Beruflich Dokumente
Kultur Dokumente
Abbreviations
API BP CEP EOI FDC FPP GMP ICH Int.Ph. Ph.Eur. SmPC TB USP
Feb 2005
Active pharmaceutical ingredient British Pharmacopoeia EU certificate of suitability Expression of interest Fixed dose combination Finished pharmaceutical product Good manufacturing practices International Conference on Harmonization International Pharmacopoeia European Pharmacopoeia Summary of product characteristics Tuberculosis United States Pharmacopeia
2
TG Dekker WHO, Malaysia
Presentation approach
1. Collect and interpret all available information on the APIs (pre-dossier studies):
Feb 2005
The possible manufacturer(s) Literature, all aspects Monographs in pharmacopoeia Nomenclature Properties Manufacturing and site Specifications Container closure Stability testing / re-test period
3
TG Dekker WHO, Malaysia
2. Dossier requirements
1. Is the manufacturer reliable / reputable? 2. Is the open part of DMF available and according to all requirements? 3. Is a valid CEP available? 4. GMP inspection of API site by FPP manufacturer
Feb 2005
DMF 2 3 3 5 1 14
6
CEP 1 1 3
5
TG Dekker WHO, Malaysia
Literature information
Know your API before development, through: Standard works / series / books such as:
(Analytical) Profiles of Drug Substances and Excipients [ed: (Florey) Brittain) 30 volumes] The Merck Index (for structures, properties) Pharmaceutical Codex (12th edition) International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts & internet
Feb 2005
APr Cod BP EP US
Int
MI
10
MI
Feb 2005
Water
Water: Slightly 1,2 pH 7.5: 0.3% 2 pH 5.3: 0.4% 2 pH 2.0: 10% 2 50% 2 Sparingly 2 14% 1 1.5% 1
2
CHCl3
Freely 1,2
Ethanol
Slightly 2
20% 2 2% 1 0.6% 2
Feb 2005
12
13
Rifampicin structure
hydrolysis
oxidation
hydrolysis
Feb 2005
14
Feb 2005
15
Tertiary amine
Moderately prone towards oxidation (to N-oxide) Enhances solubility in acid medium
Oxidation enhanced by
Metal ions Low pH
Feb 2005
16
Light sensitive
Due to conjugation in molecule (unsaturated)
17
18
Isoniazid structure
Feb 2005
Pyrazinamide structure
20
Pyrazinamide synthesis
21
Small molecule
Basic amino groups (in free base) No vulnerable groups for degradation under mild conditions (2-aminobutanol synthesis impurity) 2 chiral carbon atoms, optically active (test) Hygroscopic (solubility in water: 50% m/m) Can dissolve in absorbed water at high relative humidity Forms metal complexes USP: Preserve in well-closed containers
Feb 2005
22
p-Aminosalicylic acid
+ CO2
Carboxylic acid and phenolic group: acidic Weak basic group (amphoteric) Saturated solution: pH of 3.0-3.5 (USP) Sodium salt available (monograph in USP) Labile: Decarboxylate when heated Limit test for m-aminophenol in USP (API & tablets) More stable in alkaline medium than in acid medium Store in cool place!! 23
TG Dekker WHO, Malaysia
Feb 2005
Cycloserine
R-configuration
Optically active
H20
Stable in anhydrous solid state, protected from water Degrades in solution, or when solid is exposed to moisture Pathway1: Dimerisation through one molecule attacking other Pathway 2: Hydrolysis to -aminoxy-D-alanine Stability: alkaline medium > neutral >> acid medium Dissolution medium capsules: buffer pH 6.8 !!! (USP) Primary amine: react with aldehydes/ketones 24
TG Dekker WHO, Malaysia
Feb 2005
Ofloxacin
Moxifloxacin
Structurally related as encircled (see also ciprofloxacin) Both APIs contain acid and basic groups Chirality: both intrinsic chiral (optically active) Ofloxacin: 1 chiral centre: racemate ( ) used Moxifloxacin: 2 chiral centra: S,S-enatiomer used Both APIs have enone system (in circle): photosensitive?
Feb 2005
25
hydrolysis
Feb 2005
26
Feb 2005
27
28
29
Part 2. Dossier requirements for Active pharmaceutical ingredient (API) 2.1 2.2 2.3 2.4 2.5 2.6 2.7
-
3/33
Nomenclature (INN, Systematic, CAS, etc.) Properties (structure, stereochemistry, etc) Site of manufacture Route of synthesis (impurities, etc) Specifications (pharmacopoeia?) Container closure system Stability testing re-test period & storage
Open part of Drug Master File - submit (DMF) CEP (only limited information required)
Feb 2005
30
31
32
33
Feb 2005
34
Feb 2005
35
A full description of each process, including purification and reprocessing (justified) (Possible) process impurities should be discussed:
Organic compounds Catalysts and other inorganic impurities Residual solvents
Feb 2005
36
No CEP
Same as for non-compendial APIs
Feb 2005
37
38
39
Valid CoAs for at least 2 batches 2.5.3 Container-closure system for API 4/33
see guideline
Feb 2005
40
Feb 2005
41
42
Feb 2005
43
Some conclusions
1. Get to know your API by
Analysis of literature information Analysis of the structures / functional groups Lab studies, e.g. forced degradation, spectral data and physical data Considering the dossier requirements DMF quality, GMP inspection, CEP availability
2. Decision on API manufacturer should include 3. API manufacturers are encouraged to apply for CEPs for their APIs
Feb 2005
44