JP7147017B2 - Method for producing sterile injection containing teriparatide or its salt - Google Patents

Description

The present invention relates to a method for producing a sterile injectable preparation containing teriparatide or a salt thereof, and the like.

There are two methods for manufacturing aseptic pharmaceuticals, the terminal sterilization method and the aseptic operation method. It has been reported that this is a method used for producing sterile pharmaceutical products after filter sterilization or through a series of aseptic processes from the raw material stage (Non-Patent Document 1).

In addition, the Ministry of Health, Labor and Welfare of Japan has issued "Guidelines for the production of sterile pharmaceuticals by terminal sterilization" (Non-Patent Document 2) and "Guidelines for the production of sterile pharmaceuticals by aseptic operation" (Non-Patent Document 3)
Isolators and Restricted Access Barrier Systems (RA
BS: Restricted Access Barrier System) is known (Non-Patent Document 3).

In addition, isolator sterility is provided by physical isolation of workers, elimination of the risk of introducing contamination from the air, and systems that prevent the introduction of non-sterile material into the isolator [4]; In order to maintain the sterility of the isolator, it has been reported that everything brought inside must be sterile (Non-Patent Document 5). An example is also disclosed in which the filling and seaming processes are performed in an isolator, which is a grade A environment, and the inspection and packaging processes are performed in a grade D environment (Non-Patent Document 5).

On the other hand, it has been reported that containerized protein solution preparations, in which erythropoietin, granular colony-stimulating factor, insulin, monoclonal antibodies, and other protein preparations are liquefied and housed in containers such as syringes, have been widely used. (Patent document 1).

Since prefilled syringes and vials for filling pharmaceuticals are small, they are sometimes packaged together and brought into a sterile work room. It has also been reported that syringes and the like are often contained in packages that must have their surfaces decontaminated before being brought into a controlled sterile environment (US Pat.

On the other hand, isolators generally require periodic sanitization with chemical agents such as vaporized hydrogen peroxide (VHP), which is often It has also been reported that the efficacy of the resulting drug may be reduced (Patent Document 5).

In addition, a therapeutic agent for osteoporosis containing teriparatide or its acetate as an active ingredient has been marketed (Non-Patent Documents 7-8), and a method for producing a freeze-dried preparation containing PTH has also been reported (
Patent Document 4).

WO2016/051962 JP 2016-129677 A Japanese Patent Publication No. 2004-514476 WO2012/169435 Japanese Patent Publication No. 2010-509563

Nakasada Hiroshi, ``Aseptic Operation Certification'', February 20, 2015, 7th Education Program on ``Manufacturing Standards'' for In-Hospital Manufactured PET Drugs Ministry of Health, Labor and Welfare, Pharmaceutical and Food Safety Bureau, Monitoring and Guidance and Narcotics Division, "Guidelines for Manufacture of Sterile Drugs by the Final Sterilization Method", November 9, 2012 Ministry of Health, Labor and Welfare, Pharmaceutical and Food Safety Bureau, Monitoring and Guidance and Narcotics Division, April 20, 2011, regarding the revision of the "Guidelines for the production of sterile pharmaceuticals using aseptic procedures" Kazuhito Tanimoto et al., PDA Journal of GMP and Validation in Japan, (2017), Vol.19, No.2, pp.45-55 Tomoya Deguchi, PDA Journal of GMP and Validation in Japan, (2010) , Vol.12, No.2, pp.70-77 Japanese Pharmacopoeia 16th Edition General Test Methods "8.01 Sterilization and Aseptic Procedures", Ministry of Health, Labor and Welfare Notification No. 65, March 24, 2011 Forteo (registered trademark) subcutaneous injection kit 600 μg package insert (revised January 2018 (8th edition)) Teribone (registered trademark) for subcutaneous injection 56.5 μg package insert (revised January 2018 (8th edition))

An object of the present invention is to provide a method for producing a sterile injection containing teriparatide or a salt thereof by an aseptic method, which is of high quality and excellent in storage stability.

The present invention relates to the following [1] to [7].
[1]
A method for producing a sterile injectable formulation containing teriparatide or a salt thereof by aseptic technique, comprising the steps of transferring a package containing drug-free injection containers into an apparatus or system having an aseptic operating area, and , a step of decontaminating the exterior surface of the package with hydrogen peroxide or alcohol before the delivery, respectively.
[2]
A method for producing a sterile injectable containing teriparatide or a salt thereof by an aseptic technique, comprising a step of decontaminating the exterior surface of a package containing a drug-free injection container with hydrogen peroxide or alcohol, and A method for producing a sterile injectable, comprising the step of loading the package obtained in the decontamination step into an apparatus or system having an aseptic operation area.
[3]
The method for producing a sterile injection according to the above [1], wherein the device or system having a sterile operation area is an isolator.
[4]
The amount of teriparatide or its salt contained in the sterile injection is 28.2 μg in terms of teriparatide
The manufacturing method according to the above [1] or [2].
[5]
A method for stabilizing a sterile injection containing teriparatide or a salt thereof as an active ingredient,
A process of decontaminating the outer surface of a package containing an injection container that does not contain a drug solution containing the active ingredient with hydrogen peroxide or alcohol, and a device having an aseptic operation area for the package obtained in the decontamination process. Or a method for stabilizing a sterile injectable, characterized in that the sterile injectable is manufactured by a manufacturing method using an aseptic operation method, which includes a step of carrying the drug into the system, and a step of aseptically filling the injection container with the drug solution.
[6]
A method for stabilizing an active ingredient during storage of a sterile injectable containing teriparatide or a salt thereof as an active ingredient, comprising peroxidizing the exterior surface of a package containing an injection container containing no drug solution containing the active ingredient. decontaminating with hydrogen or alcohol, and carrying the package resulting from the decontamination step into an apparatus or system having an aseptic operating area; and
A method for stabilizing an active ingredient during storage of a sterile injectable, characterized in that the sterile injectable is manufactured by a manufacturing method using an aseptic method including a step of aseptically filling the drug solution into the injection container.
[7]
A method for suppressing oxidation and/or cleavage of an active ingredient during storage of a sterile injectable containing teriparatide or a salt thereof as an active ingredient, comprising a package containing an injection container that does not contain a drug solution containing the active ingredient. A step of decontaminating the exterior surface of with hydrogen peroxide or alcohol, and a step of carrying the package obtained in the decontamination step into a device or system having an aseptic operation area, and aseptically putting the drug solution into the injection container 1. A method for suppressing oxidation and/or cleavage of an active ingredient during storage of a sterile injectable, which comprises manufacturing a sterile injectable by an aseptic manufacturing method including a filling step.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for producing a sterile injection containing teriparatide or a salt thereof by an aseptic method, which is of high quality and excellent in storage stability. Further, according to the present invention, a method for stabilizing a sterile injectable containing teriparatide or a salt thereof as an active ingredient, a method for stabilizing an active ingredient during storage of the sterile injectable,
A method for suppressing oxidation and/or cleavage of active ingredients during storage of sterile injectables can also be provided. Hereinafter, the production method of the present invention will be described as an example, but each of the above methods (method for stabilizing a sterile injectable, method for stabilizing an active ingredient, method for suppressing oxidation and/or cleavage of an active ingredient) It is the same.

The production method of the present invention is a method for producing a sterile injectable containing teriparatide or a salt thereof by an aseptic method, which is a package containing a drug-free injection container, the exterior surface of which is excessively thick. It includes the step of transporting the hydrogen oxide or alcohol decontaminated material into a device or system having an aseptic operating area.

1. Aseptic operation method Aseptic operation method is a technology used for pharmaceuticals that do not apply final sterilization, which is a method of sterilizing after filling the final container (container that is used for the final drug). It refers to a method used for manufacturing sterile pharmaceutical products after sterilization or through a series of aseptic processes from the raw material stage (Non-Patent Documents 1 and 6). In general, it is preferable to apply the terminal sterilization method to manufacture drugs that are stable in solution with high heat resistance, and for drugs that are not stable in solution or have low heat resistance. It is preferably manufactured by applying an aseptic method. Since the teriparatide solution is not necessarily sufficiently stable, it is preferable to apply an aseptic method for production. Sterile pharmaceuticals per se are generally known and can be easily understood (Non-Patent Documents 2 to 6). For example, sterile pharmaceuticals include injections (sterile injections), eye drops, eye ointments, and the like, which are administered for the purpose of treatment/prevention/diagnosis of mammals including humans. The production method of the present invention relates to a method for producing sterile injectables among sterile pharmaceuticals obtained by aseptic procedures.

In the production method of the present invention, sterilization means sterilization or removal of microorganisms in an object to the extent that the purpose of sterilization is achieved. For example, according to Non-Patent Document 3, sterilization means "
It means a state in which all kinds of microorganisms are killed or removed, and no viable microorganisms exist in the object. Generally, the sterilization method can be carried out by examining appropriate selection of the method and optimization of the operation method and conditions according to the type of microorganisms, the contamination status, and the nature and condition of the object to be sterilized.

2. Teriparatide or a Salt Thereof In the production method of the present invention, teriparatide means free human PTH (1-34). Human PTH (1-34) is human parathyroid hormone, human PTH (1-8
A peptide represented by a partial amino acid sequence consisting of the 1st to 34th amino acid residues as viewed from the N-terminal side in the amino acid sequence of 4).

Teriparatide can also be in the form of a salt. Teriparatide salts include any salt formed with teriparatide and one or more volatile organic acids. When teriparatide and a volatile organic acid form a salt, the ratio between the two is not particularly limited as long as the salt is formed. Acetic acid is preferred as the volatile organic acid. That is, teriparatide acetate can be preferably exemplified as the salt of teriparatide in the production method of the present invention.

In the production method of the present invention, the amount of teriparatide or a salt thereof contained in the sterile injection is not particularly limited, but the following are suitable examples. That is, the lower limit is preferably 20 μg or more, more preferably 25 μg or more, 27 μg or more, and further preferably 28 μg or more. In addition, the upper limit is preferably 50 μg or less, 40 μg or less, 35 μg or less.
g or less, 30 μg or less, and more preferably 29 μg or less. Among them, 28.
Preferably 2 μg or 29.2 μg. In the present specification, the amount of teriparatide salt is the amount in terms of teriparatide. For example, 30.3 μg of teriparatide pentaacetate or 31
. In the case of 3 μg, the equivalent amount of teriparatide is 28.2 μg or 29.2 μg.

3. Injection container In the production method of the present invention, the injection container is not particularly limited as long as it is a medical container that stores a drug for injection. Examples include vials, bottles, bags, and the like. The material of the injection container is also not particularly limited, and may be either glass or plastic.
However, glass-made injection containers are heavy and easily broken, so plastic-made injection containers are preferable, and plastic-made syringes are more preferable as injection containers in the manufacturing method of the present invention. The plastic material is not particularly limited, and may be polypropylene, polyethylene, cyclic olefin polymer, polyvinyl chloride, polyester, polyamide, polycarbonate,
Polymethacrylate and the like can be exemplified. Injection containers must also be sterilized when manufactured by aseptic techniques. The method of sterilizing the container is not particularly limited, and examples include high-pressure steam sterilization, dry heat sterilization, and radiation sterilization using gamma rays or electron beams.

4. Package In the manufacturing method of the present invention, the package is not particularly limited as long as it is a packaging body for housing an injection container that does not contain a drug, and for example, it is a package mainly composed of a tank and a lid. Thus, all or part of the lid can be a package that can be easily opened by a peel-away procedure (US Pat. The material of the package is not particularly limited, and for example, plastic resin can be used. Although the condition of the injection container housed in the package is not limited, it is preferably sterilized. The method of housing the injection container in the package is not particularly limited, but it is preferable that the structure is such that the multiple injection containers contained in the package do not come into contact with each other during the transportation or filling process of the package, and the package has a multilayer structure. , the injection containers may be stored over a plurality of stages, or the injection containers may be stored in a grid-like arrangement. Examples of such packages include "sterilized glass syringe D2F (registered trademark)", "
Sterile packaging solution-D2F (registered trademark)” (manufactured by Nipro) can be exemplified.

The exterior surface of the package used in the manufacturing method of the present invention is decontaminated. In general, the exterior of a package containing a drug-free injection container is often contaminated by outside air or the like during the process of being transported to a sterile injection manufacturing site. In order to avoid contamination of the package containing the injection container, it may be brought into the manufacturing site in a sterile bag or outer wrapper. It is necessary to take out, and the risk of being contaminated at that time cannot be denied. Therefore, when a sterile injectable drug is produced by aseptic operation using an injection container housed in the package, the package must be pre-packaged before being carried into an apparatus or system having an aseptic operation area at the manufacturing site. It is extremely important to decontaminate the exterior surfaces of

In the manufacturing method of the present invention, the exterior surface of the package is decontaminated with hydrogen peroxide or alcohol. It has been newly found that a sterile injectable preparation containing teriparatide or a salt thereof can unexpectedly be produced using such a package to obtain a sterile injectable preparation of high quality and excellent storage stability.

When decontaminating package exterior surfaces with hydrogen peroxide or alcohol, it is preferable to decontaminate all potentially contaminated exterior surfaces. For example, if the package is a box-like package consisting of 6 parts: a bottom, 4 walls and a lid, it is preferable to decontaminate each of the 6 exterior surfaces.

Although the method of hydrogen peroxide decontamination is not particularly limited, for example, a method of fumigation sterilization with hydrogen peroxide gas can be preferably mentioned. At this time, the hydrogen peroxide can be vaporized to an appropriate concentration (eg, about 10 to 1000 ppm) around the package, and the exterior of the package can be decontaminated under the hydrogen peroxide gas. It is generally understood that the main mechanism of action of hydrogen peroxide decontamination is to kill microorganisms through oxidation.

Although the method of alcohol decontamination is not particularly limited, for example, around the package, 50
The package exterior can be decontaminated by spraying or vaporizing ~90% isopropanol or ethanol, and wiping all surfaces of the package exterior with a cloth moistened with 50-90% isopropanol or ethanol. can also It is generally understood that the main mechanism of action of alcohol decontamination is the killing of microorganisms through the denaturing action of proteins and nucleic acids.

Here, "decontamination" means removing viable microorganisms by a reproducible method or reducing them to a pre-specified level (Non-Patent Document 3). As a practical matter, one may ensure a 4-6 log reduction of spores highly resistant to the applied decontaminant.

5. Apparatus or system having an aseptic operation area In the manufacturing method of the present invention, the aseptic operation area means "to control microorganisms and fine particles to below the allowable level. means a controlled environment. Aseptic operation areas can be further divided into critical areas and direct support areas (see
Non-Patent Document 3).

Critical areas are areas where the air cleanliness level is grade A (ISO 5), and manufacturing processes such as aseptic work (aseptic connection, addition of aseptic raw materials) before drug filling, aseptic filling, container closing and stoppering. is preferably done in critical areas. A direct support area is an area where the air cleanliness level is grade B (ISO 7) and is the background area of the critical area.

As a device or system having an aseptic operation area, for example, an isolator or a Restricted Access Barrier System (RABS) is known (Non-Patent Document 3).

6. Optional Components The sterile injectable preparation according to the production method of the present invention may be filled with various components such as inorganic salts/organic salts, buffers and additives. Such components include, for example, disaccharides (e.g. sucrose), inorganic salts hydrochlorides or sodium salts (e.g. sodium chloride), neutral amino acids (e.g. L-methionine), and sugar alcohols (e.g. : D-mannitol). The pH of the sterile injection is also not particularly limited, and can be, for example, in the range of 3-6.

7. Other Steps The manufacturing method of the present invention is not particularly limited as long as it includes a step of carrying a package containing an injection container containing no drug into an apparatus or system having an aseptic operation area. A further step of decontamination with hydrogen peroxide or alcohol may be included. That is, the manufacturing method of the present invention includes a step of decontaminating the exterior surface of a package containing an injection container containing no drug with hydrogen peroxide or alcohol, and the package obtained in the decontamination step is subjected to aseptic operation. It may also include the step of loading into a device or system having a zone.

It can also be a manufacturing method that includes a drug preparation step, a drug filtering step, an aseptic filling step, an injection container closure or capping step, and a sterile injection preparation and packaging step. All of these manufacturing steps are preferably carried out in an apparatus or system having an aseptic operating area, and as mentioned above, the aseptic filling process and injection container closing or capping process are performed in critical areas (Grade A areas). ).

8. sterile injection

The sterile injectable preparation according to the manufacturing method of the present invention is not particularly limited as long as it is a liquid pharmaceutical preparation for injection. As a sterile injectable preparation according to the production method of the present invention, for example, an ampoule preparation, a vial preparation, a prefilled syringe preparation, etc. in which a drug containing teriparatide or a salt thereof is encapsulated or filled can preferably be mentioned. The administration route for administering (injecting) the sterile injectable preparation according to the production method of the present invention is not particularly limited, but for example, intravenous administration, intramuscular administration,
Examples include intradermal administration and subcutaneous administration.

The sterile injectable preparation according to the manufacturing method of the present invention is a high-quality sterile injectable preparation. Here, high quality means that the amount of teriparatide or its salt analogues contained in the produced sterile injectable preparation is reduced. Analogs of teriparatide or salts thereof are not particularly limited, but octaoxidants,
18-oxidant, 8-18-oxidant, truncation, or all of these. Here, the 8-oxidant is an oxidant in which the 8th methionine residue from the N-terminus of teriparatide or a salt thereof is methoxy, and the 18-oxidant is the 18th methionine from the N-terminus of teriparatide or a salt thereof. An oxidized form in which residues are methoxy and an 8-18 oxidized form refer to an oxidized form in which methionine residues at positions 8 and 18 of teriparatide or a salt thereof are both methoxy. The truncated form is a partial peptide of teriparatide or a salt thereof, and for example, a 1-30 truncated form can be exemplified, and the 1-30 truncated form consists of amino acid residues 1 to 30 from the N-terminal of teriparatide. means a peptide or a salt thereof.

The total amount of the analog at the time of production contained in the sterile injection according to the production method of the present invention (total amount of the analog)
is preferably 1.5% or less, more preferably 1.2% or less, and still more preferably 1.5% or less.
It is 0% or less, more preferably 0.9% or less, and the lower limit is not particularly limited, but 0.1%
It can be as above. In addition, the amount of cut body contained in the sterile injection at the time of production is preferably 0.3% or less, more preferably 0.2% or less, still more preferably 0.1% or less, and most preferably 0.0%. is. These numerical values are HPLC area percentages, that is, the ratio (%) when the total amount (total peak area) of teriparatide or its salts and analogous substances thereof is set to 100.

The sterile injectable preparation according to the production method of the present invention is a sterile injectable preparation that can be stably stored after its production. Here, stably storable means that the specific analog does not increase or decrease when the sterile injectable is stored. More specifically, for example, 25° C./60% R
If the amount of 18-oxidant contained in the sterile injectable does not substantially increase over several months under the storage conditions of H, it can be considered that the sterile injectable can be stably stored. The above storage conditions are the conditions in the accelerated test, and the storage conditions for the sterile injectable preparation according to the production method of the present invention can be premised on refrigerated storage.

EXAMPLES The present invention will be described in more detail below with reference to examples. However, the present invention is not bound by the following examples, and can be embodied in any form without departing from the scope of the present invention.

(1) Production Examples 1 and 2 of Sterile Injection, Comparative Example 1
Teriparatide acetate, mannitol, sodium chloride, and
After preparing a drug containing L-methionine and sterilizing it by filtration, the steps of aseptic filling, stoppering, and packaging are carried out in accordance with conventional methods in an isolator to produce a sterile injection containing teriparatide acetate. manufactured.

The injection containers used in the production were sterilized plastic syringes, which were arranged and housed in a lattice pattern in the package without drug filling. the package is transported and
Since it was brought into a pharmaceutical manufacturing factory, the outer surface of the package was preliminarily decontaminated with hydrogen peroxide (Example 1) or alcohol (Example 2) before being carried into the isolator. The decontamination conditions are as follows.

(1-1) Hydrogen peroxide decontamination conditions By dripping hydrogen peroxide onto a heated iron plate, the hydrogen peroxide is vaporized, and the package containing the drug-unfilled syringe is transformed into the vaporized hydrogen peroxide. The exterior was decontaminated by exposure.

(1-2) Alcohol decontamination conditions The exterior was decontaminated by wiping all surfaces of the exterior with about 70% ethanol for disinfection.

After loading, the lid of the package loaded into the isolator is peeled off (peel-away pr
ocedure), remove the plastic syringe, and mount the syringe on a sterile filling line. After mounting, aseptic filling and capping steps were carried out according to conventional methods to produce sterile injectables (Examples 1 and 2). In addition, for the purpose of evaluating the decontamination effect, a package that had not been decontaminated was carried into the isolator, and the lid of the package was peeled away.
ure), removed the plastic syringe, and mounted the syringe on a sterile filling line. After the packaging, each step of aseptic filling and capping was carried out according to conventional methods to produce a sterile injectable (Comparative Example 1).

(2) Stability test

The sterile injections produced in Examples 1 and 2 and Comparative Example 1 were each subjected to an accelerated test, sampling was performed over time, stability was measured by high performance liquid chromatography, and impurities produced were analyzed. Specific conditions for each test are as follows.

(2-1) Accelerated test conditions The sterile injections produced in Examples 1 and 2 and Comparative Example 1 were stored in a storage cabinet at 25°C and 60% RH.

(2-2) High Performance Liquid Chromatography Conditions 1. Detector: UV absorption photometer (measurement wavelength: 214 nm)
2. Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm is packed with 3.5 μm octadecylsilylated silica gel for liquid chromatography (Agilent Techno
Zorbax 300SB-C18 manufactured by Logies, or equivalent)
3. Column temperature: constant temperature around 40° C.4. Mobile phase Mobile phase A: Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, add phosphoric acid to pH
After adjusting to 2.3, add water to make up to 1000 mL. 100 mL of acetonitrile is added to 900 mL of this liquid.
Mobile phase B: Dissolve 28.4 g of anhydrous sodium sulfate in 900 mL of water, add phosphoric acid to pH
After adjusting to 2.3, add water to make up to 1000 mL. 500 mL of acetonitrile is added to 500 mL of this liquid.
5. Transfer of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 below to control the concentration gradient.
6. Flow rate: 1.0 mL per minute
7. Detection time: 45 minutes after sample solution injection. However, start after the solvent peak.

(3) Test results (impurity analysis)
The test results are given in Table 2 below. The numerical values in the table indicate the ratio (%) when the total amount of teriparatide and its analogues contained in the formulation is set to 100. "0M" means immediately before the accelerated test (immediately after manufacture), "1M" means one month after the start of the accelerated test, and "3M" means three months after the start of the accelerated test.

"Hydrogen peroxide (%)" means the content (%) of each analogue in a sterile injectable prepared by decontamination of the package with hydrogen peroxide. "alcohol(%
)” means the content (%) of each analogue in the sterile injection obtained by decontamination of the package with alcohol. "None (%)" means the content (%) of each analogue in sterile injectables produced without decontamination of the package. A slash (/) in the table indicates the fact that impurity analysis was not performed.

As can be seen from Table 2, the sterile injectables obtained in Examples 1 and 2 have a lower amount of the analogs than the one obtained in Comparative Example 1 and are of high quality. In addition, the sterile injections obtained in Examples 1 and 2 did not increase the amount of 18-oxidant even after 3 months from the start of the accelerated test.
It turns out that it is excellent in storage stability.

The method for producing a sterile injectable preparation of the present invention provides a sterile injectable product that is of high quality and can be stored stably after production. INDUSTRIAL APPLICABILITY The present invention is extremely useful in the pharmaceutical industry, for example in the osteoporosis treatment field.

Claims (6)

A method for reducing the amount of teriparatide or analogues thereof contained in a sterile injection containing teriparatide or a salt thereof in the production of a sterile injection containing teriparatide or a salt thereof by an aseptic method, wherein the production process is an injection containing no drug. carrying the package containing the container into an apparatus or system having an aseptic operating area, wherein the outer surface of the package has been decontaminated with hydrogen peroxide or alcohol, and teriparatide or a salt analogue thereof is present. 18 oxidized form or 1-30 truncated form (however, 18 oxidized form is an oxidized form in which the 18th methionine residue from the N-terminus of teriparatide or a salt thereof is methoxy, and 1-30 truncated form is a peptide consisting of the 1st to 30th amino acid residues at the N-terminus of teriparatide or a salt thereof, respectively) ; A method for reducing the amount of teriparatide or analogues thereof contained in a sterile injection containing teriparatide or a salt thereof in the production of a sterile injection containing teriparatide or a salt thereof by an aseptic method, wherein the production process is an injection containing no drug. decontaminating the outer surface of the package containing the container with hydrogen peroxide or alcohol; The analogue of the salt is the 18-oxidized form or the 1-30 truncated form (where the 18-oxidized form is an oxidized form in which the 18th methionine residue from the N-terminus of teriparatide or a salt thereof is methoxy, and 1- 30 truncation means a peptide consisting of 1st to 30th amino acid residues at the N-terminus of teriparatide or a salt thereof, respectively) , a method for reducing analogues of teriparatide or its salts contained in sterile injectables. 3. A reduction method according to claim 1 or 2, wherein the device or system with a sterile operating area is an isolator or a RABS. The reduction method according to any one of claims 1 to 3, wherein the amount of teriparatide or a salt thereof contained in the sterile injection is 28.2 µg in terms of teriparatide. A method for suppressing the post-production increase of teriparatide or an analogue of a salt thereof in a sterile injection containing teriparatide or a salt thereof produced by an aseptic method, wherein the production process comprises a drug-free injection container. into an apparatus or system having an aseptic operating area, wherein the outer surface of the package has been decontaminated with hydrogen peroxide or alcohol, and teriparatide or a salt analogue thereof containing 18 It is an oxidized form or a 1-30 truncated form (however, the 18 oxidized form is an oxidized form in which the 18th methionine residue from the N-terminus of teriparatide or a salt thereof is methoxy, and the 1-30 truncated form is teriparatide or a salt thereof consisting of the 1st to 30th amino acid residues at the N-terminus of ) , and a method for suppressing the increase of teriparatide or its salt analogs contained in a sterile injectable. A method for suppressing the post-production increase of teriparatide or an analogue of a salt thereof in a sterile injection containing teriparatide or a salt thereof produced by an aseptic method, wherein the production process comprises a drug-free injection container. decontaminating the outer surface of the package containing teriparatide or its salt with hydrogen peroxide or alcohol, and carrying the package obtained from the decontamination step into an apparatus or system having an aseptic operation area, is an 18-oxidized form or a 1-30 truncated form (however, the 18-oxidized form is an oxidized form in which the 18th methionine residue from the N-terminus of teriparatide or a salt thereof is methoxy, and 1-30 A truncated form means a peptide consisting of the 1st to 30th amino acid residues at the N-terminus of teriparatide or a salt thereof, respectively) ;