 work programme

ph int monographs tb fdc dosage forms
Ph.Int. monographs: TB FDC dosage forms

4FDC: Rifampicin / Isoniazid / Pyrazinamide / Ethambutol HCl tablets

3FDC: Rifampicin / Isoniazid / Pyrazinamide tablets Rifampicin / Isoniazid / Pyrazinamide dispersible tablets (new) Rifampicin / Isoniazid / Ethambutol HCl tablets (new)

2FDC: Rifampicin / Isoniazid tablets Rifampicin / Isoniazid dispersible tablets (new) Isoniazid / Ethambutol HCl tablets

Rifampicin tablets Rifampicin capsules

Basic approach for monograph development: top down

9 monographs !

ph int monographs tb fdc dosage forms8
Ph.Int. monographs: TB FDC dosage forms

Strategy

  • Start with the most complex combination (4FDC tablets)
  • Work down to most simple situation using same procedures

4FDC

Isoniazid

3FDC

Rifampicin

2FDC

Ethambutol

Pyrazinamide

tb 4fdc tablets monograph requirements
TB 4FDC tabletsMonograph: Requirements

read General monographfor Tablets

?

tb 4fdc tablets monograph identity tests
TB 4FDC tabletsMonograph: Identity tests

Requirement:

  • Specific for each API in the 4FDC tablet
    • identification should be conclusive on presence / absence of the APIs
  • More than one test may apply for conclusive identification
    • tests X and Y
  • There may be a choice between tests
    • either test X or test Y may be applied

read instruction in monograph carefully

tb 4fdc tablets monograph identity tests12
TB 4FDC tabletsMonograph: Identity tests

The TB 4FDC monograph states the following:

  • Either tests A and B or test C may be applied

Tests A and B are the 2 HPLC assay tests

    • retention time compared to ICRS (reference substance)

Test C is a TLC test

    • position (Rf), appearance & intensity of spot compared to ICRS
      • note 3 parameters in one test
    • Choice with respect to visualisation of spots
      • UV or visible (after exposure to iodine vapour)

Test C first

tb 4fdc tablets monograph identity test results
TB 4FDC tabletsMonograph: Identity test (results)

Method C.2

In daylight,after exposure to I2

Method C.1

In UV (254 nm),after exposure to I2

Eth INH PY Rif Tab

In UV (254 nm),before exposure to I2

structures of the apis in tb 4fdc tablet
Structures of the APIs in TB 4FDC tablet

Isoniazid

Yes

Yes

Rifampicin

UV absorbing groups?

Yes

No

Pyrazinamide

Ethambutol

tb 4fdc tablets monograph related substances
TB 4FDC tabletsMonograph: Related substances

General recommendation for FDCs

  • Related substances (degradation products) should be tested in the FDC products for
    • APIs which are unstable
    • Very stable APIs may not be required
  • What is the situation in the case of the TB 4FDC tablets?
    • Consult literature for stability
    • Do stress testing under various conditions (part of validation)
      • Temperature, pH, oxidation, light, …
      • API-API interactions
information from literature structure rifampicin
Information from literature & structure Rifampicin

hydrolysis (to 25-desacetyl)

light sensitive

oxidation

(to N-oxide)

quinone

hydrolysis(to 3-formyl rifamycin)

oxidation

(to quinone)

information from literature structure rifampicin summary
Information from literature & structure Rifampicin - summary

Rifampicin known degradation products

  • Oxidation
    • Rifampicin quinone
    • Rifampicin N-Oxide
  • Hydrolysis
    • 3-Formyl rifamycin
    • 25-desacetyl rifampicin
  • Reaction with Isoniazid
    • isonicotinoyl hydrazone
      • 3-(isonicotinoylhydrazinomethyl)rifamycin

light sensitive

information from literature structure rifampicin21
Information from literature & structureRifampicin

Special storage conditions for the API?

International Pharmacopoeia:

  • Rifampicin should be kept in
    • a tightly closed container
      • (exclude exposure to air - moisture and oxygen)
        • (container of low permeability)
    • protected from light and
    • stored at a temperature not exceeding 15°C, or
    • in an atmosphere of nitrogen at a temperature not exceeding 30°C
      • (absence of air oxygen)
rifampicin impurities tlc
Rifampicin impurities (TLC)
  • Reference: Int.Ph. related substances test for rifampicin
    • Silica gel R1
    • CHCl3/methanol : 85/15
    • Daylight detection

a Rifampicin test substance: 20 mg/ml

b Quinone: 0.8 mg/ml (4.0%)

c N-oxide: 0.3 mg/ml (1.5%)

d 3-Formyl rifamycin: 0.1 mg/ml (0.5%)

e Rifampicin: 0.2 mg/ml (1.0%)

a b c d e

information from literature isoniazid
Information from literatureIsoniazid

Small molecule

  • Quite stable
  • Can hydrolyze under stress conditions to inter alia isonicotinic acid & hydrazine
  • Primary amine - react with aldehydes, for example
    • reducing sugars / lactose
    • 3-Formyl rifamycin(rifampicin degradation product)
information from literature pyrazinamide
Information from literaturePyrazinamide

Small molecule

    • Quite stable
    • Amide group can hydrolyse under strong conditions to pyrazinoic acid & ammonia
  • Test D in Ph.Int. monograph for Pyrazinamide API:
    • Boil 20 mg with 5 ml of sodium hydroxide (~200 g/l) TS; ammonia, perceptible by its odour, is evolved.
information from literature ethambutol hydrochloride
Information from literatureEthambutol hydrochloride

Small molecule

  • Quite stable
      • (2-aminobutanol – synthesis impurity)
  • Hygroscopic (solubility in water: 50% m/m)
    • In FDC tablets ethambutol can absorb water
      • absorbed water helps degradation of rifampicin
  • Forms metal complexes
    • Very useful in FDC assay test

S,S-isomer pharmaceutical

:N—C

:N—C

Cu++

information from literature what is important for monograph development
Information from literatureWhat is important for monograph development?
  • Rifampicin related substances to be tested for
    • Rifampicin quinone
    • Rifampicin N-Oxide
    • 3-Formyl rifamycin
    • isonicotinoyl hydrazone = product with isoniazid
    • 25-desacetyl rifampicin
  • Protect from light (mainly due to rifampicin)
    • Product (packaging) and sample / test solutions
  • Protect from moisture
    • “Manufacture”► protective packaging + set moisture limit
    • QC testing► protect tablet powder from moisture uptake
tb 4fdc tablets examples of water uptake
TB 4FDC tabletsExamples of water uptake

ProductsB A

FPPs (packed products)

Unpacked tablets (control)

After 5 days at 40°C/75% RH

After 5 days at 40°C/75% RH + Light

S. Singh, Int. J. Tuberc. Lung. Dis., 7, 298 (2003)

Quality of the products not known

“bleeding”

tb 4fdc tablets example of poor fpp
TB 4FDC tabletsExample of poor FPP

Have you seen a TB 4FDC tablet like this when opening the primary packaging?

Hopefully not

  • Example: TB 4-FDC tablets
    • one year from expiry

Photo from:

S. Singh & B. Mohan, Int. J. Tuberc. Lung. Dis., 7, 298 (2003)

tb 4fdc tablets monograph requirements29
TB 4FDC tabletsMonograph: Requirements

read General monographfor Tablets

?

tb 4fdc tablets assay and related substances
TB 4FDC tabletsAssay and related substances

The objectives

  • To develop assay methods for
    • all four APIs in the TB 4FDC tablet
    • HPLC as only option
  • To develop methods for determination of degradationproducts (related substances)
    • Only for rifampicin
    • HPLC as only option
assay tb 4fdc tablets assay and related substances
Assay TB 4FDC tabletsAssay and related substances

The approach to HPLC methods

  • Minimise the number of HPLC methods
    • Not 4 HPLC methods for assay of the 4 APIs
  • The column(s) should be easily obtainable
  • The use of an isocratic profile instead of a gradient profile
    • the test can be carried out by any laboratory
  • The assay method(s) should be stability-indicating
  • It would be advantageous if the related substances could be determined with the method(s) used for assay
assay tb 4fdc tablets assay and related substances32
Assay TB 4FDC tabletsAssay and related substances

Strategy followed

  • Screening of existing methods
    • Literature
    • Manufacturers
  • Selecting promising candidates
    • Desk and experimental evaluation
  • Optimisation of selected method(s)
  • Validation
assay tb 4fdc tablets assay and related substances33
Assay TB 4FDC tabletsAssay and related substances

The outcome

  • Two HPLC methods have been developed
  • One method for simultaneous assay of one or more of
    • Isoniazid
    • Pyrazinamide
    • Ethambutol hydrochloride
  • Another method for rifampicin
    • Assay
    • Related substances (degradation products)
assay tb 4fdc tablets isoniazid pyrazinamide ethambutol hplc
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC

Ethambutol properties were key to assay method

  • Problem
    • Ethambutol lacks useful absorption in UV/visible region
      • USP method - detection at 200 nm
  • Answer
    • Ethambutol compexes with Cu2+
      • Maximum absorption at 270-280 nm
  • Method principle
    • Copper(II) acetate in mobile phase
assay tb 4fdc tablets isoniazid pyrazinamide ethambutol hplc35
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC

buffer pH 5.0

Cu2+ in mobile phase

Pyrazinamid

Detection at 270 nm

resolution ≥ 2

Ethambutol

Isoniazid

10 min

assay tb 4fdc tablets isoniazid pyrazinamide ethambutol hplc36
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC

Validation

  • All parameters were validated
    • ICH Q2(R1)
  • Specificity of particular interest
    • No “innovator” product
    • Placebo constructed from all known excipients in 4FDC tablets
      • information from package inserts
    • Stress testing
      • water, alkali, acid, hydrogen peroxide at 40°C on one product
    • DAD (Diode Array Detection) for peak purity
assay related substances tb 4fdc tablets rifampicin hplc
Assay / related substances TB 4FDC tabletsRifampicin HPLC

Rifampicin related substances to be tested for

  • Rifampicin quinone
  • Rifampicin N-Oxide
  • 3-Formyl rifamycin
  • 3-(isonicotinoylhydrazinomethyl)rifamycin
    • "hydrazone“ obtained from 3-formylrifamycin & isoniazid reaction
    • Sample donated by Dr S. Singh, NIPER, India
  • 25-desacetyl rifampicin

Also applicable to:

    • 3FDC, 2FDC tablets and rifampicin tablets and capsules
assay related substances tb 4fdc tablets rifampicin hplc isonicotinoyl hydrazone
Assay / related substances TB 4FDC tabletsRifampicin HPLC – Isonicotinoyl hydrazone

In situ preparation of

    • 3-(isonicotinoylhydrazinomethyl)rifamycin
      • hydrazone formed from rifampicin and isoniazid reaction
    • solution (5)
  • For solution (5) dissolve 4 mg of rifampicin RS and 2 mg of isoniazid RS in 25.0 ml of acetic acid (~60g/l) TS and keep the solution at room temperature for 30 minutes
  • Rationale of in situ preparation based on molecules structures/interactions
assay tb 4fdc tablets rifampicin hplc
Assay TB 4FDC tabletsRifampicin HPLC

Validation

  • All parameters were validated
    • ICH Q2(R1)
  • Specificity of particular interest
    • No “innovator” product
    • Placebo constructed from all known excipients in 4FDC tablets
      • information from package inserts
    • Known impurities& validation
    • Stress testing
      • water, alkali, acid, hydrogen peroxide at 40°C on one product
    • DAD (Diode Array Detection) for peak purity
dissolution disintegration specifications bcs
Dissolution / disintegration specificationsBCS
  • The Biopharmaceutics Classification System (BCS) of an API is based on its
    • aqueous solubility and
    • intestinal permeability
  • According to the BCS an API falls in one of four classes:
dissolution disintegration specifications bcs41
Dissolution / disintegration specificationsBCS

High solubility definition

  • The highest single unit dose of an API is completely soluble in 250 ml or less of aqueous medium over the pH range 1.0 - 6.8 (at 37°C)
  • No relevance to Ph.Int. solubility definitions, e.g. diazepam
    • Ph.Int.
      • Very slightly soluble (1 gram in 1000 to10 000 ml of water at 20°C)
    • BCS
      • High solubility (5 mg in ≤ 250 ml at 37°C)
dissolution disintegration specifications bcs42
Dissolution / disintegration specificationsBCS

Classification of TB APIs

WHO Technical Report Series 937, Annex 8 (2006)

dissolution disintegration specifications isoniazid ethambutol tablets
Dissolution / disintegration specificationsIsoniazid/Ethambutol tablets

Acceptance criteria

Either (A) Dissolution or (B) Disintegration may be applied

  • DissolutionAll 6 units≥ 80% of label claim dissolved in 30 min.
    • If one tablet fails, average of 12 tablets ≥ 75%, none <60%
    • Criteria as set at EC meeting of Oct. 2007
  • Comply with 5.4 Disintegration test for tablets and capsules, operating the apparatus for 10 minutes
    • If the tablets do not comply, carry out test A above
    • More stringent than dissolution test

Generally applicable to Class 1 & 3 APIs

dissolution disintegration specifications isoniazid ethambutol tablets44
Dissolution / disintegration specificationsIsoniazid/Ethambutol tablets

Dissolution conditions of Ph.Int. for

  • Tablets/capsules containing a BCS highly soluble API
  • Samples analysed by HPLC method for assay

A

B

C

D

isoniazid ethambutol tablets discussion of results
Isoniazid/Ethambutol tabletsDiscussion of results
  • The dissolution profiles of the 2 APIs in a particular product are similar (this is true for all 4 products)
    • Both APIs are highly soluble (BCS definition)
  • The products show different dissolution rates
    • Dissolution rate A > B ≈ C >> D
    • Disintegration (min) 7 11 11 21
    • Dissolution rate is related to disintegration time
    • Acceptance criteria: Disintegration tighter than dissolution
  • For BCS highly soluble APIs
    • The dissolution rate is controlled mainly by disintegration of the tablets/capsules
closing remarks
Closing remarks
  • Approach for development of TB FDC tablet monographs
    • Top down (4FDC → 3FDC → 2FDC → rifampicin tabs/caps)
    • In this way all monographs can have same test methods
  • For rifampicin and rifampicin related substances
    • One HPLC method
    • Includes detection of isonicotinoyl hydrazone (API-API reaction)
  • For isoniazid, pyrazinamide & ethambutol hydrochloride
    • One method, no related substances
  • Dissolution/disintegration for isoniazid/ethambutol 2HCl tablets
    • Acceptance criteria: Disintegration tighter than dissolution
    • Ph.Int. takes lead with setting alternative criteria forClass 1 & 3 API tablets/capsules
more information
More information…

Information extracted from

The International Pharmacopoeia

http://www.who.int/medicines/publications/pharmacopoeia/en/

WHO Prequalification: Training Material and workshops

International Pharmacopoeia – Development of monographs for tuberculosis fixed-dose combination tablets – Professor. T. Dekker

http://apps.who.int/prequal/

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