Patent Publication Number: US-2023158238-A1

Title: Injection spring for aged prefilled syringe and auto injector

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/576,670, filed Sep. 19, 2019, and published as U.S. Patent App. Pub. No. 2020/0093992 on Mar. 26, 2020, which is claims priority to U.S. Provisional App. No. 62/734,209, filed Sep. 20, 2018, the entire disclosure of which is hereby expressly incorporated herein by reference. 
    
    
     BACKGROUND 
     An auto injector is a device for automatically injecting therapeutic fluid into a patient. Auto injectors have had rapidly increasing popularity over recent years due to a variety of factors. For example, auto injectors are convenient for both caregivers and for patients who self-administer therapeutic fluids. They decrease the number of steps required to administer therapeutic fluid. Moreover, because auto injectors are labeled and the syringes are prefilled by suppliers of the medications, there is no need to manually fill the syringe using vials of therapeutic fluid. The use of prefilled syringes reduces the risk of errors in dosage, misidentification of the medication, and contamination. 
     In use, an auto injector is typically loaded with a prefilled syringe and has a compressed spring or other biasing member for pushing a stopper to eject the therapeutic fluid. A button or other actuator is connected to a mechanism for releasing the compressed spring so that it extends. As the spring extends, it drives a piston rod or plunger, which in turn pushes the stopper within the syringe. The stopper then expels the therapeutic fluid from the syringe barrel, through the needle, and into the patient&#39;s tissue at the site of administration. 
     Before bringing a pharmaceutical product such as a prefilled syringe and auto injector on the market, a company typically must gain approval from a government regulatory agency such as the United States Food and Drug Administration or similar agency in foreign countries. For drugs contained in prefilled syringes and delivered through auto injector systems, a pharmaceutical company typically needs to provide the agency with stability testing reports, which may include a variety of information that demonstrates proper performance throughout the product shelf life. Some of the performance characteristics that must be provided might include dose accuracy within an expected injection time throughout the product shelf life. 
     Typically, a prefilled syringe containing the therapeutic fluid is defined early in the development process. An auto injector is later selected and an injection time of the prefilled syringe in the auto injector has to meet an expected injection time. In order to meet the expected injection time, injection time simulations are generally used. Injection time simulations are generally mathematical in nature and based on the geometry of the prefilled syringe. The geometry of the prefilled syringe notably comprises the following parameters of needle length, needle diameter, and barrel diameter. Such simulations are also generally based on parameters of the drug such as viscosity. These parameters enable simulation of the hydrodynamic forces that the fluid applies against the stopper. The Hagen-Poiseuille equation is an example of a formula that models hydrodynamic forces. Friction forces during delivery are generally approximated using step-wise functions to simulate a constant break loose force in a start of injection period and a constant gliding force in the rest of injection period. 
     In practice, friction forces between the prefilled syringe&#39;s stopper and barrel typically are considered as constant in injection time simulations. The constant force is typically extrapolated from a measured extrusion force on an empty prefilled syringe when the stopper is moved at a speed comparable with the speed corresponding to the expected injection time. Some more complex simulations may estimate friction forces using the formula: 
         F   friction =((2πμ oil   r   b   l   stopper )/ d   oil ) υ   (1)
 
     where μ oil  is the viscosity of the lubricant, r b  is the internal radius of the syringe barrel, l stopper  is the length of the stopper in contact with the syringe barrel, d oil  is the thickness of the lubrication, and  υ  is the injection speed (linear piston speed with dimensions of length over time). 
     In general, for Newtonian fluids, neglecting the pressure drop across the syringe barrel, the hydrodynamic force can be estimated at a given temperature using the Hagen-Poiseuille equation: 
         F   hydrodynamic =((8πμ L   n   r   b   4 )/ r   n   4 ) υ   (2)
 
     where μ is the viscosity of the fluid, L n  is the length of the needle channel, r b  is the internal radius of the syringe barrel, and r n  is the internal radius of the needle channel. 
     Injection time simulations also are generally based on features of the auto injector, such as a dispensing force applied by the auto injector on the stopper of the prefilled syringe barrel. The dispensing force is based on the parameters and configuration of the auto injector&#39;s injection spring or other structure that powers movement of the auto injector&#39;s injection mechanism. Potential resistive forces internal to the auto injector may also be taken into account. 
     By calculating the forces applied to the stopper using these various mathematical models, an injection time to fulfill injection can be simulated. The simulated injection time then can be used to confirm whether the parameters and configuration of the injection spring will provide enough dispensing force against the stopper to satisfy the expected injection time. 
     SUMMARY 
     In general terms, this patent document is directed to determining a spring for an auto injector. Another aspect is directed to determining an auto injector having a determined spring. 
     One aspect of this patent document is a method of making an auto injector. The method comprising aging a prefilled syringe, the prefilled syringe having a stopper, measuring a force required to move the stopper within the aged prefilled syringe a determined distance within a determined time, and selecting a spring having a determined spring force, the determined spring force moving the stopper the determined distance within the determined time. 
     One aspect of this patent document is a method of making an auto injector to dispense a therapeutic fluid contained in an operative prefilled syringe, the operative prefilled syringe including an operative barrel and an operative stopper movably positioned within the operative barrel, the operative stopper movable along an operative path of travel from a first operative position to a second operative position, the auto injector to comprise an injection spring having a spring force, the injection spring configured to apply a dispensing force to the operative stopper by driving a piston rod toward the operative stopper upon actuation of the auto injector, the dispensing force being at least a portion of the spring force. The method comprises aging a prefilled syringe at an accelerated rate to form a reference prefilled syringe, the reference prefilled syringe including a reference barrel and a reference stopper positioned in the reference barrel; moving the reference stopper of the reference prefilled syringe along a reference path of travel from at least a first reference position to at least a second reference position; as the reference stopper moves within the reference barrel along the reference path of travel, measuring a plurality of exertion forces applied to the reference stopper and measuring a plurality of reference stopper positions; generating an exertion force profile, the exertion force profile including at least some of the exertion forces and reference stopper positions measured while the reference stopper was moving between the first and second reference positions, at least one of the measured exertion forces correlating to at least one of the measured reference stopper positions; and selecting the injection spring so that the dispensing force applied to the operative stopper at each position of the operative stopper as it moves along the operative path of travel between the first and second operative positions is greater than the measured exertion force at a corresponding one of the measured reference stopper positions. 
     Another aspect of this patent document also relates to an auto injector having an aged prefilled syringe, a stopper within the prefilled syringe, and an injection spring. The injection spring having a spring force with a magnitude great enough to move the stopper a determined distance. 
     Another aspect of this patent document is an auto injector arrangement comprising a prefilled syringe including a barrel extending along a longitudinal axis between a distal end and a proximal end, an inner diameter of the barrel being of about 8.65 mm, a needle disposed at the distal end of the barrel, the needle having an inner diameter of about 0.27 mm and a length of about 19.5 mm or less, a volume in the range from about 1.51 mL to about 1.66 mL of therapeutic fluid held within the barrel, the therapeutic fluid comprising fremanezumab, a viscosity of the therapeutic fluid being about 8.8 cSt at 22° C., and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, the barrel defining a path of travel for the stopper, the path of travel having a first initial position for the stopper and a second initial position for the stopper, the first position being an initial position of the stopper before delivery of the therapeutic fluid, the second position being a final position of the stopper upon delivery of a full dose of the therapeutic fluid. An auto injector holds the prefilled syringe. The auto injector comprises an injection spring arranged to apply a dispensing force to the stopper by driving a piston rod toward the stopper. When the auto injector is actuated, the injection spring is configured to provide an initial dispensing force to the stopper of at least about 20 N when the stopper is positioned at the first initial position and a final dispensing force of at least 12 N to the stopper when the stopper is positioned at the second final position, the dispensing force being at least a portion of a spring force for the injection spring. 
     Another aspect of this patent document also relates to an auto injector having an aged prefilled syringe, a stopper within the prefilled syringe, and an injection spring. The injection spring having a spring force with a magnitude great enough to move the stopper a determined distance within a determined time. 
     Another aspect of this patent document is an auto injector arrangement comprising a prefilled syringe. The prefilled syringe comprises a barrel formed at least in part by glass, a needle in fluid communication with the barrel, and a stopper positioned in the barrel, the barrel defining an inner surface, the barrel having an inner diameter, the barrel diameter being about 8.65 mm, the barrel defining a path of travel for the stopper, the path of travel having a first position for the stopper and a second position for the stopper, the needle having an inner diameter of about 0.27 mm and a length of about 19.5 mm or less, a therapeutic fluid held within the barrel, a viscosity of the therapeutic fluid being about 10 cP or less at 22° C. About 0.35 mg to about 1.1 mg of silicone oil lubricates the inner surface of the barrel, the silicone oil having a viscosity in a range from about 500 cSt at 25° C. to about 1500 cSt at 25° C. before the prefilled syringe is aged. An auto injector holds the prefilled syringe. The auto injector comprises a plunger and an injection spring. The plunger engages the stopper, and the injection spring biases the plunger towards the stopper. The injection spring, when in the first position, has a force determined according to the actions recited in claim  1 ; has a spring force in the range from about 20 N to about 30 N; has a stored spring energy in the range from about 0.9 J to about 2 J; has a spring constant in the range from about 0.2 N/mm to about 0.4 N/mm; a compressed length in the range from about 50 mm to about 100 mm; has a stored energy about 25% greater than a minimum spring energy required to move the stopper from the first position to the second position without stalling before the prefilled syringe is aged; and has a force sufficient to move the stopper along the path of travel from the first position to the second position within about 5 seconds to about 25 seconds. 
     Another aspect of this patent document also relates to an auto injector having an aged syringe prefilled with fremanezumab, a stopper within the prefilled syringe, and an injection spring. The injection spring having a spring force with a magnitude great enough to move the stopper a determined distance. 
     Another aspect of this patent document is a prefilled syringe comprising a stopper and a therapeutic fluid including fremanezumab; and an auto injector having an injection spring and a piston rod arranged to move the stopper from a first position to a second position with a force of about 30 N or less and in about 19 seconds or less, the distance between the first and second positions corresponding to one dose of the therapeutic fluid. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a schematic diagram of an example syringe prefilled with a fluid in accordance with the principles of the present disclosure; 
         FIG.  2    shows sequence listings for fremanezumab, which can be loaded in the prefilled syringe shown in  FIG.  1   ; 
         FIG.  3 A  is a graph plotting one set of measured exertion forces against displacement of the drive member acting on a stopper of an unaged prefilled syringe; 
         FIG.  3 B  is a chart showing maximum exertion force measured for prefilled syringes of various artificial ages; 
         FIG.  3 C  is a graph plotting one set of measured exertion forces against displacement of the drive member acting on a stopper of a prefilled syringe artificially aged to 24 months; 
         FIG.  3 D  is a chart showing injection times observed for prefilled syringes of various natural and artificial ages; 
         FIG.  4 A  is a side elevational view in partial cross-section showing a fixture for testing a prefilled syringe; 
         FIG.  4 B  is a side elevational view in partial cross-section showing an alternative fixture for testing a prefilled syringe and auto injector mechanism; 
         FIG.  4 C  is a side cross-sectional view of a fixture for testing spring forces in an auto injector; 
         FIG.  5    is a side elevational view of an instrument for measuring performance of prefilled syringes and auto injectors for use with the fixtures illustrated in  FIGS.  4 A- 4 C ; 
         FIG.  6    is a flowchart illustrating a determination process by which a spring constant can be selected for the injection spring of an auto injector; 
         FIG.  7    is a schematic diagram of an example oven used in artificially aging one or more prefilled syringes; 
         FIGS.  8 - 10    illustrate various testing processes that are each suitable for implementing the test operation of the determination process of  FIG.  6   ; 
         FIG.  11    is a flowchart illustrating a method for performing at least the move operations and the measure operations of the testing processes of  FIGS.  8 - 10    using the testing equipment of  FIG.  5   ; 
         FIG.  12    is a flowchart illustrating an assembly process for assembling an auto injector; 
         FIG.  13    illustrates the components of the auto injector exploded from each other for ease in viewing; 
         FIG.  14    is a cross-section of the auto injector of  FIG.  13   , the auto injector being disposed in a pre-injection configuration; 
         FIG.  15    shows the auto injector of  FIG.  14    in a mid-injection configuration; 
         FIG.  16    shows the auto injector of  FIG.  14    in an end of injection configuration; 
         FIG.  17    shows the auto injector of  FIG.  16    rotated 90°; 
         FIG.  18    is a flowchart illustrating a use process for using the auto injector with the prefilled syringe and the selected injection spring; and 
         FIG.  19    illustrates the auto injector being actuated by a user. 
     
    
    
     DETAILED DESCRIPTION 
     Various embodiments will be described in detail with reference to the drawings, wherein like reference numerals represent like parts and assemblies throughout the several views. Reference to various embodiments does not limit the scope of the claims attached hereto. Additionally, any examples set forth in this specification are not intended to be limiting and merely set forth some of the many possible embodiments for the appended claims. 
     For purposes of this patent document, the terms “or” and “and” shall mean “and/or” unless stated otherwise or clearly intended otherwise by the context of their use. Whenever appropriate, terms used in the singular also will include the plural and vice versa. The use of “a” herein means “one or more” unless stated otherwise or where the use of “one or more” is clearly inappropriate. The use of “or” means “and/or” unless stated otherwise. The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “having,” and “has” are interchangeable and not intended to be limiting. The term “such as” also is not intended to be limiting. For example, the term “including” shall mean “including, but not limited to.” 
     All ranges provided herein include the upper and lower values of the range unless explicitly noted. Although values are disclosed herein when disclosing certain exemplary embodiments, other embodiments within the scope of the pending claims can have values other than the specific values disclosed herein or values that are outside the ranges disclosed herein. 
     Terms such as “substantially” or “about” when used with values or structural elements provide a tolerance that is ordinarily found during testing and production due to variations and inexact tolerances in factor such as material and equipment. These terms also provide a tolerance for variations found in nature and environmental conditions due to factors such as changes in temperature, humidity. 
     As used herein, the term “fremanezumab” is used interchangeably to refer to an anti-CGRP antagonist antibody produced by expression vectors having deposit numbers of ATCC PTA-6867 and ATCC PTA-6866. The amino acid sequence of the heavy chain and light chain variable regions are shown in SEQ ID NOs: 1 and 2, respectively. The CDR amino acid sequences of the G1 heavy chain variable region are shown in SEQ ID NOs: 7-9 (Kabat and Chothia CDRs are indicated). The CDR amino acid sequences of the G1 light chain variable region are shown in SEQ ID NOs: 10-12. Exemplary polynucleotides encoding the G1 heavy and light chain variable regions are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively. The G1 heavy chain full length amino acid sequence is shown in SEQ ID NO: 3. The G1 light chain full length amino acid sequence is shown in SEQ ID NO: 4. Exemplary polynucleotides encoding the G1 full length heavy chain and light chains are shown in SEQ ID NO: 3 and SEQ ID NO: 4, respectively. The characterization of G1 is described in PCT Publication No. WO 2007/054809 and WHO Drug Information 30(2): 280-1 (2016), which are hereby incorporated by reference in its entirety. 
       FIG.  1    illustrates an example embodiment of a prefilled syringe  150  suitable for holding a therapeutic fluid  160  for injection. The prefilled syringe  150  includes a barrel  151 , a needle  155 , and a stopper  157 . The barrel  151  defines an interior  154  sized to hold a predetermined amount of the fluid  160  (e.g., at least one dose of the therapeutic fluid). The fluid  160  is held within the interior  154  of the barrel  151  between the stopper  157  and the needle  155 . An example of a syringe that can be used for the prefilled syringe  150  is a 2.25 mL EZ-Fill syringe supplied by Ompi (Piombino Dese, Italy). Other types of syringes can be used and syringes from other manufacturers also can be used. 
     The barrel  151  extends between a distal end  152  and an open proximal end  153 . The prefilled syringe  150  also has a tip  161  at the distal end  152 . The barrel  151  defines a proximally facing shoulder  151   a  at the distal end  152  of the interior  154  that extends between the barrel  151  and the tip  161 . 
     The syringe barrel  151  is configured to hold about 2.25 mL of fluid. However, other barrel sizes can be utilized. For example, the barrel  151  can be sized to hold about 1 mL of fluid. In other embodiments, the barrel  151  is sized to a volume of therapeutic fluid  160  in the range from about 1 mL to about 3 mL, about 1 mL to about 2.5 mL, or about 2 mL to about 2.5 mL. Other embodiments of the prefilled syringe  150  can hold other volumes of therapeutic fluid  160 . 
     Additionally, the syringe barrel  151  has an inner diameter or other inner cross-dimension of about 8.65 mm. In alternative embodiments, however, the barrel  151  can have an inner diameter in the range from about 6 mm to about 10 mm, or from about 8.5 mm to about 8.8 mm. Yet other possible embodiments can have an inner diameter other than in these ranges. 
     In certain examples, the syringe barrel  151  is formed from Borosilicate glass. In certain examples, the syringe barrel  151  is formed from clear, type I Borosilicate glass. For example, the syringe barrel  151  can be composed of a mixture of SiO 2 , B 2 O 3 , Al 2 O 3 , Na 2 O, and CaO. In a more specific example, the syringe barrel  151  is formed with 75% SiO 2 , 10.5% B 2 O 3 , 5% Al 2 O 3 , 7% Na 2 O, and 1.5% CaO. Alternative embodiments with other mixtures of these materials can be used to form the glass for the syringe barrel  151 . Other embodiments can use other types of glass or even materials other than glass to form the syringe barrel  151 . For example, the syringe barrel  151  can be formed with plastic. In at least some embodiments, the syringe barrel  151  is a Borosilicate glass barrel supplied by Schott Corporation of Elmsford, NY. Syringe barrels  151  from other manufacturers can be used. 
     The stopper  157  is axially moveable within the interior  154  of the barrel  151  along a path of travel, P, in a distal direction. The stopper  157  has a main body that is substantially cylindrical or otherwise has a cross-section shape similar to a cross-section of the inner surface  156  for the barrel  151 . The stopper  157  has one or more flanges or ribs  158  that extend radially from the main body. Additionally, the stopper  157  has a compressed state and an uncompressed state, the stopper  157  is in the compressed state when it is inserted into the syringe barrel  151 . 
     The main body of the stopper  157  has a first engagement surface  157   a  facing an exterior of the prefilled syringe  150  in a proximal direction and a second engagement surface  157   b  facing the fluid  160  contained within the barrel  151 . The first engagement surface  157   a  is flat and the end of a piston rod (e.g.,  107  of  FIGS.  14 - 17   ) abuts the engagement surface  157   a  during use. In alternative embodiments, the first engagement surface  157   a  may include a threaded hole (not shown) or other connection structure (not shown) so that the stopper  157  can be threaded onto or otherwise connected to the end of a piston rod in the auto injector. To move the stopper  157  distally within the syringe barrel  151 , a dispensing force can be applied to the first engagement surface  157   a  of the stopper  157  to push the stopper  157  along the path of travel, P. The main body of the stopper  157  has a length of about 7.7 mm. In alternative embodiments, the stopper  157  may have a length in the range from about 7.3 mm to about 8.1 mm, or from about 7 mm to about 9 mm. Alternative embodiments of the stopper  157  can have a length that is longer or shorter than these ranges. Additionally, the outer diameter of the main body for the stopper  157  when it is in the compressed state is about 8.95 mm. In some alternative embodiments, the outer diameter of the main body is in the range from about 8.85 mm to about 9.05 mm, or from about 5.5 mm to about 9.5 mm. Alternative embodiments can have a main body with an outer diameter that is outside of these ranges. Additionally, the outer diameter is measured from the base of a flange  158 , across the main body to the base of the flange  158  on the opposite side of the main body. 
     The plurality of annular flanges  158  engage the inner surface  156  of the syringe barrel  151 . The flanges  158  create a substantially air-tight seal against the inner surface  156  of the syringe barrel  151  and holds the therapeutic fluid  160  within the interior  154 . The stopper  157  includes four flanges  158 . In alternative embodiments, the stopper  157  may have a greater or lesser number of flanges  158 . For example, the stopper  157  could have one flange, two flanges, three flanges, or more than four flanges. Alternative embodiments might also include no flanges so that the entire outer surface  162  between the first and second engagement surfaces  157   a ,  157   b  engages the inner surface  156  of the syringe barrel  151 . In the compressed state, the stopper  157  has an outer diameter or cross-dimension of about 8.95 mm. In alternative embodiments, the outer diameter of the stopper  157  in the compressed state may be in the range from about 6 mm to about 10 mm, or from about 6.5 mm to about 9.5 mm. In some examples, the outer diameter of the stopper  157  is the outer diameter across the largest portion of the stopper  157  (e.g., across at least one of the flanges  158 ), and it is at least slightly larger than the inner diameter or inner cross-dimension of the syringe barrel  151  to ensure a seal between the two. When in the uncompressed state, at least some possible embodiments of the stopper  157  have an outer diameter in the range from about 9.25 mm to about 9.45 mm. 
     The stopper  157  is formed from a rubber such as Bromobutyl rubber, although materials other than rubber or other than Bromobutyl can be used to form the stopper  157 . An example formulation that can be used to form the Bromobutyl rubber, such as the formulation  4023 / 50 /GREY from West Pharmaceutical Services, PA, USA. Other formulations are possible. In other embodiments, material other types of rubber or material other than rubber is used to form the stopper  157 . Additionally, the stopper  157  can have a fluoropolymer coating on its outer surface  162  or have a laminated outer surface  162 . In an example, the coating can cover the entire outer surface  162  of the stopper  157 . In an alternative example, the coating can cover some or all of the second engagement surface  157   b , some or all of the flanges  158 , some or all of the portions of the outer surface  162  that opposes the inner surface  156  of the syringe barrel  151 , some or all of first engagement surface  157   a , or combinations of these surfaces. An example of the fluoropolymer material that can be used to coat the stopper  157  is ethylene tetrafluoroethylene (ETFE). An advantage of coating the stopper  157  with fluoropolymer is that it prevents absorption or adsorption of the therapeutic fluid  160 . 
     Material other than fluoropolymer can be used to coat or laminate the stopper  157 . An example of an alternative material is silicone. Alternatively, the stopper  157  can be coated or laminated with two or more materials. For example, the stopper  157  can have fluoropolymer coating the portion of its surface that comes into contact with the therapeutic fluid  160 , and silicone oil coating the portion of its surface that does not come into contact with the therapeutic fluid  160 . The coatings on the stopper  157  can operate as a lubricant, provide increased biocompatibility with the therapeutic fluid  160 , prevent absorption or adsorption of the therapeutic fluid  160  or its constituents, or a combination of the foregoing. In yet other embodiments, the stopper  157  does not have any type of coating or lamination. 
     In use, the second engagement surface  157   b  of the stopper  157  pushes the fluid  160  towards the needle  155  to expel the fluid  160  from the prefilled syringe  150 . The stopper  157  is moved from a first position, D 1 , along a path of travel, P to a second position, D 2 , along the path of travel, P. In an example embodiment, the first position, D 1 , is a position adjacent to the fluid  160  before any amount of a dose of the therapeutic fluid  160  is delivered, and the second position, D 2 , is the location of the second engagement surface  157   b  upon completing delivery of a complete dose of the therapeutic fluid  160 . When in the second position, D 2 , the stopper  157  is directly adjacent or even touching the shoulder  151   a  of the syringe barrel  151 . In an alternative embodiment, there can be a gap or air bubble between the therapeutic fluid  160  and the stopper  157  when the stopper  157  is in the first position, D 1 , or the stopper  157  can be spaced from the shoulder  151   a  of the syringe barrel  151  when the stopper  157  is in the second position, D 2 . 
     The path of travel, P, can be about 29.6 mm, which is sometimes referred to as a “30 mm” path of travel. In alternative embodiments, the path of travel, P, can be in the range from about 25.7 mm to about 28.2 mm, from about 25 mm to about 29 mm, or from about 25 mm to about 40 mm. In some embodiments, the path of travel, P, can be 29.6 mm. In other embodiments, the length of the path of travel, P, can be a distance outside these ranges. A volume of therapeutic fluid  160  in the prefilled syringe  150  that is held in the prefilled syringe  150  between the first and second positions D 1 , D 2  of the stopper  157  is about 1.585 mL, which corresponds directly to the interior volume of the syringe barrel  151  between the first and second positions D 1 , D 2 . In alternative embodiments, the volume of fluid  160  between the first and second stopper  157  positions D 1 , D 2  is in the range from about 1.51 mL to about 1.66 mL. Alternative embodiments can have different volumes of fluid  160  between the first and second positions D 1 , D 2  of the stopper  157 . The volume of fluid  160  may correspond to one full dose of therapeutic fluid  160 , multiple doses of the therapeutic fluid  160 , or a partial dose of the therapeutic fluid  160 . 
     The force applied to the stopper  157  by the auto injector  140  is the dispensing force. The amount of dispensing force required to push the stopper  157  in the prefilled syringe  150  can vary due to a variety of factors. Examples of such factors include the lubrication  159 , the syringe geometry and material, the stopper geometry and material, the therapeutic fluid  160  in the prefilled syringe  150 , desired injection time, and other resistive forces that oppose movement of the stopper  157 . Additionally, because the stopper  157  is compressible, it can absorb some of the dispensing force applied to it by the piston rod of an auto injector  140 . The selected injection spring would have to have enough force to overcome this absorption if absorption becomes significant enough to affect performance of the auto injector  140 . 
     Lubrication  159  may be disposed along an inner surface  156  of the barrel  151  to facilitate movement of the stopper  157  within the barrel  151 . The lubrication  159  is disposed between the inner surface  156  of the barrel  151  and an outer contact surface  162  of the stopper  157  as the stopper  157  moves along the path of travel P. The lubrication  159  reduces the friction between the outer contact surface  162  of the stopper  157  and the inner surface  156  of the barrel  151 . 
     The lubricant used to form the layer of lubrication  159  is a silicone oil. An example of silicone oil that can be used is polydimethylsioxane. In alternative embodiments, a lubricant other than silicone oil, a silicone oil other than polydimethylsioxane, or any other suitable lubricant is used to lubricate the inner surface  156  of the barrel  151 . The lubrication  159  can cover the entire inner surface  156  of the syringe barrel  151  including the wall of the barrel  151  and the shoulder  151   a . In other examples, the lubrication  159  covers less than the entire inner surface  156  of the prefilled syringe  150  such as only along the wall of the barrel  151 , or only along those portions of the wall of the barrel  151  that extend along the path of travel, P. 
     In at least some embodiments, the layer of lubrication  159  has a substantially uniform thickness along the path of travel P. Alternatively, the layer of lubrication  159  has a substantially uniform thickness along substantially the entire length of the syringe barrel  151 . Additionally, in at least some embodiments, the layer of lubrication  159  has a substantially uniform thickness around the inner circumference of the syringe barrel  151 . In other embodiments, the thickness of the layer of lubrication  159  varies over the length of the syringe barrel  151  or along the path of travel P. For example, the thickness of the lubrication  159  can gradually thin toward the distal end  152  of the prefilled syringe  150  compared to the proximal end  153  of the prefilled syringe  150 . As discussed in more detail herein, the thickness of the lubrication  159  can have other variations and also can carry around the circumference of the syringe barrel  151 . 
     In possible embodiments, the thickness of the lubrication layer  159  is about 0.5 μm. Other thicknesses are possible. For example, the lubrication layer  159  may have a thickness between about 0.1 μm and about 1 μm along the path of travel, P. In other examples, the lubrication layer  159  may have a thickness between about 0.1 μm and about 0.3 μm along the path of travel, P. 
     In at least some embodiments, the prefilled syringe  150  includes about 0.7 mg of silicone oil to form the lubricating layer  159 . In other embodiments, the amount of silicone oil is in the range from about 0.4 mg to about 1.1 mg. In yet other embodiments, the amount of silicone oil is in the range from about 0.35 mg to about 1.0 mg. 
     In an example embodiment, the lubricant forming the lubrication layer  159  has a viscosity of about 1000 cSt at 25° C. In an alternative embodiment, the lubricant has a viscosity in the range from about 500 cSt to about 1000 cSt at 25° C., from about 100 cSt to about 1000 cSt at 25° C., or less than about 1250 cSt at 25° C. In yet other embodiments, the lubricant has a viscosity outside of these ranges. 
     The needle  155  is disposed at the distal end  152  of the barrel  151  and is connected to the tip  161 . The needle  155  is secured to the tip  161  with an adhesive. In alternative embodiments, the needle  155  is connected to the tip  161  using a hub or other structure. 
     The needle  155  extends between a first end and a second end. The needle  155  is connected to the distal end  152  of the syringe barrel  151  at or adjacent to the first end of the needle  155 . The second end of the needle  155  may be sufficiently sharp or pointed to assist in breaking skin  192  at an injection site  198  of a user  190  (see  FIG.  19   ). The needle  155  defines a channel  155   a  that is in fluid communication with the interior  154  of the prefilled syringe  150 . In operation, fluid  160  flows through the channel  155   a  to exit the syringe barrel  151 . The channel  155   a  of the needle  155  has an internal diameter or cross-dimension, which is the distance from one point on the periphery to another point on the opposite side of the periphery. An internal diameter is an example of the cross-dimension when the channel  155   a  is circular in cross-section. In an example, the channel  155   a  has a constant internal diameter or cross-dimension along a length of the needle  155 . In other embodiments, however, the internal diameter or cross-dimension can vary along the length of the channel  155   a.    
     The needle  155  is a stainless steel needle such as a Grade AISI 304 stainless steel needle supplied by Chirana T. Injecta of Slovakia. Additionally, the needle  155  has an ISO-name 4301-304-00-1 and an ISO designation X5CrNi18-9. Other materials can be used to form the needle  155 . Other embodiments can use needles  155  from other manufacturers, and needles  155  having alternative ISO certifications or no certification at all. 
     The needle  155  has a length of 19.5 mm. In alternative embodiments, the needle  155  can have a length in the range from about 15 mm to about 25 mm, from about 18.3 mm to about 20.7 mm, or less than 19.5 mm. Other embodiments can have a needle length that is longer or shorter than these ranges. Additionally, the needle channel  155   a  has an inner diameter or inner cross-dimension of 0.27 mm, from about 0.15 mm to about 0.3 mm, from about 0.25 mm to about 0.29 mm, from about 0.21 mm to about 0.3 mm, or less than 0.27 mm. In other embodiments, the needle  155  has an inner diameter of about 0.29 mm or less. Other embodiments have an inner diameter that is narrower or wider than these ranges. 
     The therapeutic fluid  160  can contain drugs having pharmacological or other active ingredients, biologics, biosimilars, or any other composition for treating a body. Depending on the composition of the therapeutic fluid  160  and prescribed treatment, the therapeutic fluid  160  can have one of a variety of different volumes and viscosities. In at least some possible embodiments, for example, the therapeutic fluid  160  has a volume of about 1.585 mL. In other embodiments, the volume of therapeutic fluid  160  is in the range from about 1.51 mL to about 1.66 mL. In other embodiments, the volume of therapeutic fluid  160  is in the range from about 1 mL to about 2.25 mL. Yet other embodiments have other volumes of therapeutic fluid  160  loaded in the prefilled syringe  150 . 
     The therapeutic fluid  160  may be a liquid pharmaceutical composition comprising fremanezumab, disodium ethylenediaminetetraacetic acid dihydrate (EDTA), L-histidine, L-histidine hydrochloride monohydrate, polysorbate-80, sucrose, and water for injection. An example of a particular formula for the therapeutic fluid  160  is about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mg sucrose, and water for injection at a pH of about 5.5. In an alternative embodiment, the therapeutic fluid  160  can be formulated at 150 mg/mL nominal concentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, 1.2 mg/mL PS80, pH 5.5. In some embodiments, at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isoform. In some embodiments of any of the compositions provided herein, about 72% of the antibody molecules in the composition are of the disulfide isoform B, wherein about 22% of the antibody molecules in the composition are of the IgG2-A/B, and wherein about 6% of the antibody molecules in the composition are of the IgG2-A disulfide isoform. Other embodiments of the therapeutic fluid  160 , including those for fremanezumab, can have other formulations including other constituents. Additionally, the therapeutic fluid  160  can have drugs, biologics, or biosimilars other than fremanezumab. 
     The viscosity of the liquid pharmaceutical composition may be about 8.8 cSt at 22° C. Other viscosities are possible. For example, the therapeutic fluid  160  may have a viscosity ranging from about 4 cSt at 22° C. to about 14 cSt at 22° C. In certain examples, the therapeutic fluid  160  has a viscosity ranging from about 8 cP at 22° C. to about 10 cP at 22° C. In certain examples, the therapeutic fluid  160  has a viscosity less than about 10 cSt at 22° C. 
     The therapeutic fluid  160  can be used for the treatment or prevention of a variety of different temporary or chronic diseases, conditions, or other maladies. The therapeutic fluid  160  can be used for the treatment or prevention of any disease or disorder associated with CGRP (Calcitonin Gene-Related Peptide) activity or CGRP upregulation. In one possible embodiment, the therapeutic fluid  160  comprises a biologic such as for treating episodic or chronic migraine headaches. For example, the therapeutic fluid  160  can include a immunoglobulin G 2  (IgG2) monoclonal antibody. In another example, the therapeutic fluid  160  includes a humanized IgG2 monoclonal antibody. The antibody also may be expressed in CHO cells. In another example, the therapeutic fluid  160  includes an anti-CGRP protein. 
     In a more specific example, and with reference to  FIG.  2   , the therapeutic fluid  160  includes an antibody comprising a heavy chain variable region V H  domain that is at least 90%, optionally 95%, 97%, 99%, or 100% identical in amino acid sequence to SEQ ID NO: 1 and a light chain variable region V L  domain that is at least 90%, optionally 95%, 97%, 99%, or 100% identical in amino acid sequence to SEQ ID NO: 2. In certain examples, the therapeutic fluid  160  includes the antibody produced by the expression vectors with ATCC Accession Nos. PTA-6867 and PTA-6866. In another example, the therapeutic fluid  160  includes fremanezumab. 
     In other examples, the therapeutic fluid  160  includes an antibody comprising the following CDRs: CDR H1 as set forth in SEQ ID NO: 3; CDR H2 as set forth in SEQ ID NO: 4; CDR H3 as set forth in SEQ ID NO: 5; CDR L1 as set forth in SEQ ID NO: 6; CDR L2 as set forth in SEQ ID NO: 7; and CDR L3 as set forth in SEQ ID NO: 8. 
     The therapeutic effects of fremanezumab are long lasting and can be taken by injection relatively infrequently. In one embodiment, for example, fremanezumab can be administered about one time per month or less frequently. In another example, fremanezumab can be administered about once every two months or less frequently. In another example, fremanezumab can be administered about once every three months or less frequently. In another example, fremanezumab can be administered about once every four months or less frequently. Fremanezumab is disclosed in more detail in U.S. Pat. No. 8,007,794, which issued on Aug. 30, 2011, and is entitled “Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide and Methods Using the Same”, the entire disclosure of which is hereby incorporated herein by reference. 
     The therapeutic fluid  160  also can be used for the treatment or prevention of other conditions such as cluster headaches, posttraumatic headaches, fibromyalgia, and Interstitial Cystitis/Bladder Pain Syndrome (ICBPS). 
     In certain implementations, the therapeutic fluid  160  is expected to have a shelf life of about 24 months when stored between 2° C. and 8° C. In an example, the therapeutic fluid  160  is expected to have a shelf life of about 2 years when stored at 5° C. In other embodiments, the therapeutic fluid  160  is expected to have a shelf life of at least 12 months when stored between 2° C. and 8° C. In certain examples, the therapeutic fluid  160  is expected to have a shelf life of at least 18 months when stored between 2° C. and 8° C. In certain examples, the therapeutic fluid  160  is expected to have a shelf life of at least 30 months when stored between 2° C. and 8° C. In certain examples, the therapeutic fluid  160  is expected to have a shelf life of at least 36 months when stored between 2° C. and 8° C. In certain examples, the therapeutic fluid  160  is expected to have a shelf life of at least 6 months when stored between 2° C. and 8° C. In certain examples, the therapeutic fluid  160  is expected to have a shelf life of at least 9 months when stored between 2° C. and 8° C. 
     It has been discovered that traditional injection time simulations for prefilled syringes  150  have several disadvantages. For example, several aspects of a prefilled syringe  150  change over time and, given enough time, some of the changes can cause significant problems with performance of the prefilled syringe  150  and an auto injector  140  in which the prefilled syringe  150  is mounted. Many of these changes are not commonly taken into account by current injection time simulations, and can include changes to the prefilled syringe  150  that increase resistive forces opposing movement of the stopper  157  within the syringe barrel  151 . 
     The increase in resistive forces can be great enough to slow the speed of the syringe stopper  157  within the syringe barrel  151  compared to the prefilled syringe  150  before the changes occurred. Sometimes, the speed of injection due to these increased resistive forces may cause discomfort to the patient. The slow injection also could result in an impatient user  190 , who is self-administering the therapeutic fluid  160 , to pull the needle  155  out of their body prematurely, thereby resulting in an incomplete delivery of the fluid  160 . In yet another embodiment, movement of the stopper  157  can even stall, resulting in delivery of only a partial dose. 
     Friction and hydrodynamic forces are examples of resistive forces that oppose movement of the stopper  157  and may affect the break-loose force and glide force, and thereby the injection time and dose accuracy. The break-loose force is the amount of force required to set the stopper  157  in motion, and the glide force is the amount of force required to sustain movement of the stopper  157 . Friction can be between the stopper  157  and the syringe barrel  151 . Other types of friction also can oppose movement of the stopper  157 . Hydrodynamic force is the force required to push the fluid  160  through the barrel  151 , into the needle  155 , and then through the needle  155 . 
     There are several changes that can occur over time and increase friction between the stopper  157  and syringe barrel  151 . For example, the lubrication  159  in the syringe barrel  151  or on the stopper  157  can degrade or breakdown, whether due to time or interaction with the constituents of the therapeutic fluid  160 . The degradation of the lubrication  159  can cause the viscosity of the lubrication  159  to increase. The degradation also can cause the layer of lubrication  159  on the barrel wall  156  to thin over time. Furthermore, the lubrication  159  is a fluid and flows along the barrel wall  156  over time, which can cause variations in the thickness of the lubrication  159  resulting in areas of increased friction along the stopper&#39;s path of travel, P, because the layer of lubrication  159  thins or is gone entirely. 
     There also are several examples of changes that can increase hydrodynamic forces. For example, some therapeutic fluids  160  can change over time. The therapeutic fluid  160  can aggregate or crystalize over time forming larger clumps that can become stuck in the channel  155   a  of the hypodermic needle  155 . The blockage created by these clumps may increase the hydrodynamic force required to move the fluid  160  through the needle  155 . The result is greater resistance against movement of the stopper  157 . 
     If a developer of therapeutic fluids or prefilled syringes wants to use actual, real world data to design an auto injector or to use for regulatory approval, they may choose to test a prefilled syringe that has been aged at least as long as its desired shelf life. A problem with using actual, real world data is that many therapeutic fluids and prefilled syringes are expected to have a long shelf life, some as long as 24 months or even longer. 
     Waiting this long to submit an application for regulatory approval of a drug delivered by an auto injector until after the natural shelf life of the therapeutic fluid lapses can significantly delay the approval process for the medication and the time at which the pharmaceutical company can put the therapeutic fluid on the market. As a result, potentially life-altering or even life-saving medications are delayed in reaching patients. In addition, this delay makes it more difficult for the pharmaceutical company to recover the huge investment required to research and find a successful medication. To speed up the regulatory approval process, the pharmaceutical companies may use simulated or accelerated aging to replicate the effects of time. For example, the pharmaceutical company can use mathematical modeling to approximate the performance of a prefilled syringe after a certain period of time. In another example, the pharmaceutical companies heat the prefilled syringe at a determined temperature and for a determined period of time to simulate aging. The relationship between the length of time heating the prefilled syringe and the actual, non-accelerated length of time can be defined according to the Arrhenius calculation: 
         K=Ae   −EA/(RT)   (3)
 
     where “K” is the rate constant, “T” is the absolute temperature (in Kelvin), “Ae −EA ” are constants for a given reaction, and “R” is a universal gas constant. 
     It was discovered that artificial aging of the prefilled syringes  150  or the therapeutic fluid  160  can lead to complications during stability testing. For example, during stability testing using artificial aging, it was discovered that the combination of an aged prefilled syringe  150  and an auto injector (e.g., the auto injector  140  shown in  FIGS.  13 - 17   ) could result in various operation failures, including failure to inject within the intended injection time. It was further discovered that artificial aging of the prefilled syringe  150  led to higher than expected resistive forces on the stopper  157 . For example, the resistive force exerted on the stopper  157  towards the end of an injection stroke along the path of travel, P, was higher than expected. Accordingly, the injection spring  109  used in a standard auto injector device was not able to consistently successfully operate the auto injector with the artificially aged prefilled syringe  150  as the simulated aging increased. 
     In particular, it was discovered that heating the prefilled syringe  150  exaggerates certain changes that occur over time. For example, heating causes changes to the prefilled syringe  150  to occur faster than they would during an equivalent amount of time for natural aging. For example, when compared to a prefilled syringe  150  that is naturally aged at a non-accelerated rate for 24 months, a prefilled syringe  150  subject to accelerated aging by heating for a simulated 24-month period will show changes of a greater magnitude or even more types of changes, such as changes to the thickness of the lubricating layer  159 , greater decreases to the viscosity of the lubricant, greater variations in the thickness of the lubricating layer  159 , more interaction between the therapeutic fluid  160  and the lubricant, and the like. 
     All of these exaggerated changes that occur during artificial or accelerated aging unnaturally increase friction and hydrodynamic forces as compared to a prefilled syringe  150  that ages naturally. When an artificially aged prefilled syringe  150  having increased resistance to movement of the stopper  157  is combined with an auto injector (e.g., the auto injector  140  described in more detail herein), there can be operational failures including failure to inject the therapeutic fluid  160  within the intended injection time or even injection stalls. Yet the pharmaceutical company must show data that the auto injector  140  can move the stopper  157  to deliver a full dose of the therapeutic fluid  160  within a reasonable period of time and not stall. To enable an effective regulatory path by allowing artificial aging and meeting stability requirements, it is herein proposed to adapt the auto injector  140 . An injection spring  109  for the auto injector  140  that has enough spring force to meet acceptable delivery specifications for an artificially aged prefilled syringe  150  is used. However, it is noted that the prefilled syringes used in the auto injectors on the market will be naturally aged. Further, it is noted that increasing unnecessarily the spring force is generally not beneficial because it may lead to some discomfort, bruising of the patient, or breakage of the prefilled syringe. 
     An example of this problem with artificially aged prefilled syringes  150  is illustrated in the charts shown in  FIGS.  3 A- 3 D . To generate the data shown in  FIGS.  3 A- 3 D , the prefilled syringes  150  used were 2.25 mL EZ-Fill syringes with an internal barrel diameter of about 8.65 mm supplied by Ompi of Piombino Dese, Italy, the stopper  157  was a FluroTec plunger from West Pharmaceutical Services, PA of Exton, Pa., USA, and the needle  155  was a Grade AISI 304 stainless steel needle supplied by Chirana T. Injecta of Slovakia with an internal diameter of about 0.27 mm and a length of about 19.5 mm. The syringe barrels  151  were lubricated with 0.7 mg of silicone oil having a viscosity of about 1000 cSt at 25° C. The therapeutic fluid  160  loaded in the prefilled syringes  150  consisted of about 1.585 mL of a formulation of fremanezumab formulated at 150 mg/mL nominal concentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, and 1.2 mg/mL P580 at a pH of 5.5. The therapeutic fluid  160  had a viscosity of 8.8 cSt at 22° C. Multiple unaged prefilled syringes  150  were tested. The path of travel, P, of the stopper  157  in the barrel  151  corresponding to the extrusion of the therapeutic fluid  160  is of about 30 mm. 
       FIG.  3 A  is a graph plotting the force exerted against the syringe stopper  157  of an unaged prefilled syringe  150  versus displacement of the stopper  157  when the stopper  157  is moved at a constant speed. The graph may be obtained using the test equipment described with reference to  FIGS.  4 A and  5   . The y-axis shows the force exerted against the stopper  157  measured in Newton, N. Because the stopper  157  is moved at a substantially constant speed, this exertion force is substantially equal to the resistive force that acts against movement of the stopper  157 . The displacement is the displacement from a first (initial) position of the stopper  157  at the beginning of an injection and a second (final) position of the stopper  157 . The chart in  FIG.  3 A  shows the maximum resistance force during movement of the stopper  157  is about 8 N until just before the displacement reaches about 30 mm, which corresponds to the stopper  157  reaching and hitting the shoulder  151   a  in the syringe barrel  151 . 
       FIG.  3 B  is a bar chart showing the maximum force exerted on the stopper  157  of a prefilled syringe  150  subjected to accelerated aging. The prefilled syringes  150  exposed to accelerated aging were heated at 40° C. for a period of time equivalent to simulate a desired natural age. For each prefilled syringe  150 , the stopper  157  was pressed for extruding the therapeutic fluid  160  at a constant speed and the force exerted against the stopper  157  was measured. The force exerted against the stopper  157  is equivalent to or corresponds to the force resistive to movement of the stopper  157 . The graph was obtained using the test equipment described with reference to  FIGS.  4 A and  5   . The y-axis shows the maximum force exerted against the syringe stopper  157  in Newton while it is moved to deliver a dose of therapeutic fluid  160  at a constant speed. The x-axis shows the simulated age of the prefilled syringe  150  after it goes through accelerated aging. The first bar shows the maximum exertion force before accelerated aging. The second bar shows the maximum exertion force for a prefilled syringe  150  that has a simulated age of 3 months (T3). The third bar shows the maximum exertion force for a prefilled syringe  150  that has a simulated age of 6 months (T6). The fourth bar shows the maximum exertion force for a prefilled syringe  150  that has a simulated age of 9 months (T9). The fifth bar shows the maximum exertion force for a prefilled syringe  150  that has a simulated age of 14 months (T14). The sixth bar shows the maximum exertion force for a prefilled syringe  150  that has a simulated age of 24 months (T24). 
     As can be seen, the maximum force measured while moving the stopper  157  during testing gradually increases to about 14 N, which is much greater than the 8 N measured for an unaged prefilled syringe  150 . Each bar on the chart represents a group of prefilled syringes  150  tested at each simulated age and shows the range of measured exertion forces for the group from the highest maximum exertion force measured to the lowest maximum exertion force measured for the group. Each bar also presents a box representing the middle two quartiles or the middle 50% of the measured exertion forces. 
       FIG.  3 C  is a graph plotting the force exerted against the syringe stopper  157  of a prefilled syringe  150  having a simulated age of 24 months versus displacement of the stopper  157 . The prefilled syringes  150  exposed to accelerated aging were heated at 40° C. for a period of time equivalent to simulate a desired natural age. For each prefilled syringe  150 , the stopper  157  was pressed for extruding the therapeutic fluid  160  at a constant speed and the force exerted against the stopper  157  was measured. The force exerted against the stopper  157  is equivalent to or corresponds to the force resistive to movement of the stopper  157 . The y-axis shows the force exerted against the stopper  157  measured in Newton, N. The graph was obtained using the test equipment described with reference to  FIGS.  4 A and  5   . Because the stopper  157  moves at a substantially constant speed, this exertion force is substantially equal to the resistive force that acts against movement of the stopper  157 . The displacement is the displacement from a first position of the stopper  157  at the beginning of an injection and the ending position of the stopper  157 . The chart in  FIG.  3 C  shows the maximum resistance force during movement of the stopper  157  is about 14 N until just before the displacement reaches 30 mm, which corresponds to the stopper  157  reaching and hitting the shoulder  151   a  in the syringe barrel  151 . 
     As can be seen in  FIGS.  3 B and  3 C , the peak or maximum force required to move the stopper  157  a distance of 30 mm for a prefilled syringe  150  that had a simulated or accelerated age of 24 months was in the range from about 13 N to about 14 N. The peak force for the accelerated aged prefilled syringe  150  is in sharp contrast to the only 8 N to 9 N peak force required to move the stopper  157  of the naturally aged prefilled syringe  150  as shown in  FIG.  3 A . These charts show a significant increase in the force required to move the stopper  157  for an artificially aged prefilled syringe  150  used in testing compared to a naturally aged prefilled syringe  150 . 
       FIG.  3 D  is a bar chart showing injection time or how long it takes to move the stopper  157  from the first position, D 1 , to the second position, D 2 , for prefilled syringes  150  subject to natural aging and prefilled syringes  150  subject to accelerated aging. The y-axis shows the injection time in seconds, and the x-axis shows the age of the prefilled syringe  150 . Data for naturally aged prefilled syringes  150  is shown with bars without a cross hatch, and data for accelerated aged prefilled syringes  150  is shown with bars with a cross hatch. To generate the data in  FIG.  3 D , an auto injector  140  with a prefilled syringe  150  was mounted in a fixture, which held the auto injector  140  upright with the needle  155  pointed down. A container was placed under the auto injector  140  to collect fluid  160  as it was dispensed. The auto injector  140  was actuated. A stopwatch was manually started simultaneously with actuating the auto injector  140  and stopped immediately when therapeutic fluid  160  stopped flowing from the needle  155 . A digital stop clock having an accuracy of within 100th of a second was used. Eight samples of naturally aged prefilled syringes  150  were tested at zero months, 1 month, 6 months, 9 months, 13 months, 19 months, and 24 months. Four samples of accelerated aged prefilled syringes  150  were tested at 12 months, 24 months, and 48 months. Each bar on the chart represents a group of prefilled syringes  150  tested at a natural age or a simulated age as labelled on the chart and shows the range of injection time for each group from the longest injection time to the shortest injection time. Each bar also presents a box representing the middle two quartiles or the middle 50% of the injection times. 
     At 12 months, the naturally aged prefilled syringes  150  had an injection time in the range from about 18.6 s to about 20.8 s, whereas the accelerated aged prefilled syringes  150  had an injection time in the range from about 16.4 s to about 39.3 s. At 24 months, the naturally aged prefilled syringes  150  had an injection time in the range from about 18 s to about 21 s, whereas the accelerated aged prefilled syringes  150  had an injection time in the range from about 19.4 s to about 46.3 s. As can be seen, the delivery time for a naturally aged prefilled syringe  150  remains relatively steady throughout the life of the prefilled syringe  150 . The delivery time for an artificially aged prefilled syringe  150  is comparable to the delivery time for a naturally aged prefilled syringe  150  until the prefilled syringe  150  is about 9 months old. After that age, the time for delivery of a full dose starts to rapidly increase for the artificially aged prefilled syringes  150 . At 24 months of simulated aging, the delivery time can reach more than 45 seconds, which exceeds a target delivery time. 
     The above-described tests and results show that artificial aging of a prefilled syringe  150  can result in an increase in the force required to complete an injection. In certain cases, artificial aging of a prefilled syringe  150  can result in an increase in the force required to complete an injection within a desired or determined period of time (e.g., from about 5 seconds to about 19 seconds). 
     As a solution to these operation failures, the auto injector  140  may be manufactured with an injection spring  109  that is sufficiently strong to accommodate the higher extrusion forces on the stopper  157  of an artificially aged prefilled syringe  150 . That is, the injection spring  109  may need a sufficiently high spring constant K and compression to overcome the increased resistive forces generated by an artificially aged prefilled syringe  150 , especially at the end of injection as the stopper  157  approaches the second position, D 2 , and the resistive force is significantly greater than the resistive force at the beginning of injection, as can be seen in  FIG.  3 B . However, increasing the strength of the injection spring  109  can lead to discomfort or even bruising of the patient. It also can lead to breakage of the syringe  150 . Accordingly, using an injection spring  109  having more power than necessary is undesirable. 
     The tests described below can be used in determining suitable spring parameters for the injection spring  109  of an auto injector  140  used to inject therapeutic fluid  160  from an artificially aged prefilled syringe  150 . For example, the tests can determine a dispensing force that is sufficiently strong to displace the syringe stopper  157  fully along the entire path of travel, P, within a predetermined time. The artificially aged prefilled syringe  150  used in these tests forms a reference prefilled syringe  150  having a reference barrel  151 , a reference stopper  157 , and a reference needle  155 . The prefilled syringe  150  that is actually used in an auto injector  140  to deliver the therapeutic fluid  160  to a patient is an operative prefilled syringe  150  having an operative barrel  151 , an operative stopper  157 , and an operative needle  155 . The reference prefilled syringe  150  is substantially similar to the operating prefilled syringe  150 . To ensure proper performance of the operative prefilled syringes  150 , the reference prefilled syringes  150  and the operative prefilled syringes  150  have substantially the same dimensions and are made from the same materials or materials that provide the same performance characteristics. In an alternative embodiment, the reference prefilled syringes  150  and operative prefilled syringes  150  can have different parameters. For example, the reference prefilled syringe  150  can have parameters that provide more resistive force against movement of the stopper  157 , which ensures that the designed injection spring  109  will still provide a suitable amount of dispensing force throughout the entire range of spring compression so that the auto injector  140  will inject a full dose of therapeutic fluid  160  within the determined time. 
       FIGS.  4 A and  4 B  illustrate a fixture for testing injection of prefilled syringes  150  to determine an injection spring  109  having sufficient force to meet performance criteria for regulatory approval of prefilled syringes  150  and auto injectors  140 .  FIG.  4 A  illustrates a fixture  315  for holding a prefilled syringe  150  and also illustrates the principles of the test. The fixture  315  includes a syringe support frame  316  having a bottom support  316   a , side supports  316   b , and a top plate  316   c . The syringe support frame  316  is of sufficient thickness and rigidness so that it does not flex or compress under application of the forces used in testing. The top plate  316   c  defines a hole  316   d  that is large enough so the syringe barrel  151  will pass through the hole  316   d , but not so large that the syringe flange  158  at the proximal end  153  of the prefilled syringe  150  will fit through the hole  316   d . In this way, the prefilled syringe  150  is supported by the top plate  316   c  with the needle  155  pointed down. A drive rod  314  is aligned with and has an end that engages the first engagement surface  157   a  of the syringe stopper  157 . A second, opposite end of the drive rod  314  is coupled to testing equipment configured to move the drive rod  314  at a substantially constant speed. The drive rod  314  also is attached to measuring equipment such as a load cell  315  (see, e.g.,  FIG.  5   ) that is positioned to measure a force applied to the drive rod  314  as it moves. 
     The needle  155  is positioned in or above a collection container  318  to collect the therapeutic fluid  160  as it is ejected from the prefilled syringe  150 . Collecting the therapeutic fluid  160  allows a comparison of the amount of fluid  160  loaded in the prefilled syringe  150  before testing to the amount of fluid  160  ejected from the prefilled syringe  150  after testing to ensure a full dose is ejected during testing. Alternatively, the tip  161  of the needle  155  can be inserted into a mass to simulate injection into a patient. Inserting the tip  161  of the needle  155  into a mass enables the test apparatus to include the resistance to flow in its measurements of total resistance acting against movement of the syringe stopper  157 . Examples of a mass that can simulate an injection include cadaver tissue, animal tissue such as pig, and synthetic tissue. 
     During the test, the drive rod  314  is advanced or pushed against the stopper  157  to push the stopper  157  for a consistent speed and for a determined distance. In at least some possible embodiments, the determined distance corresponds to the stopper  157  moving from the first position, D 1 , to the second position, D 2 , to deliver a full dose of therapeutic fluid  160 . The speed at which the drive rod  314  is pushed downward is selected to simulate a desired timing for injection of the prefilled syringe  150  within an auto injector  140 . In some embodiments, the drive rod  314  is advanced from the first position, D 1 , to the second position, D 2 , at a time in the range from about 5 s to about 12 s. 
     As the drive rod  314  is advanced against the syringe stopper  157 , the load cell  315  measures the force applied to the drive rod  314  and the relative position of the drive rod  314  is measured. The displacement of the drive rod  314  will substantially equal the displacement of the syringe stopper  157 . The force measurements and the displacement of the drive rod  314  at the time of each force measurement are recorded. 
     During testing, the force applied to the drive rod  314  to advance or push the syringe stopper  157  is an exertion force, F e . Forces that oppose movement of the stopper  157  due to friction, hydrodynamics, and any force that resists movement of the stopper  157  is a resistive force, F r . Because the stopper  157  moves at a substantially constant speed during the test, the exertion force will substantially equal a resistive force. The exertion force may vary during advancement of the stopper  157  due to changing resistive forces acting against movement of the stopper  157 . 
       FIG.  4 B  illustrates an alternative fixture  319  for testing prefilled syringes  150  in combination with an auto injector  140 . This embodiment is substantially similar to the fixture in  FIG.  4 A , and includes the syringe support frame  316 , which is supporting the prefilled syringe  150 . Additionally, a clamp  317  is mounted on the top plate  316   c  of the syringe frame  316  and includes first and second opposing jaws  317   a ,  317   b . Each of the first and second jaws  317   a ,  317   b  defines opposing contours such as semicircular cutouts, which are shaped to receive and securely hold a portion of the auto injector  140  when the jaws  317   a ,  317   b  are closed. In operation, an auto injector  140  has its injection spring  109  removed and is mounted in the clamp  317  and is positioned so the piston rod  107  from the auto injector  140  is axially aligned with the syringe barrel  151 . The piston rod  107  is inserted into the syringe barrel  151  so that the end of the piston rod  107  for the auto injector  140  engages the first engagement surface  157   a  of the stopper  157 . 
     As described in more detail herein, the auto injector  140  includes a subassembly that moves in response to decompression of the injection spring  109 . The subassembly will include a structure for advancing the piston rod  107 . The subassembly also may include additional moving structures and secondary spring mechanisms that also are moved or driven by the injection spring  109  as it decompresses. In example embodiments, the entire auto injector  140 , minus the injection spring  109 , can be mounted in the clamp  317  provided there is access to insert the drive rod  314  into the auto injector  140  so that it can engage and move the piston rod  107  and other auto injector components that operate in response to movement of the piston rod  107 . Alternatively, the subassembly can be removed from the auto injector  140  or otherwise exposed and mounted in the clamp  317  without components of the auto injector  140  that are not operated by the injection spring  109 . 
     The drive rod  314  connected to the test equipment engages and moves the piston rod  107  at a constant speed for a determined distance. In at least some embodiments, the determined distance corresponds to the distance the stopper  157  is moving from the first position, D 1 , to the second position, D 2 , to deliver a full dose of the therapeutic fluid  160 . The exertion forces applied to the drive rod  314  and the displacement of the drive rod  314  are recorded. In this test setup, the measured exertion force may correspond to the total resistance force including friction in the prefilled syringe  150 , hydrodynamic forces, friction in the subassembly, any force required to compress secondary springs in the subassembly, and any other resistive force that acts against movement of the stopper  157  and movement of the subassembly. 
       FIG.  4 C  illustrates a fixture  320  for testing an auto injector  140  to determine the spring strength for the injection spring  109 . It is used to simulate operation of the auto injector  140  and measure the dispensing force of the piston rod  107  as the injection spring  109  decompresses. It is useful to verify proper operation of an auto injector  140  after an injection spring  109  is selected as described in more detail herein. 
     The fixture  320  includes a base  321  that can be secured to a workbench  324  for stability during testing. The base  321  is secured to the workbench  324  using bolts  326   a ,  326   b . A tube  327  extends upward from the base  321  and defines a cavity  323  that is sized to receive an auto injector  140 . The length of the cavity  323  is about the same length of the housing  104  for the auto injector  140 , although in various embodiments it can be longer or shorter. The cross-sectional shape and area of the cavity  323  is sized to allow the auto injector  140  to slide into the cavity  323 , but still hold the auto injector  140  securely without twisting or wobbling. A cap  322  is secured over the top end of the tube  327  to enclose and secure the auto injector  140  within the cavity  323 . The cap  322  defines a hole  325  that is axially aligned with the cavity  323  and sized to receive the drive rod  314 . 
     As explained in more detail herein, the auto injector  140  has a housing  102  and cover sleeve  103  that telescopes into the housing  102  (see, e.g.,  FIGS.  13 - 17   ). Sliding the cover sleeve  103  into the housing  102  cocks the auto injector  140  so that the internal piston rod  107  is free to move. To test the auto injector  140  in fixture  320 , the prefilled syringe  150  is removed from the auto injector  140  so that the piston rod  107  is exposed. The auto injector  140  is then inserted in the cavity  323  and orientated so that the cover sleeve  103  points upward and extends from the top of the tube  327 . The cap  322  is placed over the end of the tube  327 . The drive rod  314  is then inserted through the hole  325  and into the auto injector  140  so that the end of the drive rod  314  engages the end of the piston rod  107 . A second, opposite end of the drive rod  314  is coupled to testing equipment configured to move the drive rod  314  at a substantially constant speed. The drive rod  314  also is attached to measuring equipment such as a load cell  315  (see, e.g.,  FIG.  5   ) that is positioned to measure a force applied to the drive rod  314  as it moves. 
     The cap  322  is then pushed down until the cover sleeve  103  telescopes into the housing  102 , which cocks the auto injector  140  and frees the injection spring  109  to decompress and the piston rod  107  to move. The cap  322  is locked onto the end of the tube  327  so it stays in place. Any suitable mechanism can be used to secure the cap  322  in place. For example, the cap  322  can be threaded onto the end of the tube  327 . Alternatively, the tube  327  can include a key that projects form the side of the fixture  320  and the cap  322  can include an L-shaped slot that receives the key and holds the cap  322  in place. The methods and testing apparatuses disclosed herein also can be used to test alternative embodiments of spring-driven auto injectors. 
     At the start of the test, the injection spring  109  is compressed and the piston rod  107  is in a position that corresponds to the stopper  157  being in its first position. The drive rod  314  is then raised at a constant speed and for a determined distance. In at least some possible embodiments, the determined distance corresponds to the stopper  157  moving from the first position, D 1 , to the second position, D 2 , to deliver a full dose of therapeutic fluid  160 . For example, the drive rod  314  can be raised about 30 mm. Additionally, the speed at which the drive rod  314  is raised is selected to simulate a desired timing for injection of the prefilled syringe  150  within an auto injector  140 . As the drive rod  314  is raised and the piston rod  107  advances, the load cell  315  measures the force applied to the drive rod  314  and the relative position of the drive rod  314 . The displacement of the drive rod  314  will substantially equal the displacement of the syringe stopper  157 . The force measurements and the displacement of the drive rod  314  at the time of each force measurement are recorded to form a dispensing force profile. Such force measurements can be used to verify the injection spring  109  causes the piston rod  107  to exert a desired dispensing force as it advances between positions corresponding to the first and second positions D 1 , D 2  of the stopper  157 . 
     Although the fixture  320  is illustrated as holding an auto injector  140  having a telescoping sleeve  103  to cock the auto injector  140  and free the piston rod  107  to move, it can be adapted to hold and cock auto injectors  140  having alternative mechanisms such as push buttons, knobs, levers, and sliding buttons. 
       FIG.  5    illustrates the fixture  315  shown in  FIG.  4 A  in a test setup for operating the drive rod  314  and measuring performance of the prefilled syringe  150 . In this set up, a universal testing machine  310  has a cross head  312  that moves up and down and can be moved a constant and determined speed. The fixture  316  is mounted in the universal testing machine  310  and positioned so that the drive rod  314  is axially aligned with cross head  312 . A load cell  315  is positioned between the drive rod  314  and the cross head  312  and measures the force exerted against the drive rod  314  as the cross head  312  moves downward or otherwise advances toward the stopper  157 . Additionally, a gauge for measuring displacement of the cross head  312  or drive rod  314  is positioned and configured to measure movement of the cross head  312 . As noted herein, linear movement of the cross head  312  and drive rod  314  will be substantially equal to linear movement of the syringe stopper  157 . Although the fixture  316  is illustrated being used with the universal testing machine  310 , it should be appreciated that the fixture  319  illustrated in  FIG.  4 B  and the fixture  320  illustrated in  FIG.  4 C  can be used with the universal testing machine  310  and drive rod  314  in a substantially similar manner. 
     The load cell  315 , gauge, and universal testing machine  310  are operated by a programmable controller  311  such as a computer that controls movement of the cross head  312  and records output from the load cell  315  an instrument for measuring distance. Measurements from the load cell  315  and the gauge are synchronized so that the recorded exertion force is correlated to the displacement of the drive rod  314 /stopper  157  at the time a force measurement is made. The force and displacement measurements form an exertion force profile correlating the measured force to displacement of the drive rod  314  and stopper  157 . This data can be used to generate graphs and charts similar to those illustrated in  FIGS.  3 A- 3 C . The computer controller  311  also can record the time intervals for each measurement made and the total time it takes to fully displace the stopper  157  for delivery of a full dose of therapeutic fluid  160 . 
     The load cell  315  can be any type of instrument or sensor that measures force such as a strain gauge or piezo electric cell. The gauge can be any type of instrument for measuring distance including light-, laser-, and magnetic-based measuring instruments. The gauge also could be virtual in that the motor driving the cross head  312  is a stepper motor and distance is determined by the number of steps during rotation of the armature on the motor. An example of a universal testing machine  310  that can be used is a MultiTest 2.5-I tensometer available from Mecmesin of the United Kingdom. An example of a load cell  315  may be of 25N or 200N. An example of control software may be Emperor v1.18. Other universal machines that can be adapted to measure force and displacement can be used. In operation, and as discussed herein, the programmable controller  311  controls the universal testing machine  310  to move the cross head  312  at a substantially constant speed. Alternative embodiments can apply acceleration or deceleration to movement of the cross head  312 . In an alternative test setup, the fixture  320  holding both the prefilled syringe  150  and auto injector  140  can be used with the universal testing machine  310 . 
     It is desirable to select an injection spring  109  for an auto injector  140  that has enough force to apply a dispensing force against the stopper  157  and to also operate the related subassemblies in the auto injector  140  within a determined time, such as about 19 seconds, when the prefilled syringe  150  is subjected to accelerated aging so that the spring  109  specifications can be used in the regulatory approval process. It is also desirable to select a spring  109  that is not too strong and deliver the therapeutic fluid  160  too fast for a commercialized auto injector  140  and prefilled syringe  150  combination, especially because the effects of natural aging are not as significant as they are for artificial aging. The dispensing force is that portion of the spring force that is applied to the stopper  157  during operation of the auto injector  140 , the remaining portion of the spring force operates any subassembly that is also driven by the injection spring  109 . 
       FIGS.  6 - 11    illustrate various methods to determine an injection spring  109  having enough stored energy to: (i) move the syringe stopper  157  a desired distance along the path of travel, P, within a determined time; (ii) have enough stored energy to maintain a relatively steady speed movement as the stopper  157  approaches the second position, D 2 , to prevent the stopper  157  from stalling; and (iii) operate components in the auto injector  140  other than the piston rod  107  that also are powered by the injection spring  109 . Examples of components in the auto injector  140  that are powered by the injection spring  109  include the piston rod  107 , the holding pin  106 , and the holding sleeve  108 , which the spring  109  holds distally against the bias of the cover sleeve spring  110 . In yet other alternative embodiments, the only structure moved by decompression of the injection spring  109  is the syringe stopper  157  itself. The portion of the syringe force that is applied to the stopper  157  through the piston rod  107  is a dispensing force. The remaining portion of the spring force that is used to operate mechanisms in the auto injector  140  other than the piston rod  107  is an operation force. 
       FIG.  6    is a flowchart illustrating a determination process  200  by which parameters can be selected for the injection spring  109  of an auto injector  140 . Examples of parameters for the injection spring  109  include the spring constant, uncompressed spring length, and compressed spring length. The determination process  200  includes an age operation  202 , a test operation  204 , and a select operation  206 . The determination process  200  optionally may include a second select operation  208 . 
     At the age operation  202 , one or more prefilled syringes  150 , such as the prefilled syringes  150  shown in  FIG.  1   , can be aged to at least a simulated age that is at least equal to the desired shelf life for the therapeutic fluid  160  and the prefilled syringe  150 . As shown in  FIG.  7   , in certain implementations, the prefilled syringes  150  or therapeutic fluid  160  are artificially aged using a heat source. For example, one or more syringes  150  prefilled with a therapeutic fluid  160  can be disposed within an interior  182  of an oven  180 . In some implementations, humidity is not controlled during the artificial aging process. In other implementations, humidity is controlled during the artificial aging process. 
     To accelerate aging for the prefilled syringe  150 , one or more prefilled syringes  150  are in an oven  180  at a predetermined temperature. The greater the temperature the faster the prefilled syringes  150  age to a simulated age. In some embodiments, the prefilled syringes  150  are heated at a temperature in the range from about 20° C. to about 60° C. For example, the prefilled syringes  150  can be heated at temperatures of about 5° C., about 25° C., or about 40° C. Each of the sample sets  170  is kept at the predetermined temperature for a different period of time (e.g., minutes, days, weeks, months, years). The temperature and length of time for heating the prefilled syringes  150  can be determined according to the Arrhenius calculation of Equation (1). The number of prefilled syringes  150  that are heated to accelerate aging depends on the number of samples to be tested for selection of an injection spring  109 . The more samples that are tested, the more data will be available to select a spring  109 . Additionally, sets of prefilled syringes  150  can be heated at different temperatures or tested for different lengths of time. Heating different sets of prefilled syringes  150  in this manner allows data simulating different shelf lives and different circumstances to be used in the spring  109  selection process. 
     At the test operation  204 , one or more force tests can be performed on the aged prefilled syringes  150  using any suitable testing techniques including the testing techniques illustrated herein in more detail (see, e.g.,  FIGS.  4 A,  4 B, and  5   ). In general, the test or tests include measuring one or more exertion forces F e  applied to the stopper  157  of each prefilled syringe  150  as it moves from the first position, D 1 , to the second position, D 2 , and as therapeutic fluid  160  is dispensed. The exertion force measurements are associated with the corresponding position (i.e., displacement) of the stopper  157  along the path of travel P. 
     In some embodiments, the exertion force is measured for moving only the stopper  157  of the prefilled syringe  150  (see, e.g.,  FIGS.  4 A and  5   ). In other examples, the exertion force is measured for moving the stopper  157  via the piston rod simultaneously operating other components of the auto injector that are powered by the injection spring (see, e.g.,  FIGS.  4 B and  5   ). 
     At the select operation  206 , the measured exertion forces are analyzed to determine an injection spring  109  that has enough energy to deliver a suitable amount of force and that also has suitable parameters for operating within the auto injector. The spring force is determined according to Hooke&#39;s law: 
         F   spring   =K ( l   0-x )  (4)
 
     where F spring  is the force of the spring, “K” is the spring constant for the particular injection spring, l 0  is the uncompressed spring length, and x is the current spring length. 
     In the following, the term compression of the spring or spring compression in a determined state is used to refer to the difference between the uncompressed length of the spring and the length of the spring in said determined state. In least some embodiment such as auto injector  140 , there is a gap between the piston rod  107  and the stopper  157  at the start of operation. At the start of operation, the injection spring  109  must decompress slightly to engage the piston rod  107  against the stopper  157 . In these embodiments, the spring length, at the start of operation—before actuation of the auto injector  140 —is shorter than an initial spring length, l i , when the piston rod  107  is against the stopper  157  and begins to push the stopper  157  from its first position, D 1 . In these embodiments, the dispensing force also can be modeled as: 
         F   d   =K ( C   i   −x   stopper ), wherein  C   i   =l   0   −l   i   (5)
 
     where C i  is the initial compression of the spring, l i  is the length of the spring when the piston rod engages the stopper and the stopper is in the initial position, and x stopper  is the displacement of the stopper with reference to the first initial position of the stopper. In addition, the stored energy available for dispensing the drug in the auto injector may be modeled as: 
     
       
         
           
             
               
                 
                   E 
                   = 
                   
                     
                       1 
                       2 
                     
                     ⁢ 
                     
                       KC 
                       i 
                       2 
                     
                   
                 
               
               
                 
                   ( 
                   6 
                   ) 
                 
               
             
           
         
       
     
     Using these equations, a spring constant and uncompressed spring length for the injection spring  109  can be selected to provide a sufficient dispensing force to the stopper  157  to successfully move the stopper  157  along the path of travel, P for a displacement that is at least long enough to deliver a full dose of the therapeutic fluid  160  and within a desired time. It is noted that the initial spring length depends on the geometry of the auto injector  140  such as the spring length at the start of operation (i.e., the assembled spring length or cocked length) and the gap between the plunger rod  107  and the stopper  157  in the initial position. 
     Because equations (4) and (5) are linear, a spring force for the injection spring  109  can be represented in the graph shown in  FIG.  3 C  by a line plotting a decreasing force over increasing displacement. In a possible embodiment, a measured exertion force may be used to determine the suitable spring  109 . In this embodiment, the reference force, F ref , used to calculate the spring force can be the maximum exertion force measured as the drive rod  314  of the test equipment  310  moves the stopper  157  from the first position, D 1 , to the second position, D 2 . For accelerated aged prefilled syringes  150  as disclosed herein, that maximum exertion force can be a glide force measured as the stopper  157  approaches the second position, D 2 , as illustrated in  FIG.  3 C . In other embodiments or circumstances, the maximum exertion force can be a glide force as the stopper  157  moves along an intermediate portion of the path of travel, P. In yet other embodiments or circumstances, the maximum exertion force can be the break-loose force as the stopper  157  begins movement from the first position, D 1 . 
     An additional condition that may be used for determining the spring parameters (e.g., spring constant, compressed length, uncompressed length) may be that the final spring force should be no less than 50% of the initial spring force, which is the spring force for the injection spring  109  when the piston rod  107  first engages the stopper  157  at the first position, D 1 . In other embodiments, the final spring force should be no less than 60%, 70%, 80%, or 90% of the initial spring force. These design specifications and parameters for the injection spring  109  may lead to several alternatives for a suitable spring  109 . Other conditions such as market availability and price may then be considered when selecting an injection spring  109 . In some embodiments, selecting a suitable spring  109  may involve maximizing a utility function including one or several of the conditions mentioned herein. In some embodiments, the injection spring  109  has a spring force when the stopper  157  is at the first position, D 1 , and is engaged by the piston rod  107  in the range from about 20 N to about 40 N. In some embodiments, the injection spring  109  has a spring force when the stopper  157  is at the first position, D 1  and is engaged by the piston rod  107  in the range from about 20 N to about 30 N. Additionally, in some embodiments, the injection spring  109  can have a spring force when the stopper  157  is at the second position, D 2 , in the range from about 14 N to about 20 N. Additionally, in some embodiments, the injection spring  109  can have a spring force when the stopper  157  is at the second position, D 2 , in the range from about 15 N to about 18 N. 
     In some embodiments, several measured exertion forces may be used to determine the suitable spring  109 . For example, an initial exertion force (break loose force) may be used to determine the suitable spring  109  together with exertion force(s) at the end of travel path, P. In another example, a reference energy for moving the stopper  157  in a prefilled syringe  150  may be calculated based on a measured force profile acquired by moving a stopper  157  using equipment as described in  FIGS.  4 - 5   . The reference energy may be calculated for a stopper  157  moving in one or more aged reference prefilled syringes  150  or one or more unaged prefilled syringes  150 . In at least some embodiments, the selected spring  109  will have a stored energy when the stopper  157  is at the first position, D 1  and engaged by the piston rod  107  that is about 25% or more than the reference stored energy. In other possible embodiments, the stored energy is about 20%, 30%, 40%, 50%, or 60% greater than the reference stored energy. Therefore, a possible design parameter for some embodiments is that injection spring  109  has about 25% more stored energy when the stopper  157  is at the first position, D 1 , and is engaged by the piston rod  107  than is actually required to move the stopper  157  in an unaged prefilled syringe  150  from the first position, D 1 , to the second position, D 2 , without stalling. In some embodiments, the stored energy in the injection spring  109  when the stopper  157  is in the first position, D 1 , and is engaged by the piston rod  107  is in the range from about 0.9 J to about 2 J. 
     Furthermore, it has been found that to ensure proper stopper  157  movement, it is beneficial that the dispensing force when the stopper  157  reaches the second position, D 2 , be as high as possible. Having this high dispensing force at the second position, D 2 , lowers the risk of stalling at the end of the dose delivery. Further, it has been found that it is beneficial that the initial dispensing force be as low as possible to avoid high initial impact. As a result, some possible embodiments have injection springs  109  that have a longer initial spring compression length over an injection spring  109  having a high spring constant. In some embodiments, the spring parameters may be selected to maximize the initial spring compression length of the injection spring  109  and minimize the spring constant. In other words, when several spring parameters would provide a suitable spring  109 , the spring  109  having the lowest spring constant and the highest initial compression is preferred. 
     In some embodiments, the initial spring compression length is in the range from about 50 mm to about 100 mm with a spring constant in the range from about 0.2 N/mm to about 0.4 N/mm. In alternative embodiments, the initial spring compression length is in the range from about 75 mm to about 95 mm with a spring constant in the range from about 0.28 N/mm to about 0.32 N/mm. In another example, the spring constant is about 0.3 N/mm. 
     Once the spring parameters are determined, an injection spring  109  is selected that will cause the piston rod  107  of the auto injector  140  to exert a dispensing force against the syringe stopper  157  that is greater than the maximum measured exertion force so that the injection spring  109  will overcome all resistive forces acting against movement of the stopper  157  and have enough force to move the stopper  157  to the second position, D 2 , within a determined time. 
     Additionally, in some embodiments, parameters for the injection spring  109  are selected based on a maximum exertion force measured during testing of prefilled syringes  150  exposed to accelerated aging. In other examples, the parameters for the injection spring  109  are selected based on multiple exertion forces measured during the testing. For example, spring constants, uncompressed spring lengths, and compressed spring lengths can be calculated based on or for the multiple exertion forces, which can provide a more favorable slope of the spring force as the spring  109  decompresses. 
     Additionally, the embodiment shown herein used a helical spring for the injection spring  109 . A helical spring is a linear rate spring. Other embodiments can use other types of springs  109  such as conical springs, constant force springs, variable force springs, torsion springs, gas springs, or hydraulic springs. Hooke&#39;s law for springs such as gas and hydraulic springs is not linear. However, it is substantially linear over the first part of the gas or hydraulic spring&#39;s displacement and the spring forces can still be approximated using equation (4) or a similar linear relationship. In alternative embodiments, suitable mathematical relationships and models other than Hooke&#39;s law can be used to determine forces for springs including linear and non-linear springs. 
       FIGS.  8 - 10    illustrate various testing processes  220 ,  230 ,  240  that are each suitable for implementing the test operation  204  of the determination process  200 . In certain implementations, the testing processes  220 ,  230 ,  240  are implemented using automated or semi-automated testing equipment, such as the testing equipment  310  described herein with relation to  FIGS.  4 A,  4 B, and  5   . Suitable processes for using the testing equipment  310  will be described in more detail herein with reference to  FIG.  11   . 
     Each of the testing processes  220 ,  230 ,  240  can be performed on a prefilled syringe  150 , either alone or in combination with an auto injector  140  or components thereof. In some examples, the testing equipment  310  directly acts on the stopper  157  of a prefilled syringe  150 . In other examples, the testing equipment  310  acts on a drive member  314  (e.g., piston rod  107 ) of the auto injector  140 , which is operationally coupled to the syringe stopper  157 . 
     The prefilled syringe  150  may be naturally aged or artificially aged. Each of the testing processes  220 ,  230 ,  240  also can be performed on unaged prefilled syringes  150 . In some examples, the testing processes  220 ,  230 ,  240  are performed on prefilled syringes  150  prefilled with a therapeutic fluid  160 . In other examples, the testing processes  220 ,  230 ,  240  are performed on syringes  150  prefilled with other types of fluid (e.g., saline or water). 
       FIG.  8    is a flowchart illustrating a first testing process  220  suitable for implementing the test operation  204  of the determination process  200 . The first testing process  220  includes a move operation  222 , a measure operation  224 , and a determine operation  226 . 
     At the move operation  222 , the stopper  157  of a prefilled syringe  150  is moved distally within the syringe barrel  151  along the path of travel, P, at a constant speed. For example, the stopper  157  may be moved along the path of travel, P, from a first position (e.g., a proximal position, an initial position) D 1  to a second position (e.g., a distal position, a bottomed-out position) D 2 . 
     In certain implementations, the constant speed is selected to match a displacement speed of the stopper  157  during an actual injection using the auto injector  140  in which the stopper  157  is moved from a first position, D 1 , to a second position, D 2 , and a full dose of fluid  160  is held in the syringe barrel  151  between the first and second positions D 1 , D 2 . For example, the constant speed may be selected to simulate a desired injection time in the range from about 5 seconds to about 19 seconds. Another embodiment may select a constant speed to simulate an injection time in the range from about 5 seconds to about 12 seconds. Another embodiment may select a constant speed to simulate an injection time in the range from about 6 seconds to about 20 seconds. Another embodiment may select a constant speed to simulate an injection time in the range from about 8 seconds to about 15 seconds. Another embodiment may select a constant speed to simulate an injection time in the range from about 15 seconds to about 25 seconds. In certain examples, the constant speed may be selected to simulate an injection time in the range from about 17 seconds to about 22 seconds. In an example, the constant speed may be selected to simulate an injection time of about 12 seconds. In an example, the constant speed may be selected to simulate an injection time of about 8 seconds. In an example, the constant speed may be selected to simulate an injection time of about 18 seconds. In an example, the constant speed may be selected to simulate an injection time of about 19 seconds. In an example, the constant speed may be selected to simulate an injection time of about 20 seconds. In certain examples, the constant speed is selected to be in the range from about 60 mm/min to about 360 mm/min. In other embodiments, the constant speed is selected to be between about 150 mm/min and about 200 mm/min. In certain examples, the constant speed may be selected to be between about 80 mm/min and about 90 mm/min. In an example, the constant speed is selected to be about 150 mm/min. In an example, the constant speed is selected to be about 86 mm/min. In an example, the constant speed is selected to be about 175 mm/min. 
     The measure operation  224  measures one or more exertion forces applied to the stopper  157  to move the stopper  157  distally along the path of travel, P, at the constant speed. In certain embodiments, the exertion force utilized to initiate movement of the stopper  157  relative to the syringe barrel  151  (i.e., the break-loose force) is measured. In other embodiments, the exertion force utilized to maintain movement of the stopper  157  along the path of travel, P, within the syringe barrel  151  (i.e., the glide force) is measured. For example, a maximum exertion force applied during movement of the stopper  157  along the path of travel, P, (i.e., a maximum glide force) may be measured. In certain examples, the displacement of the stopper  157  is measured at the same time as the exertion force is measured. 
     At the determine operation  226 , a reference force for use in calculating a suitable spring  109  is determined. In certain embodiments of the select operation  206 , the reference force is used to select a spring constant, uncompressed spring length, or compressed spring length. 
     In some implementations, the reference force is the maximum or peak force the injection spring  109  needs to overcome to move the stopper  157  along the path of travel, P, between the first and second positions D 1 , D 2 . Accordingly, the reference force is no less than the measured exertion force being applied to the stopper  157  to overcome any resistive forces that oppose the distal movement of the stopper  157  along the path of travel, P. In certain embodiments, the reference force is equal to the maximum measured exertion force and can be used to determine parameters for the injection spring  109 . In other embodiments, the reference force can be greater than the maximum measured exertion force. In yet other embodiments, the reference force can be lower than the maximum measured exertion force. For example, the maximum measured exertion force could be measured at a displacement outside the range of the first and second positions D 1 , D 2  for the stopper  157 . 
     In other implementations, the reference force is also determined based on resistance forces generated by components of the auto injector  140 . For example, the reference force also may account for one or more friction forces generated by movement between two or more components (e.g., the piston rod  107 , the support member  105 , the indicator sleeve  111 , and the holding sleeve  108  shown in  FIGS.  13 - 17   ) of the auto injector  140 . In an example, the reference force also may include the force needed to move or operate one or more components (e.g., the holding pin  106 , the holding sleeve  108 ) of the auto injector  140  against the bias of another spring  109  (e.g., cover sleeve spring  110  of  FIGS.  13 - 17   ). The resistive forces generated by the auto injector  140  may be separately measured, calculated or otherwise estimated. 
       FIG.  9    is a flowchart illustrating a second possible testing process  230  suitable for implementing the test operation  204  of the determination process  200 . The second testing process  230  includes a move operation  232 , a measure operation  234 , and a determine operation  236 . The move operation  232  of the second testing process  230  is the same or substantially the same as the move operation  222  of the first testing process  220 . 
     The measure operation  234  is substantially the same as the measure operation  224  of the first testing process  220 , except that multiple exertion force measurements are taken along the path of travel, P. Each exertion force measurement is associated with the corresponding displacement of the stopper  157  along the path of travel, P. In some implementations, two exertion force measurements are taken along the path of travel, P, (e.g., at the first positon D 1  and the second position D 2 ). In other implementations, three or more exertion force measurements are taken along the path of travel, P. In certain examples, the exertion force is measured at constant intervals along the path of travel, P. In certain examples, the exertion force is continuously measured along the path of travel, P. 
     In certain embodiments, the displacement of the drive rod  314 , which corresponds to displacement of the plunger  157  also is measured. The displacement can be measured at the same time as each measurement is made of the exertion forces. In certain embodiments, the displacement and exertion force measurements can be correlated to form a force profile. 
     The determine operation  236  is the same or substantially the same as the determine operation  226  of the first testing process  220 , except that two or more reference forces are determined. For example, one determined reference force can correspond to the break-loose force, and another determined reference force can correspond to the maximum measured glide force. In other embodiments, two or more determined reference forces can correspond to different measured glide forces. In other embodiments, one determined reference force can correspond to a glide or break-loose force, and another determined reference can correspond to a displacement of the piston rod  107  for the auto injector  140  that is outside the range of displacement for the stopper  157 . For example, a determined reference force can correspond to the force needed to begin movement of the piston rod  107  before it engages the stopper  157 . 
     In some embodiments, at least one reference force is determined based on an exertion force measured for pushing the stopper  157  from the first to the second positions D 1 , D 2  in the syringe barrel  151 , and at least another reference force is determined based on the measured force or friction related to moving or operating internal components of the auto injector  140 . And in yet another possible embodiment, at least one reference force is determined that corresponds to the exertion force measured for operating internal components of the auto injector  140  and pushing the stopper  157 . 
       FIG.  10    is a flowchart illustrating a third testing process  240  suitable for implementing the test operation  204  of the determination process  200 . The third testing process  240  determines spring parameters such that an injection spring  109  having the determined spring parameters can successfully drive the stopper  157  along the path of travel, P. The third testing process  240  includes a move operation  242 , a measure operation  244 , a determine operation  246 , a calculate operation  248 , and a select operation  250 . 
     The move operation  242  of the third testing process  240  is the same or substantially the same as the move operation  222  of the first testing process  220 . 
     In some implementations, the measure operation  244  is the same or substantially the same as the measure operation  224  of the first testing process  220 . In other implementations, the measure operation  244  is the same or substantially the same as the measure operation  234  of the second testing process  230 . 
     In some implementations, the determine operation  246  is the same or substantially the same as the determine operation  226  of the first testing process  220 . In other implementations, the determine operation  246  is the same or substantially the same as the determine operation  236  of the second testing process  230 . 
     The calculate operation  248  determines a corresponding spring constant, uncompressed spring length, or compressed spring length for each of the one or more reference forces determined in the determine operation  246 . These spring parameters are calculated based on the determined reference force (which equals or otherwise corresponds to a measured exertion force) and the corresponding displacement of the stopper  157 . The calculated spring parameters are “reference spring parameters.” 
     In some embodiments, assuming an uncompressed spring length and an auto injector geometry, the calculate operation  248  determines a minimum spring constant needed to generate an exertion force at a corresponding displacement position of the stopper  157  sufficient to drive the stopper  157  along the path of travel, P. In other embodiments, the calculate operation  248  determines a minimum spring constant needed to generate the required exertion force and to overcome resistance forces generated by the auto injector  140 . In some embodiments, the uncompressed spring length also is determined by the calculate operation  248 . In some embodiments, the calculate operation  248  determines the minimum spring constant and the maximum uncompressed spring length. In other embodiments, the calculate operation  248  may determine the maximum spring constant. 
     The second determine operation  250  compares the reference spring parameters determined in the calculate operation  248  to determine optimal spring parameters. The optimal spring parameters can be chosen based on a variety of different criteria such as desired injection time, desired spring forces, spring cost, and geometry of the auto injector  140 . 
       FIG.  11    is a flowchart  260  illustrating a method for performing at least the move operations  222 ,  232 ,  242  and the measure operations  224 ,  234 ,  244  of the testing processes  220 ,  230 ,  240  using the testing equipment  310  of  FIGS.  4 A,  4 B, and  5   . In certain implementations, the testing equipment  310  includes a tensometer or other mechanism for measuring an exertion force on the syringe stopper  157 . As described above, the testing equipment  310  may include a frame  316  to hold the prefilled syringe  150 . 
     In some examples, the operations of flowchart  260 , and the other flowcharts and operations discussed herein, are performed on a single prefilled syringe  150 . In other examples, however, the operations of the flowchart  260  are performed on multiple prefilled syringes  150 . In certain examples, the operations can be performed on prefilled syringes  150  of various ages (e.g., natural ages or artificial ages). In certain examples, the operations can be performed on unaged prefilled syringes  150 . In some examples, the operations of the flowchart  260  are implemented using a prefilled syringe  150  by itself. In other examples, the operations can be implemented using a prefilled syringe  150  in combination with one or more parts of an auto injector  140 . 
     In certain examples, portions of the auto injector  140  (e.g., portions of the drive assembly) also can be mounted to the testing equipment  310  as shown in  FIG.  4 B . In such examples, the frame  316  can be adapted to hold the auto injector  140  components. For example, an additional clamp  317  can be mounted to the frame  316  to hold a drive member  314  (e.g., piston rod  107 ) of the auto injector  140 , the entire auto injector  140 , or a portion thereof. In such examples, the drive rod  314  of the testing equipment  310  is operably coupled to the stopper  157  via the drive member  314  of the auto injector  140 . 
     At the actuate operation  266 , the testing equipment  310  generates an exertion force on the syringe stopper  157 . In certain examples, the actuate operation  266  includes advancing (e.g., lowering) the drive rod  314  of the testing equipment  310  towards the stopper  157 . In some examples, the drive rod  314  is moved automatically. In other examples, the drive rod  314  is moved manually. In certain examples, the drive rod  314  is moved at a constant speed. 
     In an example, the drive rod  314  is attached to a 25 N load cell. In other embodiments, the drive rod  314  is attached to a 200 N load cell. Other load cells are possible that have a sufficient range of sensitivity to measure the forces that can be applied to the drive rod  314 . 
     The measure operation  268  takes one or more measurements of the exertion force being applied by the drive rod  314  to the stopper  157  as the stopper  157  moves along the path of travel, P. For example, the testing equipment  310  may automatically take measurements of the exertion force applied by the drive rod  314 . The testing equipment  310  also tracks the displacement of the drive rod  314 , which directly relates to the displacement of the syringe stopper  157 . Accordingly, the measure operation  268  results in one or more exertion force readings that are each correlated with a determined displacement of the stopper  157 . 
     In an example, an exertion force measurement may be taken when the stopper  157  initially moves relative to the syringe barrel  151 . In another example, an exertion force measurement may be taken when the stopper  157  approaches or arrives at an end of the path of travel, P. In another example, multiple exertion force measurements may be taken at periodic intervals or distances along the path of travel, P. In another example, exertion force measurements are continuously taken along the path of travel, P. 
       FIG.  12    is a flowchart illustrating an assembly process  280  for assembling an auto injector, such as an auto injector  140  of  FIGS.  13 - 17   , with a prefilled syringe, such as prefilled syringe  150  of  FIG.  1   , and the selected injection spring  109 . The assembly process  280  includes at least an obtain operation  284 , a first install operation  286 , and a second install operation  288 . The assembly process  280  may optionally include a select operation  282 . 
     At the select operation  282 , the user  190  selects a spring constant for an injection spring  109  to be installed in the auto injector  140  to drive injection of the prefilled syringe  150 . The spring constant is selected to be sufficient to drive injection of the prefilled syringe  150  even if the prefilled syringe  150  has artificially aged. The user  190  can select the spring constant using any of the determination processes  200  or testing processes  220 ,  230 ,  240  described herein. 
     At the obtain operation  284 , the user  190  selects an injection spring  109  having the selected spring parameters. The selected injection spring  109  produces a biasing force at least sufficient to drive the syringe stopper  157  within the syringe barrel  151  fully along the path of travel, P. In certain examples, the selected injection spring  109  produces a biasing force sufficient to drive the stopper  157  fully along the path of travel, P, and to perform other operations within the auto injector  140 . For example, the selected injection spring  109  is sufficiently strong to bias the holding pin  106  and holding sleeve  108  to a proximal position, to charge the cover sleeve spring  110 , and to drive the stopper  157  along the path of travel, P. 
     In some implementations, the selected injection spring  109  is a compression spring. In some examples, the selected injection spring  109  is a linear rate spring. In other examples, the selected injection spring  109  is a variable rate spring. In still other examples, the selected injection spring  109  is a constant force spring. In other implementations, the selected injection spring  109  is a mechanical gas spring, a pneumatic spring, or a hydraulic spring. 
     At the first install operation  286 , the selected injection spring  109  is installed in the auto injector  140 . For example, the selected injection spring  109  can be disposed within the outer body  102  of the auto injector  140  as part of the drive assembly. In certain examples, the selected injection spring  109  is aligned with the piston rod  107  (e.g., see  FIG.  14   ). In an example, the selected injection spring  109  is compressed between the piston rod  107  and the holding pin  106  (e.g., see  FIG.  14   ). 
     At the second install operation  288 , the prefilled syringe  150  is installed in the auto injector  140 . For example, a prefilled syringe  150  can be mounted at the syringe holder  101  within the outer body  102 . 
       FIGS.  13 - 17    illustrate an example auto injector  140  suitable for injecting the prefilled syringe  150  of  FIG.  1   .  FIG.  13    illustrates the components of the auto injector  140  exploded from each other for ease in viewing.  FIG.  14    is a cross-section of the auto injector  140  of  FIG.  13   , the auto injector  140  being disposed in a pre-injection configuration.  FIG.  15    shows the auto injector  140  of  FIG.  14    in a mid-injection configuration.  FIG.  16    shows the auto injector  140  of  FIG.  14    in an end of injection configuration.  FIG.  17    shows the auto injector  140  of  FIG.  16    rotated 90°. Although an example embodiment of an auto injector  140  is disclosed and illustrated herein, any suitable spring-driven auto injector can be used with the apparatuses and methods disclosed herein. 
     The auto injector  140  has a distal end  141  and a proximal end  142  (see FIG.  14 ). The auto injector  140  is actuated by pushing the distal end  141  against the body of a patient  180  at an injection site  198 . The auto injector  140  is held at the injection site  198  until a dosage of therapeutic fluid  160  has been expelled from the prefilled syringe  150 . 
     The auto injector  140  includes an outer housing  102  and an end cap  112  mounted at the proximal end  142  of the outer housing  102 . The auto injector  140  also includes a syringe holder  101  disposed within the outer housing  102 . The syringe holder  101  and the end cap  112  are stationary with respect to the housing  102 . The syringe holder  101  is configured to hold a prefilled syringe, such as the prefilled syringe  150  of  FIG.  1   . 
     A cover sleeve  103  is mounted at the distal end  141  of the outer housing  102 . The cover sleeve  103  is telescopically slidable relative to the outer housing  102  between an extended position ( FIG.  14   ) and a retracted position ( FIG.  15   ). When in the extended position, the cover sleeve  103  surrounds the syringe needle  155  of the prefilled syringe  150 . Moving the cover sleeve  103  to the retracted position exposes the syringe needle  155 . 
     A cover sleeve spring  110  extends between a first end  110   a  and a second end  110   b . The cover sleeve spring  110  extends over a first length between the first and second ends  110   a ,  110   b  when the cover sleeve  103  is extended. The cover sleeve spring  110  is compressed to a second length between the first and second ends  110   a ,  110   b  when the cover sleeve  103  is retracted. The second length is shorter than the first length. The cover sleeve spring  110  biases the cover sleeve  103  to the extended position. The cover sleeve  103  can be moved to the retracted position against the bias of the spring  110 , thereby compressing the spring  110 . In the example shown, the spring  110  is a helical coil spring. In other examples, however, the spring  110  can be a gas-powered spring, a pneumatic spring, a hydraulic spring, or any other type of spring. 
     A needle cap remover  104  is initially disposed over the cover sleeve  103  and engages the outer housing  102 . The needle cap remover  104  inhibits movement of the cover sleeve  103  to the retracted position while the needle cap remover  104  engages the cover sleeve  103  and outer housing  102 . The needle cap remover  104  grips a rigid needle shield that is initially disposed about the needle  155  of the prefilled syringe  150 . When removed from the auto injector  140 , the needle cap remover  104  entrains the rigid needle shield, thereby removing the rigid needle shield from the syringe needle  155 . 
     A support member  105  is disposed within the outer housing  102  proximal of the syringe holder  101 . The support member  105  is axially and rotationally fixed to the end cap  112 . The distal end of the support member  105  abuts against a proximal end of the syringe holder  101 . 
     A drive assembly is disposed within the outer housing  102  proximal of the syringe holder  101 . The drive assembly includes an injection spring  109  and a subassembly biased by the injection spring  109 . In the example shown, the injection spring  109  is a helical coil spring having a variable force. In other examples, however, the injection spring  109  can be a conical spring, a torsion spring, a gas-powered spring, a pneumatic spring, a hydraulic spring, or any other type of variable force or constant force spring. The injection spring  109  also can be any other injection spring  109  or structure that biases the piston rod  107  toward the distal end  141  of the auto injector  140 . 
     The drive or subassembly includes at least a piston rod  107  aligned with the stopper  157  of the prefilled syringe  150 . The piston rod  107  is axially movable within the outer body  102  along a travel distance between a cocked position and a bottomed-out position. When in the cocked position, the piston rod  107  is proximally spaced from the prefilled syringe stopper  157 . When in the bottomed-out position, the piston rod  107  presses the stopper  157  against the proximally facing shoulder  151   a  within the interior  154  of the prefilled syringe  150 . 
     Because the piston rod  107  is spaced from the stopper  157  when in the cocked position, the injection spring  109  will not apply a dispensing force against the stopper  157  immediately upon release and expansion of the spring  109 . The injection spring  109  will decompress slightly and advance the piston rod  107  a short distance until the piston rod  107  engages the stopper  157 . Once the piston rod  107  engages the stopper  157 , the injection spring  109  will continue to decompress, but resistive forces from the prefilled syringe  150  such as resistance and hydrodynamic force will act against movement of the stopper  157  and hence against decompression of the injection spring  109 . 
     The injection spring  109  extends between a first end  109   a  and a second end  109   b . The injection spring  109  is compressed to a first cocked length between the first and second ends  109   a ,  109   b  when the piston rod  107  is disposed in the cocked position (see  FIG.  14   ). The injection spring  109  is extended to a second length between the first and second ends  109   a ,  109   b  when the piston rod  107  is disposed in the bottomed-out position (see  FIG.  16   ). The second length is longer than the first length. 
     The injection spring  109  applies an exertion force to bias the piston rod  107  distally towards the bottomed-out position. In an example, the injection spring  109  is disposed within a hollow interior of the piston rod  107 . For example, the first end  109   a  of the injection spring  109  may push against an inner shoulder of the piston rod  107  to bias the piston rod  107  distally. The first length may be about 72 mm and the second length may be of about 106 mm. The injection spring  109  may have an uncompressed length of about 157 mm. A constant of the injection spring  109  may be of about 0.30 N/mm. 
     In certain examples, the subassembly also includes a holding pin  106 . The injection spring  109  biases the holding pin  106  proximally towards the end cap  112 . For example, the second end  109   b  of the injection spring  109  may push against an inner shoulder of the holding pin  106 . In certain examples, the injection spring  109  is sandwiched between the piston rod  107  and the holding pin  106 . In an example, the injection spring  109  biases the holding pin  106  proximally while biasing the piston rod  107  distally. 
     The holding pin  106  has a locking configuration and a releasing configuration. When in the locking configuration, the holding pin  106  engages the piston rod  107  to hold the piston rod  107  in an axially fixed position relative to the holding pin  106  against the bias of the injection spring  109 . In certain examples, the holding pin  106  holds the piston rod  107  in the cocked position against the bias of the injection spring  109 . When in the releasing configuration, the holding pin  106  releases the piston rod  107  to enable relative movement between the piston rod  107  and the holding pin  106 . 
     In particular, the holding pin  106  of the drive assembly includes arms  106   a  extending from fixed ends  106   d  to free ends  106   c . The fixed ends  106   d  are attached to a base portion  106   e . The free ends  106   c  define stop members  106   b , which move radially when the arms  106   a  are flexed. In certain examples, the base portion  106   e  is sized to extend into the piston rod  107 . In certain examples, the base portion  106   e  is sized to extend through at least a portion of the injection spring  109  so that the injection spring  109  coils around the base portion  106   e.    
     The piston rod  107  defines recesses  107   a  in which the stop members  106   b  of the holding pin  106  can seat. Accordingly, the holding pin  106  is disposed in the locking configuration when the arms  106   a  are flexed radially inwardly so that the stop members  106   b  engage the recesses  107   a  to retain the piston rod  107  in the cocked position. The holding pin  106  transitions to the releasing configuration when the arms  106   a  flex radially outwardly to move the stop members  106   b  away from the recesses  107   a.    
     A holding sleeve  108  surrounds a portion of the holding pin  106 . The holding sleeve  108  moves axially between a distal position and a proximal position. When in the distal position, the holding sleeve  108  retains the holding pin  106  in the locking configuration (see  FIG.  14   ). In particular, the holding sleeve  108  radially aligns with the arms  106   a  and has a sufficiently small inner cross-dimension to inhibit outward radial flexing of the arms  106   a . Accordingly, the holding sleeve  108  inhibits outward radial movement of the stop members  106   b  of the holding pin  106  from the recesses  107   a  of the piston rod  107 . When in the proximal position, the holding sleeve  108  is axially offset from the stop members  106   b , thereby allowing the holding pin  106  to transition to the releasing configuration. 
     Prior to injection, the holding sleeve  108  is biased to the distal position by the cover sleeve spring  110  extended to the second length. In certain examples, the cover sleeve spring  110  biases the cover sleeve  103  through the holding sleeve  108 . For example, the first end  110   a  of the cover sleeve spring  110  abuts the holding sleeve  108 , which abuts a proximal end of the cover sleeve  103 . Movement of the cover sleeve  103  to the retracted position pushes the holding sleeve  108  to the proximal position and compresses the cover sleeve spring  110  to the second length. 
     In certain implementations, the holding sleeve  108  has a telescopic configuration. For example, the holding sleeve  108  may include an outer body  108   a  and an inner body  108   b  (see  FIG.  16   ). The inner body  108   b  is disposed around the support member  105 . The inner body  108   b  is rotationally fixed to, but axially movable relative to the support member  105 . The outer body  108   a  is disposed around the inner body  108   b . The first end  110   a  of the cover sleeve spring  103  abuts the outer body  108   a  to bias the holding sleeve  108  distally. 
     The outer body  108   a  and inner body  108   b  are rotationally fixed together. The outer body  108   a  and inner body  108   b  snap-fit to each other to move axially together as a unit from the distal position to the proximal position. For example, the inner body  108   b  has a ramped tooth and the outer body  108   a  defines a slot sized to receive the ramped tooth. The ramped tooth extends through the slot to be entrained by the outer body  108   a  in the proximal direction. The ramped tooth cams out of the slot as the outer body  108   a  is moved distal of the inner body  108   b.    
     An indicator sleeve  111  is disposed within the outer housing  102  proximal of the syringe holder  101 . As will be described in more detail herein, interaction between the indicator sleeve  111  and other components within the outer housing  102  generates noise (e.g., clicks) that audibly indicate stages of the injection (e.g., start of injection and end of injection). 
     The indicator sleeve  111  is axially movable relative to the outer housing  102  between a proximal position and a distal position. For example, the indicator sleeve  111  has wings  111   b  that slide in slots  105   a  defined in the support member  105  to limit axial movement between the indicator sleeve  111  and support member  105 . The indicator sleeve  111  is biased to the proximal position by the cover sleeve spring  110 . In an example, the second end  110   b  of the cover sleeve spring  110  abuts a portion of the indicator sleeve  111 . Accordingly, the cover sleeve spring  110  is sandwiched between the holding sleeve  108  and the indicator sleeve  111 . In an example, the cover sleeve spring  110  is sandwiched between the outer body  108   a  of the holding sleeve  108  and the wings  111   b  of the indicator sleeve  111 . 
     The indicator sleeve  111  limits axial movement of the holding pin  106  relative to the outer body  102 . For example, the indicator sleeve  111  defines grooves in which the stop members  106   b  of the holding pin  106  ride during axial movement of the holding pin  106  between the respective distal and proximal positions. Engagement between the stop members  106   b  and the grooves limits distal movement of the holding pin  106  relative to the indicator sleeve  111 , which limits the distal movement of the holding pin  106  relative to the support member  105 , which is axially fixed relative to the outer body  102 . 
     The indicator sleeve  111  selectively engages the piston rod  107 . For example, the indicator sleeve  111  may have one or more arms  111   c  with detents  111   d  at the free ends. The arms  111   c  flex to move the detents  111   d  radially relative to the piston rod  107 . The detents  111   d  are sized to snap into corresponding slots  107   c  defined in the piston rod  107 . 
       FIG.  14    illustrates the auto injector  140  in a pre-injection configuration. The needle cap remover  104  and rigid needle shield have been removed. The syringe stopper  157  is disposed at the first position, D 1 , along the path of travel, P, within the prefilled syringe  150 . The piston rod  107  is held at a location spaced proximally from the syringe stopper  157  by the holding pin  106 . 
     The holding pin  106  and piston rod  107  are positioned relative to each other such that the stop members  106   b  of the holding pin  106  radially align with the recesses  107   a  of the piston rod  107 . The holding sleeve  108  is disposed in the distal position at which the holding sleeve  108  (e.g., the inner body  108   b  of the holding sleeve  108 ) radially aligns with the stop members  106   b  of the holding pin  106 . Accordingly, the holding sleeve  108  presses the stop members  106   b  into the recesses  107   a  and inhibits radial movement of the stop members  106   b  out of the recesses  107   a.    
     The indicator sleeve  111  also is disposed in the distal position. The detents  111   d  of the indicator sleeve  111  are disposed within the slots  107   c  of the piston rod  107 . The holding sleeve  108  (e.g., the inner body  108   b  of the holding sleeve  108 ) radially aligns with the detents  111   d . The inner cross-dimension of the inner body  108   b  of the holding sleeve  108  is sufficiently small to retain the detents  111   d  within the slots  107   c  when radially aligned with the detents  111   d.    
     As shown in  FIG.  15   , injection is initiated by proximal movement of the cover sleeve  103  relative to the housing  102  to the retracted position. A proximal end of the cover sleeve  103  abuts the holding sleeve  108  (e.g., an outer body  108   a  of the holding sleeve  108 ) and pushes the holding sleeve  108  to its proximal position. When in the proximal position, the holding sleeve  108  is not radially aligned with the stop members  106   b  of the holding pin  106 . Accordingly, the bias of the injection spring  109  acting on the piston rod  107  is sufficient to cam the stop members  106   b  out of the recesses  107   a  in the piston rod  107 . 
     Accordingly, the piston rod  107  is free to move distally under the bias of the injection spring  109  towards the stopper  157  of the prefilled syringe  150 . While moving distally, the piston rod  107  engages the stopper  157  of the prefilled syringe  150  and pushes the stopper  157  distally along the path of travel, P, within the syringe barrel  151 . Distal movement of the stopper  157  pushes the fluid  160  through the needle  155  at the distal end  152  of the prefilled syringe  150 . 
     Releasing the stop members  106   b  from the recesses  107   a  of the piston rod  107  also frees the holding pin  106  for movement relative to the piston rod  107 . In certain implementations, the injection spring  109  biases the holding pin  106  proximally towards the end cap  112 . 
     The stop members  106   b  of the holding pin  106  engage the distal end of the inner body  108   b  of the holding sleeve  108 . The holding pin  106  entrains the inner body  108   b  of the holding sleeve  108  during this proximal movement until the inner body  108   b  abuts the support member  105 . The impact between the inner body  108   b  of the holding sleeve  108  and the support member  105  creates a noise (e.g., a first click) that provides an audible indication that injection has started. 
     The stop members  106   b  inhibit movement of the inner body  108   b  of the holding sleeve  108  back to the distal position (see  FIG.  16   ). The stop members  106   b  do not engage the outer body  108   a  of the holding sleeve  108 . Accordingly, the outer body  108   a  can move distally over the stop members  106   b  (see  FIG.  16   ). 
     When the piston rod  107  begins moving distally, the piston rod  107  entrains the indicator sleeve  111  via the engagement between the detents  111   d  and the slots  107   c . Accordingly, the piston rod  107  moves the indicator sleeve  111  to the distal position against the bias of the cover sleeve spring  110 . Engagement between the wings  111   b  of the indicator sleeve  111  and the support member  105  prohibits further distal movement of the indicator sleeve  111 . 
     When the indicator sleeve  111  is disposed in the distal position, the detents  111   d  are axially offset from the holding sleeve  108  (see  FIG.  17   ), which is disposed in the proximal position. Accordingly, the detents  111   d  are free to cam out of the slots  107   c  of the piston rod  107 , thereby allowing the piston rod  107  to continue being moved distally by the injection spring  109 . When moved radially outwardly, the detents  111   d  engage the distal end of the holding sleeve  108  (e.g., the inner body  108   a ), thereby preventing proximal movement of the indicator sleeve  111 . The body of the piston rod  107  prevents radially inward deflection of the arms  111   c  and detents  111   d  during injection. 
     As shown in  FIG.  16   , the piston rod  107  moves the stopper  157  within the syringe barrel  151  until the stopper  157  bottoms out within the syringe barrel  151  (e.g., at the proximally facing shoulder  151   a ). The injection spring  109  continues to press the piston rod  107  against the stopper  157  when the stopper  157  is disposed in the bottomed-out position. 
     After injection is complete, the auto injector  140  is moved away from the injection site  198 . The cover sleeve  103  is biased distally over the needle  155 . In particular, the cover sleeve spring  110  biases the outer body  108   a  of the holding sleeve  108  distally. The stop members  106   b  of the holding pin  106  prevent distal movement of the inner body  108   b  of the holding sleeve  108 . Accordingly, the outer body  108   a  moves distally relative to the inner body  108   b  until the inner body  108   b  and outer body  108   a  axially lock relative to each other. For example, a detent on the inner body  108   b  may snap into a recess defined by the outer body  108   a.    
     Distal movement of the outer body  108   a  of the holding sleeve  108  pushes the cover sleeve  103  to the extended position. The outer body  108   a  is locked from proximal movement by the inner body  108   b . The outer body  108   a  abuts the cover sleeve  103  to prevent proximal movement of the cover sleeve  103  back to the retracted position. Accordingly, the cover sleeve  103  is locked in the extended position covering the syringe needle  155 . 
     As shown in  FIG.  17   , notches  107   d  defined at the proximal end of the piston rod  107  align with the detents  111   d  of the indicator sleeve  111  when the piston rod  107  reaches the bottomed-out position. The notches  107   d  allow the detents  111   d  to cam radially inwardly, thereby disengaging from the holding sleeve  108 . Releasing the detents  111   d  from the holding sleeve  108  frees the indicator sleeve  111  for movement back to the proximal position under the bias of the cover sleeve spring  110 . The cover sleeve spring  110  pushes the indicator sleeve  111  proximally against the end cap  112 , which creates another noise (e.g., a second click) that provides an audible indication that injection has ended. 
     An example of an auto injector suitable for use with the apparatuses, methods, and uses disclosed herein include the YpsoMate® brand auto injector available from Yypsomed AG of Burgdof, Switzerland. Further details pertaining to example auto injectors suitable for use in actuating a prefilled syringe can be found in U.S. Publication No. 2016/0008541, the disclosure of which is hereby incorporated by reference in its entirety. The methods, apparatuses, and uses disclosed herein can be used with any type of auto injector that injects therapeutic fluid from a prefilled syringe. 
     The auto injectors and prefilled syringes disclosed herein, including those prefilled with the therapeutic fluids disclosed herein, are for use as a medicament to treat or prevent migraine headaches as well as other diseases, conditions, chronic illnesses and disabilities, and other therapeutic purposes. The prefilled syringes and auto injectors can be sold as a single unit with the prefilled syringe already inserted into the auto injector. Alternatively, the prefilled syringe and auto injector can be sold as a kit wherein the prefilled syringe and auto injector are either separate from one another but combined in the same packaging or sold together but in separate packages such that the prefilled syringe is in one package or box and the auto injector is in a different package or box. 
       FIG.  18    is a flowchart illustrating a use process  290  for using the auto injector  140  with prefilled syringe  150  and the selected injection spring  109 . The disclosed methods and apparatuses can be used as needed, periodically or on a continuous schedule. For example, they can be used once a day, once a week, once a month, on a schedule of no more than once every month, no more than once every two months, no more than once every three months, or no more than once every four months.  FIG.  19    illustrates the auto injector  140  being actuated by a user  190 . The use process  290  includes at least an align operation  294 , a press operation  296 , and a hold operation  298 . The use process  290  may optionally include an obtain operation  292 . 
     At the obtain operation  292 , the user  190  obtains an auto injector  140  containing a prefilled syringe  150 . The auto injector  140  includes an injection spring  109  having a spring constant that is sufficient to drive injection of the prefilled syringe  150  even if the prefilled syringe  150  has aged. The injection spring  109  also is sufficiently strong to perform other operations within the auto injector  140  (e.g., charging the cover sleeve spring  110 ) in addition to biasing the stopper  157 . 
     At the align operation  294 , a distal end  141  of the auto injector  140  is aligned with the injection site  198  at the body  192  of a user  190 . 
     At the press operation  296 , the distal end  141  of the auto injector  140  is pressed against the injection site  198  (see  FIG.  19   ). For example, the user  190  may push the outer body  102  of the auto injector  140  distally towards the injection site  198  as the cover sleeve  103  retracts into the outer body  102  to expose the needle  155 . As described herein, retraction of the cover sleeve  103  within the body  102  automatically actuates the drive assembly to trigger injection of the prefilled syringe  150 . 
     At the hold operation  298 , the user  190  holds the auto injector  140  at the injection site  198  with the cover sleeve  103  retracted into the outer body  102  until the end of the injection. In certain examples, the end of the injection is indicated by an audible noise (e.g., a click) generated by the auto injector  140 . 
     The methods, apparatuses, and uses disclosed herein have many aspects including the following. 
     One aspect is a method of adapting an auto injector configured to actuate a prefilled syringe, the auto injector having an injection spring having a spring constant, the prefilled syringe being filled with a volume of therapeutic fluid, the prefilled syringe including a barrel, stopper, and a needle, the stopper having a path of travel, the injection spring arranged to move the stopper along the path of travel the method comprising: aging the prefilled syringe at an accelerated rate to form an aged prefilled syringe; moving the stopper within the barrel of the aged prefilled syringe at a predetermined speed from at least a first position along the path of travel to at least a second position along the path of travel; measuring a plurality of exertion forces exerted on the stopper as the stopper moves within the barrel along the path of travel; determining a resistive force opposing movement of the stopper along the path of travel, the resistive force corresponding to the plurality of exertion forces; and selecting a spring constant for the injection spring, the act of selecting the spring constant comprising selecting the spring constant to correspond to the resistive force. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the operative prefilled syringe includes an operative barrel and an operative stopper movably positioned within the operative barrel, the operative stopper movable along an operative path of travel from a first operative position to a second operative position, the auto injector to comprise an injection spring having a spring force, the injection spring configured to apply a dispensing force to the operative stopper by driving a piston rod toward the operative stopper upon actuation of the auto injector, the dispensing force being at least a portion of the spring force, the method comprising: aging a prefilled syringe at an accelerated rate to form a reference prefilled syringe, the reference prefilled syringe including a reference barrel and a reference stopper positioned in the reference barrel; moving the reference stopper of the reference prefilled syringe along a reference path of travel from at least a first reference position to at least a second reference position; as the reference stopper moves within the reference barrel along the reference path of travel, measuring a plurality of exertion forces applied to the reference stopper and measuring a plurality of reference stopper positions; generating an exertion force profile, the exertion force profile including at least some of the exertion forces and reference stopper positions measured while the reference stopper was moving between the first and second reference positions, at least one of the measured exertion forces correlating to at least one of the measured reference stopper positions; and selecting the injection spring so that the dispensing force applied to the operative stopper at each position of the operative stopper as it moves along the operative path of travel between the first and second operative positions is greater than the measured exertion force at a corresponding one of the measured reference stopper positions. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting the injection spring comprises selecting a measured exertion force from the exertion force profile, and selecting at least one spring parameter, the selected at least one spring parameter corresponding to the selected exertion force. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting the at least one spring parameter comprises selecting a spring constant for the injection spring and an uncompressed length for the injection spring. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting at least one spring parameter comprises selecting a spring constant and a first compressed spring length corresponding to the reference stopper being at the first reference position along the reference path of travel. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting at least one spring parameter comprises selecting a spring constant and a second compressed spring length corresponding to the reference stopper being at a position along the reference path of travel corresponding to a maximum measured exertion force in the exertion force profile. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the selected spring has a dispensing force when the stopper is at the second final position that is greater than about 50% of the dispensing force when the stopper is at the first initial position. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the predetermined speed corresponds to a speed required to move the operative stopper along the operative path of travel from the first operative position to the second operative position in a range from about 5 seconds to about 19 seconds. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein: a plunger is operably connected to the stopper and the act of moving the stopper comprises moving the plunger; and the act of measuring a plurality of exertion forces exerted on the stopper comprises measuring a plurality of exertion forces exerted on the plunger. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the act of determining the glide force includes determining the glide force required to move the stopper along the path of travel from the first position to the second position within a determined amount of time. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining the first resistive force comprises determining the first resistive force when moving the stopper from the first position. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining a resistive force comprises determining a resistive force selected from the group of: a break loose force, a maximum glide force, or combinations thereof. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining a resistive force comprises determining a resistive force selected from the group consisting of: a break loose force, a maximum glide force, or combinations thereof. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining a resistive force comprises determining at least first and second resistive forces, the first resistive force being a break loose force, and the second resistive force being a minimum glide force for moving the stopper along the path of travel from the first position at a beginning of the path of travel to the second position at an end of the path of travel without stalling. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined amount of time is in the range from about 5 s to about 25 s. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the act of determining the minimum glide force includes determining the minimum glide force required to move the stopper along the path of travel from the first position to the second position within about 5 seconds to about 25 seconds. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the aged prefilled syringe holds a determined volume of therapeutic fluid between the first position and the second position, and the act of determining a minimum glide force required to move the stopper along the path of travel from the first position to the second position without stalling comprises ejecting the determined volume of therapeutic fluid from the aged prefilled syringe. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined volume is in the range from about 1.51 mL to about 1.66 mL. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the auto injector comprises a subassembly, the subassembly movable in response to decompression of the injection spring, the subassembly arranged to selectively move the stopper, the act of selecting the spring constant comprising: selecting the spring constant to correspond to at least the first resistive force, the second resistive force, and a third resistive force, the third resistive force resistive to movement of the subassembly. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein moving the stopper within the barrel of the aged prefilled syringe comprises moving the subassembly of the auto injector. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the auto injector comprises a subassembly, the subassembly operable in response to decompression of the injection spring, at least a portion of the subassembly arranged to selectively move the stopper, the act of selecting the spring constant comprising: selecting the spring constant to correspond to a force strong enough to operate the subassembly and to move the stopper from the first position to the second position without stalling. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein moving the stopper within the barrel of the aged prefilled syringe comprises moving the subassembly of the auto injector. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid comprises an antibody. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the antibody comprises a humanized monoclonal antibody. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the humanized monoclonal antibody comprises an immunoglobulin G 2  (IgG2) antibody. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the humanized monoclonal antibody comprises an anti-calcitonin gene-related peptide antibody. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid has a viscosity in the range from about 4 cSt to about 14 cSt at 22° C. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid comprises fremanezumab and has a viscosity in the range from about 4 cSt to about 14 cSt at 22° C. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe comprises an inner surface, and the prefilled syringe further comprises a lubricant on the inner surface. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises silicone oil. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises polydimethylsiloxane. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil coats the inner surface of the barrel and the thickness of the coating is between about 0.1 μm and about 0.3 μm before the prefilled syringe is aged. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises between about 0.35 mg and about 1.1 mg of silicone oil before the prefilled syringe is aged. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity between about 500 cSt and about 1500 cSt at 25° C. before the prefilled syringe is aged. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein aging the prefilled syringe comprises heating the prefilled syringe for a determined period of time. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined period of time is calculated according to the Arrhenius equation. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein: the determined period of time is calculated according to the Arrhenius equation; and heating the prefilled syringe for a determined period of time comprises heating the prefilled syringe at a temperature in the range from about 20° C. to about 60° C. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has a volume selected from the group of about 1 mL to about 2.25 mL. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has a volume selected from the group consisting of about 1 mL to about 2.25 mL. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the distance between the first reference position of the reference stopper and the second reference position of the reference stopper is in the range from about 25.7 mm to about 30 mm. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the distance between the first position of the stopper and the second position of the stopper is in the range from about 35 mm to about 55 mm. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the needle defines a channel and the channel has a diameter in the range from about 0.15 mm to about 0.3 mm. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the channel defined by the needle has a length in the range from about 15 mm to about 25 mm. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel comprises glass. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel comprises Borosilicate glass. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has an inner diameter in the range from about 6 mm to about 10 mm. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper comprises ethylene tetrafluoroethylene. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group of: a variable force spring, a constant force spring, a helical spring, a conical spring, a torsion spring, a gas spring, a hydraulic spring, and combinations thereof. 
     Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group consisting of: a variable force spring, a constant force spring, a helical spring, a conical spring, a torsion spring, a gas spring, a hydraulic spring, and combinations thereof. 
     Another aspect is an auto injector for actuating a prefilled syringe containing a dosage of a therapeutic fluid, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid comprising fremanezumab, and the auto injector made by a process comprising: any combination of the actions recited above; selecting a spring having the selected spring constant; and assembling the auto injector with the selected spring. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, the auto injector arrangement comprising: a prefilled syringe including a barrel extending along a longitudinal axis between a distal end and a proximal end, an inner diameter of the barrel being about 8.65 mm, a needle disposed at the distal end of the barrel, the needle having an inner diameter of about 0.21 mm and a length of about 20 mm or less, a therapeutic fluid held within the barrel, a viscosity of the therapeutic fluid being in the range of about 14 cSt or less at 22° C., and a stopper disposed within the barrel to retain the fluid within the barrel, the barrel defining a path of travel for the stopper, the path of travel having a first position for the stopper and a second position for the stopper, the therapeutic fluid comprising fremanezumab; and an auto injector holding the prefilled syringe, the auto injector comprising a plunger and an injection spring, the plunger engaging the stopper, and the injection spring biasing the plunger towards the stopper, the injection spring having a spring force of at least about 20 N when the stopper is positioned at the first position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, the auto injector arrangement comprising: a prefilled syringe including a barrel extending along a longitudinal axis between a distal end and a proximal end, an inner diameter of the barrel being of about 8.65 mm, a needle disposed at the distal end of the barrel, the needle having an inner diameter of about 0.27 mm and a length of about 19.5 mm or less, a volume in the range from about 1.51 mL to about 1.66 mL of therapeutic fluid held within the barrel, the therapeutic fluid comprising fremanezumab, a viscosity of the therapeutic fluid being about 8.8 cSt at 22° C., and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, the barrel defining a path of travel for the stopper, the path of travel having a first initial position for the stopper and a second final position for the stopper, the first position being an initial position of the stopper before delivery of the therapeutic fluid, the second position being a final position of the stopper upon delivery of a full dose of the therapeutic fluid; and an auto injector holding the prefilled syringe, the auto injector comprising an injection spring arranged to apply a dispensing force to the stopper by driving a piston rod toward the stopper, wherein, when the auto injector is actuated, the injection spring is configured to provide an initial dispensing force to the stopper of at least about 20 N when the stopper is positioned at the first initial position and a final dispensing force of about 12 N or greater to the stopper when the stopper is positioned at the second final position, the dispensing force being at least a portion of a spring force for the injection spring. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspect disclosed herein, wherein the injection spring is configured to provide a final dispensing force of at least 12.5 N to the stopper when the stopper is positioned at the second final position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspect disclosed herein, wherein the injection spring is configured to provide a final dispensing force of at least 14 N to the stopper when the stopper is positioned at the second final position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspect disclosed herein, wherein the injection spring is configured to provide a final dispensing force of at least 12 N to the stopper when the stopper is positioned at the second final position and the prefilled syringe has an accelerated age of about 24 months. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring force in the range from about 20 N to about 30 N when the stopper is positioned at the first initial position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final dispensing force in the range from about 12 N to about 20 N when the stopper is positioned at the second final position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final dispensing force in the range from about 12.5 N to about 20 N when the stopper is positioned at the second final position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, when the stopper is at the first initial position, an actual stored spring energy of the injection spring is at least about 25% greater than a minimum stored spring energy required to move the stopper from the first position to the second position without stalling an unaged prefilled syringe. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a stored energy in the range from about 0.9 J to about 2 J when the injection spring is in the first position. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring constant in the range from about 0.2 N/mm to about 0.4 N/mm and a compressed length when in the first initial position in the range from about 50 mm to about 100 mm. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring constant in the range from about 0.28 N/mm to about 0.32 N/mm and compressed length when in the first initial position in the range from about 75 mm to about 95 mm. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a force sufficient to move the stopper along the path of travel from the first position to the second position within about 5 seconds to about 25 seconds. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein: the barrel of the prefilled syringe comprises glass and defines an inner surface; and the prefilled syringe further comprises between about 0.4 mg and about 1.1 mg of silicone oil on the inner surface before the prefilled syringe is aged. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to move the stopper along the path of travel from the first position to the second position within the range from about 5 seconds to about 19 seconds. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity between about 500 cSt and about 1500 cSt at 25° C. before the prefilled syringe is aged. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity of about 1000 cSt at 25° C. before the prefilled syringe ages. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper has a length in the range from about 7.3 mm to about 8.1 mm. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper has a compressed state and an uncompressed state, and the stopper comprises: a main body, the main body being substantially cylindrical and having a diameter in the uncompressed state in the range from about 8.85 mm to about 9.05 mm; and at least one annular rib, the annular rib extending radially from the main body, the annular rib having an outer diameter in the uncompressed state in the range from about 9.25 mm to about 9.45 mm. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein a portion of the stopper is coated with ethylene tetrafluoroethylene, and a portion of the stopper is coated with silicone. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein a distance between the first position for the stopper and the second position for the stopper is in the range from about 25.7 mm to about 30 mm. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the prefilled syringe has a volume selected from the group of about 1 mL and about 2.25 mL. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the prefilled syringe has a volume selected from the group consisting of about 1 mL and about 2.25 mL. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid has a viscosity in the range from about 4 cSt to about 10 cSt at 22° C. 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is determined according to the actions recited in claim  1 . 
     Another aspect is an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, the auto injector arrangement comprising: a prefilled syringe; the prefilled syringe comprising a barrel formed at least in part by glass, a needle in fluid communication with the barrel, and a stopper positioned in the barrel, the barrel defining an inner surface, the barrel having an inner diameter, the barrel being about 8.65 mm and a volume of about 2.25 mL, the barrel defining a path of travel for the stopper, the path of travel having a first position for the stopper and a second position for the stopper, the needle having an inner diameter of about 0.21 mm and a length of about 20 mm or less, a therapeutic fluid held within the barrel, a viscosity of the therapeutic fluid being in the range of about 10 cP or less at 22° C., the therapeutic fluid comprising fremanezumab; about 0.35 mg to about 1.1 mg of silicone oil lubricating the inner surface of the barrel, the silicone oil having a viscosity between about 500 cSt and about 1500 cSt at 25° C. before the prefilled syringe is aged; and an auto injector holding the prefilled syringe, the auto injector comprising a plunger and an injection spring, the plunger engaging the stopper, and the injection spring biasing the plunger towards the stopper, the injection spring when in the first position: has a force determined according to the actions recited in claim  1 ; is in the range from about 20 N to about 30 N; is about 25% greater than spring force required to move the stopper from the first position to the second position without stalling before the prefilled syringe is aged; and has a force sufficient to move the stopper along the path of travel from the first position to the second position within about 5 seconds to about 25 seconds. 
     Another aspect is an auto injector apparatus for actuating a prefilled syringe containing a dosage of a therapeutic fluid, alone or in any combination with the previous embodiments and aspects disclosed herein, the therapeutic fluid comprising an immunoglobulin G 2  (IgG2) humanized monoclonal antibody, the auto injector made by a process comprising the operations of: aging the prefilled syringe to form an aged prefilled syringe; moving the stopper within the barrel of the aged prefilled syringe at a predetermined speed from at least a first position along the path of travel to at least a second position along the path of travel; measuring a plurality of exertion forces exerted on the stopper as the stopper moves within the barrel along the path of travel; determining at least first and second resistive forces opposing movement of the stopper along the path of travel, the first and second resistive forces corresponding to the plurality of exertion forces; selecting a spring constant for the injection spring, the act of selecting the spring constant comprising selecting the spring constant to correspond to at least one of the first and second resistive forces; selecting a spring having the selected spring constant; and assembling the auto injector with the selected spring. 
     Another aspect is an auto injector apparatus configured to move a stopper within a barrel of a syringe to effect delivery of a fluid from the syringe, alone or in any combination with the previous embodiments and aspects disclosed herein, the auto injector apparatus comprising: a syringe barrel, the syringe barrel having an empty state and a filled state, the empty state occurring before the filled state, the syringe holding a dose of therapeutic fluid when in the filled state, the therapeutic fluid comprising an immunoglobulin G 2  (IgG2) humanized monoclonal antibody; a stopper positioned in the syringe barrel, the stopper having a path of travel between a first position and a second position, the dose of therapeutic fluid being substantially positioned between the first and second positions; and an injection spring having a spring constant, the spring constant providing the injection spring with a first spring force that is at least 25% greater than a second spring force, the first spring force corresponding to the minimum spring force required to move the stopper from the first position to the second position when the barrel is in the filled state, and the second spring force corresponding to the minimum spring force required to move the stopper from the first position to the second position when the barrel is in the empty state. 
     Another aspect is an auto injector apparatus configured to move a stopper within a barrel of a syringe to effect delivery of a fluid from the syringe, alone or in any combination with the previous embodiments and aspects disclosed herein, the auto injector apparatus comprising: a prefilled syringe, the prefilled syringe having an unaged state and an aged state, the prefilled syringe holding a dose of therapeutic fluid when in the filled state, the therapeutic fluid comprising an immunoglobulin G 2  (IgG2) humanized monoclonal antibody; a stopper positioned in the prefilled syringe, the stopper having a path of travel between a first position and a second position, the dose of therapeutic fluid being substantially positioned between the first and second positions; and an injection spring having a spring constant, the spring constant providing the injection spring with a first spring force that is at least 25% greater than a second spring force, the first spring force corresponding to the minimum spring force required to move the stopper from the first position to the second position when the prefilled syringe is in the aged state, and the second spring force corresponding to the minimum spring force required to move the stopper from the first position to the second position when the prefilled syringe is in the unaged state. 
     Another aspect is a prefilled syringe combination, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament to treat or prevent migraine headaches 
     Another aspect is a prefilled syringe containing fremanezumab, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament to treat or prevent migraine headaches. 
     Another aspect is a prefilled syringe containing a therapeutic fluid comprising fremanezumab, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament to treat or prevent migraine headaches. 
     Another aspect is a prefilled syringe containing a therapeutic fluid comprising fremanezumab and formulated at 150 mg/mL nominal concentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, 1.2 mg/mL P580, pH 5.5, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament to treat or prevent migraine headaches. 
     Another aspect is a prefilled syringe containing fremanezumab in any combination with an auto injector, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament to treat or prevent migraine headaches, the prefilled syringe filled with a therapeutic fluid formulated at 150 mg/mL nominal concentration in 16 mM histidine, 6.6% sucrose, 0.136 mg/mL EDTA, 1.2 mg/mL P580, pH 5.5. 
     Another aspect is a prefilled syringe containing fremanezumab for use as a medicament to treat or prevent migraine headaches, according to a continuous schedule of no more than once every two months, either alone or in any combination with the previous embodiments and aspects. 
     Another aspect is a prefilled syringe containing fremanezumab for use as a medicament to treat or prevent migraine headaches, according to a continuous schedule of no more than once every three months, either alone or in any combination with the previous embodiments and aspects. 
     Another aspect is a prefilled syringe containing fremanezumab for use as a medicament to treat or prevent migraine headaches, according to a continuous schedule of no more than once every four months, either alone or in any combination with the previous embodiments and aspects. 
     Another aspect is an auto injector, either alone or in any combination with any of the previous embodiments and aspects, the auto injector comprising: a prefilled syringe comprising a stopper and a therapeutic fluid including fremanezumab; and an auto injector having an injection spring and a piston rod arranged to move the stopper from a first position to a second position with a force of about 30 N or less and in about 19 seconds or less, the distance between the first and second positions corresponding to one dose of the therapeutic fluid. 
     The various embodiments described above are provided by way of illustration only and should not be construed to limit the claims attached hereto. Those skilled in the art will readily recognize various modifications and changes that may be made without following the example embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the following claims. It is intended that any such modifications and equivalents be included in the scope of the claims.