the international pharmacopoeia quality standards for tb medicines caroline mendy - technical...
TRANSCRIPT
The International Pharmacopoeia
Quality standards for TB medicines
Caroline Mendy - Technical Officer - Quality Assurance and Safety: Medicines
Tutorial workshop, Beijing, March 2010
2 | Tutorial workshop, Beijing, March 2010
Quality standards for TB medicines – an issue?
Quality standards for TB medicines – 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
3 | Tutorial workshop, Beijing, March 2010
Quality standards for TB medicinesQuality standards for TB medicines
1. Monographs available in Ph.Int.
2. Monographs, requirements and identity tests
3. Assay and related substances– method development
4. Dissolution / disintegration specifications– Isoniazid and Ethambutol hydrochloride tablets
Focus: TB FDC tablets
4 | Tutorial workshop, Beijing, March 2010
Ph.Int. TB monographsPh.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)
5 | Tutorial workshop, Beijing, March 2010
Ph.Int. TB monographsPh.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)
6 | Tutorial workshop, Beijing, March 2010
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
7 | Tutorial workshop, Beijing, March 2010
Ph.Int. monographs: TB FDC dosage formsPh.Int. monographs: TB FDC dosage forms
4FDC: Rifampicin / Isoniazid / Pyrazinamide / Ethambutol HCl tablets
3FDC: Rifampicin / Isoniazid / Pyrazinamide tabletsRifampicin / Isoniazid / Pyrazinamide dispersible tablets (new)Rifampicin / Isoniazid / Ethambutol HCl tablets (new)
2FDC: Rifampicin / Isoniazid tabletsRifampicin / Isoniazid dispersible tablets (new) Isoniazid / Ethambutol HCl tablets
Rifampicin tabletsRifampicin capsules
Basic approach for monograph development: top down
9 monographs!
8 | Tutorial workshop, Beijing, March 2010
Ph.Int. monographs: TB FDC dosage formsPh.Int. monographs: TB FDC dosage forms
Strategy– Start with the most complex combination (4FDC tablets)– Work down to most simple situation using same procedures
Rifampicin
Ethambutol
Isoniazid
Pyrazinamide
4FDC
3FDC
2FDC
9 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsPh.Int. monograph: Information section
TB 4FDC tabletsPh.Int. monograph: Information section
√
?
√
10 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: Requirements
TB 4FDC tabletsMonograph: Requirements
√
√
?
read General monograph for Tablets
11 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: 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
1. More than one test may apply for conclusive identification– tests X and Y
2. There may be a choice between tests– either test X or test Y may be applied
read instruction in monograph carefully
12 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: Identity tests
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
13 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: Identity test (copy from monograph)
TB 4FDC tabletsMonograph: Identity test (copy from monograph)
HF254
14 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: Identity test (results)
TB 4FDC tabletsMonograph: Identity test (results)
Eth INH PY Rif Tab
In UV (254 nm),before exposure to I2
Method C.2In daylight,
after exposure to I2
Method C.1In UV (254 nm),
after exposure to I2
15 | Tutorial workshop, Beijing, March 2010
Structures of the APIs in TB 4FDC tabletStructures of the APIs in TB 4FDC tablet
Rifampicin
Isoniazid
Pyrazinamide Ethambutol
UV absorbing groups?
YesYes
YesNo
16 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: 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
17 | Tutorial workshop, Beijing, March 2010
Information from literature & structure Rifampicin
Information from literature & structure Rifampicin
oxidation(to N-oxide)
light sensitive
oxidation(to quinone)
hydrolysis(to 3-formyl rifamycin)
hydrolysis (to 25-desacetyl)
quinone
18 | Tutorial workshop, Beijing, March 2010
Information from literature & structure 3-Formyl rifamycin
Information from literature & structure 3-Formyl rifamycin
o
+ H2N ― R
R Isoniazid
19 | Tutorial workshop, Beijing, March 2010
Information from literature & structure “isonicotinoyl hydrazone”
Information from literature & structure “isonicotinoyl hydrazone”
o
N ― R
R Isoniazid
20 | Tutorial workshop, Beijing, March 2010
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
21 | Tutorial workshop, Beijing, March 2010
Information from literature & structureRifampicin
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)
22 | Tutorial workshop, Beijing, March 2010
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
23 | Tutorial workshop, Beijing, March 2010
Information from literatureIsoniazid
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)
24 | Tutorial workshop, Beijing, March 2010
Information from literaturePyrazinamide
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.
25 | Tutorial workshop, Beijing, March 2010
Information from literatureEthambutol hydrochlorideInformation 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—CCu++
26 | Tutorial workshop, Beijing, March 2010
Information from literatureWhat 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
27 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsExamples of water uptake
TB 4FDC tabletsExamples of water uptake
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)
ProductsB A
Quality of the products not known
“bleeding”
28 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsExample 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)
29 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsMonograph: Requirements
TB 4FDC tabletsMonograph: Requirements
√
√
?
read General monograph for Tablets
√
30 | Tutorial workshop, Beijing, March 2010
TB 4FDC tabletsAssay and related substances
TB 4FDC tabletsAssay and related substances
The objectives
1. To develop assay methods for– all four APIs in the TB 4FDC tablet– HPLC as only option
2. To develop methods for determination of degradation products (related substances)– Only for rifampicin– HPLC as only option
31 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tabletsAssay and related substances
Assay TB 4FDC tabletsAssay and related substances
The approach to HPLC methods
1. Minimise the number of HPLC methods– Not 4 HPLC methods for assay of the 4 APIs
2. The column(s) should be easily obtainable
3. The use of an isocratic profile instead of a gradient profile– the test can be carried out by any laboratory
4. The assay method(s) should be stability-indicating
5. It would be advantageous if the related substances could be determined with the method(s) used for assay
32 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tabletsAssay and related substances
Assay TB 4FDC tabletsAssay and related substances
Strategy followed
1. Screening of existing methods– Literature– Manufacturers
2. Selecting promising candidates– Desk and experimental evaluation
3. Optimisation of selected method(s)
4. Validation
33 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tabletsAssay and related substances
Assay TB 4FDC tabletsAssay and related substances
The outcome
Two HPLC methods have been developed
1. One method for simultaneous assay of one or more of– Isoniazid– Pyrazinamide– Ethambutol hydrochloride
2. Another method for rifampicin– Assay– Related substances (degradation products)
34 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tablets Isoniazid/Pyrazinamide/Ethambutol HPLC
Assay TB 4FDC tablets Isoniazid/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
35 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC
min0 1 2 3 4 5 6 7 8 9
mAU
0
200
400
600
800
1000
1200
1400
DAD1 A, Sig=270,4 Ref=360,100 (AMR_EA\27070419.D)
1.7
55
-
Iso
nia
zid
2.1
93
-
Py
raz
ina
mid
e
5.7
53
-
Eth
am
bu
tol H
Cl
Ison
iazi
dP
yraz
inam
id
Eth
ambu
tol
10 min
Cu2+ in mobile phase
Detection at 270 nm
resolution ≥ 2
buffer pH 5.0
36 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tabletsIsoniazid/Pyrazinamide/Ethambutol HPLC
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
37 | Tutorial workshop, Beijing, March 2010
Assay / related substances TB 4FDC tabletsRifampicin 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
38 | Tutorial workshop, Beijing, March 2010
Assay / related substances TB 4FDC tabletsRifampicin HPLC – Isonicotinoyl hydrazoneAssay / 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
39 | Tutorial workshop, Beijing, March 2010
Assay TB 4FDC tablets Rifampicin HPLC
Assay TB 4FDC tablets Rifampicin 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
40 | Tutorial workshop, Beijing, March 2010
Dissolution / disintegration specificationsBCS
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:
ClassSolubilityPermeability
1HighHigh
2LowHigh
3HighLow
4LowLow
41 | Tutorial workshop, Beijing, March 2010
Dissolution / disintegration specificationsBCS
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)
42 | Tutorial workshop, Beijing, March 2010
Dissolution / disintegration specificationsBCS
Dissolution / disintegration specificationsBCS
Classification of TB APIs
WHO Technical Report Series 937, Annex 8 (2006)
APIClassSolubility
Rifampicin(300 mg)
2Low
Isoniazid(300 mg)
3/1High
Pyrazinamide(400 mg)
3/1High
Ethambutol 2HCl(400 mg)
3High
43 | Tutorial workshop, Beijing, March 2010
Dissolution / disintegration specificationsIsoniazid/Ethambutol tablets
Dissolution / disintegration specificationsIsoniazid/Ethambutol tablets
Acceptance criteria
Either (A) Dissolution or (B) Disintegration may be applied
A. 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
B. 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
44 | Tutorial workshop, Beijing, March 2010
Dissolution / disintegration specificationsIsoniazid/Ethambutol tablets
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
ApparatusPaddle, 75 rpm
Dissolution medium
pH 6.8 phosphate buffer
Volume of medium
500 ml
Degassed?No (undegassed)
Temperature37°C ± 0.5°C
Sampling points
10, 15, 20, 30, 45, and 60
4 products testedAPI: Isoniazid
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Withdrawal time in minutes
Dis
so
luti
on
(%
)
4 products testedAPI: Ethambutol
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Withdrawal time in minutes
Dis
so
luti
on
(%
)
A
C
D
B
45 | Tutorial workshop, Beijing, March 2010
Isoniazid/Ethambutol tabletsDiscussion of results
Isoniazid/Ethambutol tabletsDiscussion of results
1. 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)
2. 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
3. For BCS highly soluble APIs– The dissolution rate is controlled mainly by disintegration of
the tablets/capsules
46 | Tutorial workshop, Beijing, March 2010
Closing remarksClosing remarks
1. 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
2. For rifampicin and rifampicin related substances– One HPLC method– Includes detection of isonicotinoyl hydrazone (API-API reaction)
3. For isoniazid, pyrazinamide & ethambutol hydrochloride– One method, no related substances
4. Dissolution/disintegration for isoniazid/ethambutol 2HCl tablets– Acceptance criteria: Disintegration tighter than dissolution– Ph.Int. takes lead with setting alternative criteria for
Class 1 & 3 API tablets/capsules
47 | Tutorial workshop, Beijing, March 2010
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/