Flavomycin® “The original”

2

Content

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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

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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

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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

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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”