Claims for Patent: 10,011,643

Summary for Patent: 10,011,643

Title:	Freeze-dried preparation containing high-purity PTH and method for producing same
Abstract:	[Problem] Provided is a freeze-dried preparation containing high-purity PTH peptide and a method for the production thereof. Also provided is a test method for PTH analogs to confirm the purity of a freeze-dried preparation containing PTH peptide, and the like. [Solution] In the present invention, the presence of PTH analogs produced during the manufacturing process of a freeze-dried preparation containing PTH peptide was confirmed. The production of these PTH analogs was also discovered to be markedly prevented or reduced by controlling exposure of the solution containing PTH peptide and the like to air environments within a pharmaceutical production facility.
Inventor(s):	Nishio; Fumihide (Tokyo, JP), Maejima; Takuji (Tokyo, JP), Mitome; Yoshiro (Tokyo, JP)
Assignee:	ASAHI KASEI PHARMA CORPORATION (Tokyo, JP)
Application Number:	14/990,948
Patent Claims:	1. A method for producing a freeze-dried preparation containing human parathyroid hormone (PTH) (1-34) and one or more analogs thereof, wherein the method is conducted in a pharmaceutical production facility that is sterilized by a disinfectant, the method comprising: preparing a solution containing the human PTH (1-34) and the one or more analogs thereof housed in one or more containers; loading the one or more containers containing the human PTH (1-34) and the one or more analogs thereof into a freeze-drying apparatus while controlling exposure of the solution to air environments within a pharmaceutical production facility, wherein the loading step comprises controlling inflow of air within the pharmaceutical production facility into the freeze-drying apparatus; producing a freeze-dried preparation containing the human PTH (1-34) and the one or more analogs thereof; and sealing the containers, wherein (i) the freeze-drying apparatus comprises a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit configured to be opened when the one or more containers are loaded into or are unloaded from the chamber, and the controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus comprises opening the sub-door only during the loading and quickly closing the sub-door after the loading, or (ii) the freeze-drying apparatus comprises a freeze-drying chamber having an opening created in a small door unit configured to be opened when the one or more containers are loaded into or are unloaded from the chamber, and the controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus comprises directing air flow within the pharmaceutical production facility away from the opening to the inside of the chamber by means of an airflow-adjusting cover configured to alter the air flow away from the opening of the chamber thereby controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus. 2. The method of claim 1, wherein the one or more human PTH (1-34) analogs are selected from the group consisting of: a) analog 1' an oxide of the human PTH (1-34) in which residues corresponding to position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and residue corresponding to a position 23 tryptophan is a residue of formula (a); b) analog 2' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and the residue corresponding to the position 23 tryptophan is a residue of formula (b); c) analog 3' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues; d) analog 4' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); e) analog 5' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); f) analog 6' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (b); g) analog 9' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (a); h) analog 10' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is a tryptophan monoxide residue of formula (c-1) or (c-2) below ##STR00007## i) analog 11' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (b); j) analog 7' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue; and k) analog 8' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue, wherein formula (a) is ##STR00008## and formula (b) is ##STR00009## 3. The method of claim 2, wherein the one or more human PTH (1-34) analogs are: j) analog 7'; k) analog 8'; and one or more human PTH (1-34) analogs selected from the group consisting of a) analog 1', b) analog 2', c) analog 3', d) analog 4', e) analog 5', f) analog 6', g) analog 9', h) analog 10', and i) analog 11'. 4. The method of claim 2, wherein the freeze-dried preparation comprises the human PTH (1-34) j) analog 7', k) analog 8', and one or more human PTH (1-34) analogs selected from the group consisting of a) analog 1', b) analog 2', c) analog 3', d) analog 4', e) analog 5', f) analog 6', g) analog 9', h) analog 10', and i) analog 11', wherein the human PTH (1-34) is high-purity human PTH (1-34), wherein high-purity means that (i) an amount of each of the one or more human PTH (1-34) analogs versus the sum of an amount of the human PTH (1-34) and the total amount of the human PTH (1-34) analogs in the preparation is 1.0% or less, and (ii) the total amount of human PTH (1-34) analogs versus the sum of the amount of the human PTH (1-34) and the total amount of human PTH (1-34) analogs is 5.0% or less. 5. The method of claim 1, further comprising controlling exposure of the solution containing the human PTH (1-34) and the one or more analogs thereof to air environments within the pharmaceutical production after the step of freeze drying and during the step of sealing the containers. 6. The method of claim 1, wherein loading the one or more containers containing the human PTH (1-34) and the one or more analogs thereof into the freeze-drying apparatus is carried out for a period of time of three or more hours. 7. The method of claim 1, wherein an inside of the freeze-drying apparatus is purged with an inert gas. 8. The method of claim 7, wherein the inside of the freeze-drying apparatus is purged with the inert gas after loading the containers and prior to closing the sub-door. 9. The method of claim 7, wherein the inert gas is nitrogen. 10. The method of claim 1, wherein the containers are glass vials. 11. The method of claim 1, wherein the air environment within the pharmaceutical production facility is an air environment in which 1) the air is of grade A, 2) clean air that has passed through an HEPA filter configured to trap particles having a particle size of 0.3 .mu.m at an efficiency of 99.97% or higher is maintained as a one-way air flow downward from above, and 3) the ozone concentration is 0.001-0.1 ppm. 12. The method of claim 1, wherein the air environment within the pharmaceutical production facility is an air environment containing a formaldehyde concentration of 0.1 ppm or less. 13. The method of claim 1, wherein (i) an amount of each of the one or more human PTH (1-34) analogs is 1.0% or less than the sum of an amount of the human PTH (1-34) and the total amount of the one or more human PTH (1-34) analogs, and (ii) the total amount of the one or more human PTH (1-34) analogs is 5.0% or less than a sum of the amount of the human PTH (1-34) and total amount of the one or more PTH (1-34) analogs in the freeze-dried preparation containing the human PTH (1-34). 14. A method for producing a freeze-dried preparation containing human parathyroid hormone (PTH) (1-34) and one or more analogs thereof, wherein the method is conducted in a pharmaceutical production facility that is sterilized by a disinfectant and comprises an air environment comprising substances having oxidizing capability, the method comprising: preparing a solution containing the human PTH (1-34) and one or more analogs thereof-housed in one or more containers; loading the one or more containers containing the human PTH (1-34) and one or more analogs thereof into a freeze-drying apparatus; producing a freeze-dried preparation containing the human PTH (1-34) and one or more analogs thereof; and sealing the containers; and wherein the method further comprises controlling contact of the human PTH (1-34) and one or more analogs thereof with the substances having oxidizing capability in the air environments within the pharmaceutical production facility. 15. The method of claim 2, wherein the freeze-dried preparation in the sealed containers comprises one or more human PTH (1-34) analogs selected from the group consisting of analog 1', analog 2', analog 4', analog 5', analog 6', analog 9', analog 10', and analog 11', and (i) an amount of each of the one or more human PTH (1-34) analogs versus the sum of an amount of the human PTH (1-34) and the total amount of the human PTH (1-34) analogs in the preparation is 1.0% or less, and (ii) the total amount of human PTH (1-34) analogs versus the sum of the amount of the human PTH (1-34) and the total amount of human PTH (1-34) analogs is 5.0% or less. 16. The method of claim 14, wherein the one or more human PTH (1-34) analogs are selected from the group consisting of: a) analog 1' an oxide of the human PTH (1-34) in which residues corresponding to position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and residue corresponding to a position 23 tryptophan is a residue of formula (a); b) analog 2' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and the residue corresponding to the position 23 tryptophan is a residue of formula (b); c) analog 3' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues; d) analog 4' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); e) analog 5' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); f) analog 6' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (b); g) analog 9' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (a); h) analog 10' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is a tryptophan monoxide residue of formula (c-1) or (c-2) below ##STR00010## i) analog 11' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (b); j) analog 7' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue; and k) analog 8' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue, wherein formula (a) is ##STR00011## and formula (b) is ##STR00012## 17. The method of claim 16, wherein the one or more human PTH (1-34) analogs are: j) analog 7'; k) analog 8'; and one or more human PTH (1-34) analogs selected from the group consisting of a) analog 1', b) analog 2', c) analog 3', d) analog 4', e) analog 5', f) analog 6', g) analog 9', h) analog 10', and i) analog 11'. 18. The method of claim 16, wherein the freeze-dried preparation comprises the human PTH (1-34) j) analog 7', k) analog 8', and one or more human PTH (1-34) analogs selected from the group consisting of a) analog 1', b) analog 2', c) analog 3', d) analog 4', e) analog 5', f) analog 6', g) analog 9', h) analog 10', and i) analog 11', wherein the human PTH (1-34) is high-purity human PTH (1-34), wherein high-purity means that (i) an amount of each of the one or more human PTH (1-34) analogs versus the sum of an amount of the human PTH (1-34) and the total amount of the human PTH (1-34) analogs in the preparation is 1.0% or less, and (ii) the total amount of human PTH (1-34) analogs versus the sum of the amount of the human PTH (1-34) and the total amount of human PTH (1-34) analogs is 5.0% or less. 19. The method of claim 14, further comprising controlling exposure of the solution containing the human PTH (1-34) and the one or more analogs thereof to air environments within the pharmaceutical production after the step of producing a freeze-dried preparation and during the step of sealing the containers. 20. The method of claim 14, wherein the loading step comprises controlling inflow of air within the pharmaceutical production facility into the freeze-drying apparatus. 21. The method of claim 14, wherein loading the one or more containers containing the human PTH (1-34) and the one or more analogs thereof into the freeze-drying apparatus is carried out for a period of time of three or more hours. 22. The method of claim 20, wherein the freeze-drying apparatus comprises a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit configured to be opened when the one or more containers are loaded into or are unloaded from the chamber, and the controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus comprises opening the sub-door only during the loading and quickly closing the sub-door after the loading. 23. The method of claim 20, wherein the freeze-drying apparatus comprises a freeze-drying chamber having an opening created in a small door unit configured to be opened when the one or more containers are loaded into or are unloaded from the chamber, and the controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus comprises directing air flow within the pharmaceutical production facility away from the opening to the inside of the chamber by means of an airflow-adjusting cover configured to alter the air flow away from the opening of the chamber thereby controlling the inflow of air within the pharmaceutical production facility into the freeze-drying apparatus. 24. The method of claim 14, wherein an inside of the freeze-drying apparatus is purged with an inert gas. 25. The method of claim 22, wherein the inside of the freeze-drying apparatus is purged with the inert gas after loading the containers and prior to closing the sub-door. 26. The method of claim 24, wherein the inert gas is nitrogen. 27. The method of claim 14, wherein the containers are glass vials. 28. The method of claim 14, wherein the air environment within the pharmaceutical production facility is an air environment in which 1) the air is of grade A, 2) clean air that has passed through an HEPA filter configured to trap particles having a particle size of 0.3 .mu.m at an efficiency of 99.97% or higher is maintained as a one-way air flow downward from above, and 3) the ozone concentration is 0.001-0.1 ppm. 29. The method of claim 14, wherein the air environment within the pharmaceutical production facility is an air environment containing a formaldehyde concentration of 0.1 ppm or less. 30. The method of claim 14, wherein (i) an amount of each of the one or more human PTH (1-34) analogs is 1.0% or less than the sum of an amount of the human PTH (1-34) and the total amount of the one or more human PTH (1-34) analogs, and (ii) the total amount of the one or more human PTH (1-34) analogs is 5.0% or less than a sum of the amount of the human PTH (1-34) and total amount of the one or more PTH (1-34) analogs in the freeze-dried preparation containing the human PTH (1-34). 31. A method for producing a freeze-dried preparation containing human parathyroid hormone (PTH)(1-34) and one or more analogs thereof, wherein the method is conducted in a pharmaceutical production facility that is sterilized by a disinfectant, the method comprising: preparing a solution containing the human PTH (1-34) and the one or more analogs thereof housed in one or more containers; loading the one or more containers containing the human PTH (1-34) and the one or more analogs thereof into a freeze-drying apparatus while controlling exposure of the solution to air environments within a pharmaceutical production facility; producing a freeze-dried preparation containing the human PTH (1-34) and the one or more analogs thereof; and sealing the containers, wherein the one or more human PTH (1-34) analogs are selected from the group consisting of: a) analog 1' an oxide of the human PTH (1-34) in which residues corresponding to position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and residue corresponding to a position 23 tryptophan is a residue of formula (a); b) analog 2' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and the residue corresponding to the position 23 tryptophan is a residue of formula (b); c) analog 4' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); d) analog 5' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); e) analog 6' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (b); f) analog 9' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (a); g) analog 10' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is a tryptophan monoxide residue of formula (c-1) or (c-2) below ##STR00013## and h) analog 11' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (b); wherein formula (a) is ##STR00014## and formula (b) is ##STR00015## and (i) an amount of each of the one or more human PTH (1-34) analogs versus the sum of an amount of the human PTH (1-34) and the total amount of the human PTH (1-34) analogs in the preparation is 1.0% or less, and (ii) the total amount of human PTH (1-34) analogs versus the sum of the amount of the human PTH (1-34) and the total amount of human PTH (1-34) analogs is 5.0% or less.

Details for Patent 10,011,643

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2031-06-07