Flavomycin ® “The original”. 2 Content 3 Introduction Stability Flavomycin ® compared with...
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Flavomycin® “The original”
2
Content
3
Content
• Introduction • Stability Flavomycin® compared with generics
- Flavomycin 40 and 80- in feed- in premix
• Conclusions
O
COOHCH3
HO
O
NH2
O
O
O
NHHO
O
CH3
O P
O
OH
O COOH
H
O
O
HO
HO OH
OH
O
O
CH3
HN
O
HO
CH3
O
O
OHHO
HO
NH
O
O
OH
H3C CH3 CH3
O
CH3
CH3
CH2
CH3
Flavomycin
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Introduction
• Wallhäuser et al in 1965, designated it as moenomycin• Popular names: “bambermycin”, “flavophospholipol”, Flavomycin® • Initially recovered from:
– Streptomyces bambergiensis – Three other Streptomyces spp. (S. ghanaensis, S. ederensis, and S.
geysiriensis) are also identified• Flavophospholipol is stable in:
– the pH range from 7 to 9 – the presence of a large variety of enzymes (including trypsin,
amylase, lysozyme, and lipase) • Is a complex of five active, chemically related, compounds (A, A1/2
C1, C2 and C3), all (Huber et al 1965; Lenoir et al 1970) • Characterized as very high molecular weight phosphorus containing
glycolipids (1582 g/mol)• Biologically, flavophospholipol had particular antibiotic activity against
Gram positive bacteria:– no evidence of cross resistance to other antibiotics such as penicillin,
tetracycline or macrolides (Wasielewski et al 1965)
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Flavomycin® Specifications
• Flavophospholipol content• Moisture* (2% average)• Heavy Metals
o Arsenic ≤ 5 ppmo Lead ≤ 10 ppmo Cadmium ≤ 5 ppmo Mercury ≤ 0.2 ppm
* H2O content bound inside the Flavomycin molecule determines heat stability. The Flavomycin molecule is compact due to intra-molecular bounds and contains less H2O molecules, compared with generics.
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Moisture and pH
Loss during drying
1%
3%
5%
7%
9%
Flavom
ycin
40
Gen
eric
A
Gen
eric
B
Gen
eric
C
%
7
7,5
8
8,5
9
pH
Loss of
pH
7
Specifications cont’d
• Product description Visual (aspect, color)
• Bulk density (loose) Volumetric check
• Bulk density (compacted) Volumetric check
• Flow properties Shear cell test
• Particle size distribution Laser diffraction test
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0102030405060708090
%
Components distribution %
A A1/2 C1 C3 C4
Typical distribution of FPL components: A, A1/2, C1, C3, C4
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Components without A
02468
101214161820
1 2 3 4 5 6 7 8 9
Gener
ic 1
Gener
ic 2
Gener
ic 3
%
A1/2 C1 C3 C4
Not the right % spread
Typical distribution of FPL components: A, A1/2, C1, C3, C4
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Stability data summary
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Flavomycin 40 and 80
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Stability Flavomycin Huvepharma
0
2
4
6
8
10
12
0 1 2 3 6 9
months
%
40°C RH 75% Moisture 40°C RH 75% Activity
25°C RH 60% Moisture 25°C RH 60% Activity
Flavomycin® stability data Huvepharma
(for regulatory purpose)
Fl 80
Fl 40
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Residual stability FLP
70
75
80
85
90
95
100
0 5 10 20
Time lines in days
%
Huvepharma
Generic 1
Generic 2
Generic 3
vs. Flavomycin®
Stability study performed under stress conditions during 20 days at 55°C
Flavomycin® vs. generics
Evolution of FPL content in % of the claimed activity
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Stability Flavo next to generics
283032343638404244
Declared +6md +9 md +12 md
µg
/mg
Flavomycin 40 Generic A Generic B Generic C
Stability Flavomycin® in normal storing conditions vs. generics
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IN FEED
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Stability in different extruded feeds• Flavomycin mixed into piglet and broiler feed undergoing
extrusion process
• temperature and pressure at head of extruder: 145°C, 50 bar
• duration of passage through extruder: 5 to 10 sec.
• efficiency of extruder: 300 kg of feed/h values given are the average of 4 replicates
Piglet feed Broiler feed
Content of active ingredient Mg/kg % Mg/kg %
Nominal 20 100 20 100
Actual
before conditioning 21 105 19 95
after conditioning 19 95 18.8 94
after extrusion, before cooling 21.3 106.5 20.3 101.5
after extrusion and cooling 20.8 104 20.5 102.5
Ref.: Trial report no. 1358 of International Institute of Feed Technology, Braunschweig, Germany
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Stability under Expansion Conditions
Ref.: Trial report no. 1457 of “Research Institute for Feed Technology”, IFF, Braunschweig, Germany
Broiler Feed• Production line consisted of mixer, conditioner, expander, pellet press and cooler;
expander yielded 1t / hour• two approaches were run:
• one using commercially practiced conditions• the other using maximum conditions technically possible with equipment
employed in heat, pressure and energy. Commercial conditions
parametersmaximum conditions
temperature during expansion 90 - 112 ° 124 - 135 ° after expansion 95 ° 100 ° after pelleting 97 ° 100 °pressure in expander 52 bar 70 barspecific energetic input 33.7 kWh/t 40.8 kWh/t
results
site of measurement inclusion, ppm % inclusion, ppm %after mixing 28.7 100 28.3 100after conditioning 25.7 89.5 26.0 91.9after expansion 26.3 91.6 27.0 95.4after pelleting/cooling 29.3 102.1 28.3 100
Feed contained 5.2 % fat; dosage used for FLAVOMYCIN is not a recommendation, but was used to minimize random variation
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In Premix
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Comparison of Flavomycin and Flaveco*
under different storage conditions
Storage conditions: 25 °C / 50 % h 40 °C / 75 % h
Premix: Flavomycin Flaveco Flavomycin Flaveco
Batch; Prod. Date: U023; 8/98 098051038; 5/98 U023; 8/98 098051038; 5/98
Expected content; mg/kg: 40.000 40.000 40.000 40.000
Initial content 1/99: 44.200 33.300 44.200 33.300
After 4 weeks storage: 48.133 34.567 42.250 30.000
After 8 weeks storage: 44.050 31.350 40.050 24.950
After 12 weeks storage: 42.500 31.300 37.700 23.000
After 21 weeks storage: 39.800 29.200 36.600 15.600
*Flaveco is based on Chinese FPL
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Storage condition: 25 °C / 50 % h
44.200
48.133
44.050
39.800
33.30034.567
31.350 31.30029.200
42.500
20.000
25.000
30.000
35.000
40.000
45.000
50.000
start 4 weeks 8 weeks 12 weeks 21 weeks
Flavomycin Flaveco
Comparison of Flavomycin and Flavecounder different storage conditions
expected level
21
Storage condition: 40 °C / 75 % h
44.20042.250
40.05036.600
33.30030.000
24.95023.000
15.600
37.700
10.000
15.000
20.000
25.000
30.000
35.000
40.000
45.000
50.000
start 4 weeks 8 weeks 12 weeks 21 weeks
Flavomycin Flaveco
Comparison of Flavomycin and Flavecounder different storage conditions
expected level
22
Conclusions
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Conclusion
o Better stability vs. generics of the additive itself, in feed and in premix which is related to:
– Compacter molecule, low nr of H2O molecules bound– Fermentation technology and knowledge– Fermentation medium composition– Quality of carrier and additives used in its composition
o Superior formulation– Available as dust free powder or as granule– Standardization technology– Spray dry technology
o Strict compliance of the specs of the different components – Five different components (e.g. component A between 40 and
80% of the FLP complex)– Percentage of components is calculated in accordance to the
detected potency (relative)– Water content, pH
o Investments in technology & Quality– Modern EU fermentation sites with the most important
certifications: HACCP,GMP, GMP+, FDA, ISO.
Flavomycin, the original
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Flavomycin®
“ADDING PERFORMANCE TO YOUR BUSINESS”