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Process for lyophilized pharmaceutical formulation of a therapeutic protein

a technology of lyophilized pharmaceutical formulation and therapeutic protein, which is applied in the field of biopharmaceuticals, can solve the problems of special problems of products, chemical instability, physical instability,

Inactive Publication Date: 2019-03-21
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a process for making a lyophilized drug product. The process involves measuring the concentration of the therapeutic protein in the bulk formulation, adjusting the fill weight of the protein to achieve a fixed dose, and lyophilizing the protein to achieve a final formulation with a predetermined concentration. The final formulation should contain a therapeutic protein at a concentration within a specific range. The preferred therapeutic proteins are romiplostim, blinatumomab, infliximab, trastuzumab, AMG 701, and AMG 330. The formulation includes a combination of sugars, buffers, and surfactants. The invention also includes other excipients such as trehalose, citric acid monohydrate, sodium phosphate, potassium phosphate, and glutamic acid.

Problems solved by technology

Because these molecules can be larger and / or more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such products poses special problems.
Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange.
Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example.
These designed molecules due to their synthetic nature are prevalently lyophilized (freeze dried) as the presentation can provide unproved shelf stability.
A designed molecule with specific biological targets and thee resulting dosage requirements for product poses new problems for the manufacturing process.

Method used

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  • Process for lyophilized pharmaceutical formulation of a therapeutic protein
  • Process for lyophilized pharmaceutical formulation of a therapeutic protein
  • Process for lyophilized pharmaceutical formulation of a therapeutic protein

Examples

Experimental program
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working examples

[0105]All publications, patents, and patent applications discussed and cited herein are hereby incorporated by reference m their entireties. It is understood that the disclosed invention is not limited to the particular methodology, protocols and materials described as these can vary. It is also understood that the terminology used herein is for the purposes of describing particular embodiments only and is not intended to limit the scope of the appended claims.

[0106]Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the claims that follow.

example 1

[0107]This experiment demonstrates that by adjusting fill weight targets, protein concentration can be precisely targeted for the respective reconstituted drug product.

Materials

[0108]Buffer containing: Mannitol, Sucrose, L-Histidine, Polysorbate 20 at pH 5[0109]Container Vial, 3 cc, Blowback, Type I Glass, Non-treated, 13 mm Finish with Stopper, 13 mm, 4432 / 50 V-50,[0110]romiplostim Filtered Purified Bulk

Method

[0111]1. Dilute drug to target product formulation (0.5 mg / mL) utilizing required amount of the dilution buffer.[0112]2. Filter formulated solution using a 0.22 μm Polyvinylidene difluoride (PVDF) filter.[0113]3. Ensure vials and stopper: 3 cc vials have been washed and depyrogenated.[0114]4. Fill sufficient quantity of vials to respective fill weight targets: 0.307, 0.322, 0.342, 0.357, 0.373 g.[0115]5. Partially stopper vials and place in lyophilizer.[0116]6. Run required lyophilization cycle with adequate freezing, vacuum, with primary and secondary drying, followed by stop...

example 2

[0128]The protein blinatumomab has 55 μg / mL, formulated to 200 mM L-lysine-HCl, 25 mM citric acid, 15% (w / v) trehalose dihydrate, 0.1% (w / v) polysorbate 80, pH 7.0. The formulated protein allowable range is measured at the filtered bulk stage. Bulk concentrations ranging from 48.0 μg / mL to 65.0 μg / mL are used. Target fill weights are calculated based upon the measured protein concentration to target a reconstituted drug product of 12.5 mcg / mL when reconstituted with 3 mL of water.

Creconstitution*Vreconstitution=(CFormulated−Closs)*Vfill

Where

Creconstitution*Vreconstitution=Target protein contentreconstitution

[0129]Then the Target protein content can then be multiplied by the product density and divided by the measured drug concentration (adjusted for loss due to binding if needed) to determine the Target fill weight.

[0130]The target fill weight is calculated according to the following formula, with a corresponding fill weight range of 0.634 to 0.858 gm.

Fillweight(g)=targetdose(38.5...

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Abstract

This invention concerns a process for making a lyophilized pharmaceutical formulation of a therapeutic protein, which comprises (a) providing a formulation of a bulk amount of the therapeutic protein, (b) measuring the concentration of the therapeutic protein in said bulk formulation, (c) adjusting the fill weight of the protein in said bulk formulation to achieve a fixed dose of the protein, and (d) lyophilizing the protein fill weight-adjusted formulation to achieve a final formulation in a container, wherein the product concentration post reconstitution with a fixed volume is within a predetermined acceptance range. The process is particularly suitable for formulations with low protein concentrations (e.g., 0.05 to 20 mg / mL).

Description

FIELD OF THE INVENTION[0001]This invention relates to biopharmaceuticals, particularly to therapeutic proteins, methods of use thereof, pharmaceutical formulations thereof, and processes of making pharmaceutical formulations. In particular, this invention relates to processes for making lyophilized pharmaceutical formulations.BACKGROUND OF THE INVENTION[0002]In the past ten years, advances in technology have made it possible to produce a variety of active molecules for pharmaceutical applications. As the nature of understanding of mechanisms of biological action progresses, these molecules can be designed for certain attributes, where small amounts of product can be efficacious.[0003]Because these molecules can be larger and / or more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such products poses special problems. For a product to remain biologically active, a...

Claims

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Application Information

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IPC IPC(8): A61K9/19A61K38/19C07K16/28A61K47/02C07K14/52
CPCA61K9/19A61K38/196C07K16/2848A61K47/02C07K14/524C07K16/2863A61K39/395A61K47/10A61K47/18A61K47/26A61K47/22A61K47/183A61K47/40A61K38/00A61K2039/505C07K16/2809C07K16/2878C07K16/32
Inventor TALLEY, CLEA
Owner AMGEN INC
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