ATNAA_MPID_6_2MAY2019.pdf

Page 1 of 31 Pages

NUMBER DATE

MEDICAL PROCUREMENT ITEM DESCRIPTION 6 May 2, 2019 National Stock No. Item Identification

6505-01-362-7427 ANTIDOTE TREATMENT, NERVE AGENT, Automatic, Dual-Chamber, Pralidoxime Chloride Injection, 300 mg per mL, 2 mL, and Atropine Injection, 2.99 mg per mL, 0.7 mL.

Each auto-injector shall deliver 600mg of Pralidoxime Chloride and 2.1 mg of Atropine.

TABLE OF CONTENTS

National Stock Number and Item Contents………………………………………………1 Table of Contents ………………………………………………………………………...1 Glossary of Terms ………………………………………………………………………..2

1. SCOPE AND REGULATORY REQUIREMENTS

1.1. Scope

1.2. Regulatory Requirements

2. SALIENT CHARACTERISTICS AND PRODUCT DESCRIPTION

2.1. Medications

2.2. Table 1: Formulation Ingredients Pralidoxime Chloride Injection, 300 mg per mL………………………………………………………………………………………4

2.3. Table 2: Formulation Ingredients Atropine, 2.99 mg per mL

2.4. Assay, Identification, Sterility, Clarity, Color, pH, Particulate Matter and Bacterial Endotoxin

2.5. Auto-injector

2.6. Individual ATNAA Auto-injector Package

2.7. Labeling and Marking Requirements (ATNAA)

2.8. Instruction For Use Card (IFU), ATNAA Auto-Injector

2.9. Package Insert, Antidote Treatment, Nerve Agent Auto-injector

2.10. Packaging Requirements………………………………………………………10

2.11. Shipping Information

3. QUALITY ASSURANCE PROVISIONS

3.1. Responsibility for inspection

3.2. Quality conformance inspection

4. QUALIFICATION TESTS

4.1. Table 3: Functional and Attribute Testing at Initial Qualification

4.2. Table 4: Conditions for MIL-STD-810E Testing at Initial Qualification

4.3. Table 5: CHP Functional and Attribute Testing at Initial Qualification

4.4. Table 6: Conditions for Testing the CHP at Initial Qualification

6505-01-362-7427 (MPID No. 6)

Page 2 of 31 Pages

5. RELEASE TESTS

5.1. Table 7: Chemical and Microbiological Specifications at Release of Basic Units …………………………………………………………………………………23

5.2. Table 8: Functional Testing at Release

5.3. Table 9: Classification of Defects at Release

5.4. Table 10: Labeling and Marking Requirements at Release

5.5. Table 11: Packaging Requirements at Release

6. STABILITY TESTS

6.1. Table 12: Chemical and Microbiological Specifications During Stability Testing…

7. RE-QUALIFICATION TESTS

8. SOURCE DOCUMENTS

GLOSSARY OF TERMS

AF Activation Force ANSI/ASQ American National Standards Institute/American Society for

Quality AQL Acceptable Quality Level ASTM ASTM International (formerly American Society for Testing and Materials ATNAA Antidote Treatment Nerve Agent Auto-injector Basic Unit Primary Sterile Drug Cartridge with Container Closure BDU Battle Dress Uniform C Celsius or Centigrade cGMP current Good Manufacturing Practices CHP Chemically Hardened Pouch cm Centimeter DT Dispensing Time DV Dispensed Volume EP European Pharmacopeia EU Endotoxin Unit F Fahrenheit FDA Food & Drug Administration FED Federal Ft Feet Hg Mercury Hz Hertz IFU Instructions for Use IM Intramuscular Intermediate 100 units in an intermediate box Package lbs Pounds mg Milligram MIL-STD Military Standard MIL-STD-810E Department of Defense Test Method Standard for Environmental

Engineering Considerations and Laboratory Tests mL Milliliter mm Millimeter

Page 3 of 31 Pages

MMT Meridian Medical Technologies, Inc.

MOPP 4 Mission Oriented Protective Posture, Level 4 MPID Medical Procurement Item Description N/A Not-applicable NDA New Drug Application NDC National Drug Code NEL Needle Extended Length NF National Formulary NMT No More Than NSN National Stock Number R&D Research and Development RPM Rotations per Minute Rx Prescription Unit One Injector in Chemically Hardened Pouch U.S. United States USP United States Pharmacopeia

1. SCOPE AND REGULATORY REQUIREMENTS

1.1. Scope

This Medical Procurement Item Description (MPID) covers the Antidote Treatment Nerve Agent Auto-injector (ATNAA), which contains Pralidoxime Chloride Injection and Atropine Injection in a dual chambered nose-pressure-activated automatic injector (auto-injector) suitable for intramuscular administration. Included in this MPID are salient characteristics of the product, quality assurance provisions, and descriptions of conditions, tests and specifications for initial qualification, release, stability and re-qualification processes. For all MIL-STD testing described in this MPID, MIL-STD-810E will apply.

1.2. Regulatory Requirements

1.2.1. Federal Food, Drug and Cosmetic Act

This product has been determined by the U.S. Food and Drug Administration to be under its jurisdiction. As such, the offeror/contractor shall comply, and be responsible for compliance by its subcontractors/ suppliers, with the requirements of the Federal Food, Drug and Cosmetic Act, as amended, and regulations promulgated there under. In addition, the offeror/contractor shall comply, and be responsible for compliance by its subcontractors/suppliers, with the requirements of all other applicable Federal, State and local statutes, ordinances, and regulations.

1.2.2. Recovered materials

The offeror/contractor is encouraged to use recovered material in accordance with Federal Acquisition Regulation Subpart 23.4 to the maximum extent practical.

Page 4 of 31 Pages

2. SALIENT CHARACTERISTICS AND PRODUCT DESCRIPTION

2.1. Medications

Pralidoxime Chloride Injection, 300 mg per mL, and Atropine Injection, 2.99 mg per mL, shall meet the individual requirements for each drug solution as set forth in the NDA.

The volume range of the combined solutions shall be 2.43 mL to 2.97 mL. The delivered volume shall be the total combined solution of both drugs delivered during the injection process.

The raw materials and formulation ingredients for the Pralidoxime Chloride Injection, 300 mg per mL solution shall be as follows in Table 1:

2.2. Table 1: Formulation Ingredients Pralidoxime Chloride Injection, 300 mg per mL

Ingredient Unit Formula per 1 mL

Pralidoxime Chloride, USP 330 mg (includes 10% overage)

Benzyl Alcohol, NF/EP 20.0 mg

Glycine, USP 11.26 mg

Water for Injection qs to 1 mL

Hydrochloric Acid, NF (for pH adjustment) pH 2.4 – 2.6

The raw materials and formulation ingredients for the Atropine Injection, 2.99 mg per mL solution shall be as follows in Table 2:

2.3. Table 2: Formulation Ingredients Atropine, 2.99 mg per mL

Ingredient Unit Formula per 1 mL

Atropine, USP//EP 2.99 mg

Glycerin, USP/EP 17.81 mg

Citric Acid (Monohydrate), USP/EP 5.0 mg

Sodium Citrate (Dihydrate), USP/EP 4.35 mg

Phenol, USP/EP 4.00 mg

Water for Injection, USP qs to 1.0 mL

Nitrogen, NF/EP qs sparge

Page 5 of 31 Pages

2.4. Assay, Identification, Sterility, Clarity, Color, pH, Particulate Matter and Bacterial Endotoxin

Using suitable, accurate, and reproducible methods acceptable to the Food and Drug Administration (FDA), the solution shall conform to the required specifications during, release and stability testing and shall be tested in accordance with the Assay, Identification, Sterility, Color, Clarity, Particulate Matter, Bacterial Endotoxin Test and pH tests for both Atropine and Pralidoxime chloride Injection specified in the individual NDA in accordance with Table 7 and Table 12 in Sections 5 and 6. The drug container shall be compatible with the solution so that the auto-injector shall meet functional, chemical, and microbiological specifications throughout the shelf life. The solution and all components and surfaces in contact with the solution shall be sterile. When the injector is activated and the solution is ejected, the liquid shall be sterile.

Each ingredient used to prepare the drug solutions shall comply with the designated standard. Formulation and assay shall be performed according to the processes and methods set forth in the NDA.

2.5. Auto-injector

The auto-injector shall be a specially designed unit for automatic self or buddy administration by military personnel. When activated the auto-injector sequentially administers Atropine and Pralidoxime Chloride through a single needle. The product shall conform as follows:

2.5.1 The auto-injector shall be a dual chambered nose-pressure-activated auto-injector suitable for use in rapid intramuscular administration of the contained Pralidoxime Chloride and Atropine solutions.

2.5.2 The two drug solutions shall be contained inside the auto-injector in a dual chambered molded cartridge body. A moveable plunger that prevents the mixing of the two drugs while in the cartridge body shall separate the two chambers.

2.5.3 The small end of the cartridge body shall be filled with Atropine solution and sealed by placing a needle/stopper/disc assembly into the open end of the small chamber. The needle/stopper/disc shall be inserted so that the needle and disc are in contact with the Atropine solution and so that the stopper plug creates a hermetic seal against the cartridge body wall.

A green end cap shall be snapped into place over the stopper to hold it securely in place. The green end cap shall have a hole in the face that accommodates the stopper nipple.

2.5.4 The large chamber shall then be filled with the Pralidoxime Chloride solution and shall be hermetically sealed by inserting a moveable rubber plunger in to the rear chamber.

2.5.5 All component materials in contact with the drug solutions shall be identical to the materials listed in the NDA.

Page 6 of 31 Pages

2.5.6 The auto-injector assembly shall be completed by placing the filled cartridge body onto a spring-loaded power pack and then snapping a molded outer tube in place over both items to hold the complete assembly together.

2.5.7 The completed auto-injector shall have a label placed over the long outer tube. The assembled and labeled auto-injector shall be hermetically sealed into a Chemically Hardened Pouch (CHP) that is capable of protecting the drug solutions from light as demonstrated by ICH light test while allowing the label to be read from the outside.

2.5.8 The auto-injector shall be oriented inside the CHP so that the Atropine solution (green end) will be covered by the black portion of the CHP.

2.5.9 The CHP design shall provide tamper evidence.

2.5.10 The ATNAA shall have demonstrated equal or superior drug blood levels to the Mark I, Nerve Agent Antidote Kit when tested in healthy human volunteers in a comparative bioavailability study.

2.5.11 The auto-injector shall be operable in an ambient temperature range of 32oF (0oC) to 122oF (50oC), when tested as specified in Tables 3 - 12.

2.5.12 The auto-injector shall be a cylindrically shaped, smoothly formed, spring operated, automatic injection device, with an overall length not exceeding

7.1 inches (18 cm) and a maximum diameter of the unit itself of 1 inch (2.5 mm).

2.5.13 The auto-injector shall have the needle end permanently marked with a molded green end cap and the unit shall have a removable gray safety release at the opposite end. The gray safety release shall prevent unintentional discharge.

2.5.14 The auto-injector shall be equipped with a 23-gauge needle.

2.5.15 The auto-injector shall activate when a force of no less than 2 pounds and no more than 8 pounds is applied axially when the gray safety release is removed.

2.5.16 When activated the auto-injector shall deliver 2.43 – 2.97 mL of the drug solutions in a single injection while keeping the drug solutions separate in the injector and allowing minimal mixing within the injection site.

2.5.17 The auto-injector shall be capable of delivering its combined volume through combined layers of chemical protective clothing, the BDU and undergarments.

2.5.18 Needle. Following activation of the auto-injector the extended length (needle point to front of stopper) of the needle (NEL) shall be not less than 18 mm or more than 23 mm when tested as specified in Tables 3 -

12. The needle length will be measured from the tip of the exposed

Page 7 of 31 Pages needle to the face of the stopper. The needle shall be 23 gauge and the entire needle assembly shall be constructed of AISI stainless steel, passivated.

2.5.19 Sterility. The solutions and all components and surfaces in contact with the solutions shall be sterile. The solutions shall be sterile when tested as specified in Tables 7 and 12.

2.5.20 Certification of sterility. A certificate of sterility, listing all lot (control) numbers, shall state that samples from each sterility lot have been tested in accordance with the current USP method and found to be sterile.

2.5.21 Bacterial endotoxin. The solutions shall meet the requirements when tested as specified in Tables 7 and 12.

2.5.22 Chemical/physical interactions. The drug container and solution shall be compatible such that the auto-injector shall meet functional, chemical, and microbiological specifications throughout the shelf life when tested according to tests described in Tables 7 and 12.

2.5.23 Activation force (AF). Subsequent to removal of the Gray Safety Release, the auto-injector shall activate in a range of 2.0 to 8.0 pounds of directly applied triggering force, when tested as specified in Tables 3 -

12. The front end (green end) of the auto-injector shall not become dislodged during activation.

2.5.24 Dispensed Volume (DV) and dispensing time (DT). The auto-injector shall dispense 2.43 mL to 2.97 mL of the drug solutions to deliver 600 mg of Pralidoxime Chloride and 2.1 mg of Atropine through the needle, during a test period of not more than 7 seconds from the time of activation, when tested as specified in Tables 3 - 12.

2.5.25 The auto-injector shall conform during initial qualification and release testing, respectively, to the functional requirements described in Table 3 in Section 4 and Table 8 in Section 5 with regard to:

• Activation Force (AF)

• Dispensed Volume (DV)

• Dispensing Time (DT)

• Needle Extended Length (NEL)

2.5.26 The auto-injector shall be exposed to the following conditions prior to testing and meet all functional requirements during initial qualification as described in Table 3 and Table 4.

• Product Reliability

• Temperature Range Operability

• Temperature Shock

• Accelerated Aging

• Rough Handling: Vibration Test/Secured Cargo

• Rough Handling: Vibration Test/Loose Cargo

Page 8 of 31 Pages

• Rough Handling: Shock

• Rough Handling & Safety Mechanism

• Ability to Withstand High Altitude (Low Pressure)

• Permanency of Marking

2.5.27 The auto-injector shall be tested for defects during release testing as described in Table 9 in Section 5 with regard to:

• Needle gauge

• Needle Extended Length

• Medication

• Label and Markings

• Workmanship

• Clarity

2.5.28 The auto-injector shall have an FDA-approved total expiration dating period of not less than 48 months. No less than 44 months of the expiration dating period shall remain at time of delivery to the Government.

2.6. Individual ATNAA Auto-injector Package

2.6.1 Each auto-injector shall be packaged in a chemically-hardened pouch (CHP) amber/black nylon/polyester/nylon/polyethylene laminate package measuring approximately 22 cm by 8.5 cm.

2.6.2 The CHP shall be waterproof, tamper-evident and shall be easily torn open by gloved hands.

2.6.3 The CHP shall be sufficiently transparent through the amber portion to allow visual inspection of the auto-injector and readability of the label information.

2.6.4 The black portion at the open end (needle end) of the CHP shall be sufficiently dark to protect the atropine drug contents from light when tested using ICH guidelines.

2.6.5 All edges of the CHP shall be completely sealed.

2.6.6 The CHP shall be capable of being decontaminated with standard decontamination agents as demonstrated by government-conducted testing.

2.6.7 The CHP shall be sufficiently durable to maintain its integrity while being carried by the service-member as demonstrated by government-conducted testing.

2.6.8 The CHP shall be sufficiently durable and flexible to withstand operational temperatures between 32oF and 122oF.

Page 9 of 31 Pages

2.6.9 The CHP shall have eight (8) V-shaped tear-notches, located approximately 1.5 cm from each corner. A slight variation in the placement of the notches is acceptable provided that there are still two (2) notches on each of the four (4) sides of the package (a total of eight [8] notches), that the placement does not affect the functionality of the tear-notch, and that the placement does not interfere with the placement of the rectangular orientation tab on the Gray Safety Release end of the package.

2.6.10 The CHP shall have a 19 mm by 12 mm rectangular orientation tab on the

Gray Safety Release end of the package.

2.6.11 Requirements to ensure the CHP’s integrity during initial qualification and release testing are detailed in Section 4, Table 5 and Table 6, respectively.

2.7. Labeling and marking requirements (ATNAA)

The label on each auto-injector shall bear the following information only.

Information shall be printed in non-reflective black lettering on a non-reflective white background, except where otherwise designated.

2.7.1 The item identification designated as “ANTIDOTE TREATMENT NERVE AGENT, AUTO-INJECTOR” shall appear as the first item on the label, and on separate lines centered below the item identification:

2.7.1.1 "FOR USE IN NERVE AGENT POISONING ONLY"

2.7.1.2 "ATROPINE INJECTION 2.1 MG, PRALIDOXIME CHLORIDE

INJECTION 600 MG.”

2.7.1.3 "STERILE SOLUTION FOR INTRAMUSCULAR USE ONLY"

2.7.2 The label shall contain a series of three pictograms to provide the instructions for use of the ATNAA. Each pictogram shall have the numerals 1, 2 or 3, respectively, in the upper left corner to indicate the sequence of steps for use of the ATNAA.

2.7.3 "STORE AT 25OC (77OF); EXCURSIONS PERMITTED TO 15-30OC (59-

86OF)"

2.7.4 "KEEP FROM FREEZING. PROTECT FROM LIGHT"

2.7.5 The NSN as "NSN 6505-01-362-7427" and NDC as “NDC 11704 77701”

2.7.6 A NATO yellow band and light brown band against a white background shall be printed along the entire edge of the label adjacent to the needle end of the ATNAA.

2.7.7 The logo, name and address of the manufacturer and/or distributor.

Page 10 of 31 Pages

2.7.8 The lot (control) number designed as “LOT” or “LOT NO.", expiration date prefixed by "EXP" and the legend "RX ONLY".

2.7.9 Any additional information required by FDA. In addition, the label may include the trade name and patent number.

2.7.10 Labeling and marking requirements and requirements for testing to ensure that all labeling and marking requirements are met are specified in Table 10 in Section 5 with regard to:

• Unit (Single auto-injector in CHP)

• Unit container (CHP)

• Intermediate package (100 units in box)

• Exterior (shipping) container and unitized load

• Controlled, sensitive and pilferable items

2.7.11 Permanency of marking. Each auto-injector shall be durably and legibly marked and labeled as specified herein. Labels shall be durable and waterproof when tested as specified in Tables 3 - 12. Marking shall remain entirely legible; labels shall be unaffected and shall remain firmly affixed to the auto-injector.

2.8. Instruction For Use Card (IFU), ATNAA Auto-Injector

The IFU, ATNAA Auto-injector shall be a single sheet of paper, folded to measure approximately 7 cm by 9.5 cm and can easily fit in a shirt pocket. It shall be printed on both sides and shall be packaged 25 instruction cards in a suitable sealed container.

2.9. Package Insert, Antidote Treatment, Nerve Agent Auto-injector

Package insert(s) shall be provided to the FDA with the filing.

2.10 Packaging requirements

Packaging requirements and requirements for release testing to ensure packaging and marking requirements are met are described in Table 11 in Section 5 with regard to:

• Preservation (coating of boxes)

• Unit (Single auto-injector in CHP)

• Contents per exterior shipping container

• Damage to exterior shipping container

• Intermediate package (100 units in box with 100 IFUs)

• Exterior shipping container (2 intermediate packages per exterior container – 200 units)

2.10. Shipping Information

Contractor shall ship product in refrigerated trucks using temperature verification unless otherwise specified by the Government.

Page 11 of 31 Pages

3. QUALITY ASSURANCE PROVISIONS

3.1. Responsibility for inspection

Unless otherwise specified in the contract, the contractor is responsible for the performance of all inspection requirements as specified herein. Except as otherwise specified in the contract, the contractor may use his own or any other facilities suitable for the performance of the inspection requirements specified herein unless disapproved by the Government. The Government reserves the right to perform any of the inspections set forth in the specification where such inspections are deemed necessary to assure supplies and services conform to prescribed requirements.

3.1.1 Records

Records of examinations and tests performed by or for the contractor shall be maintained by the contractor and made available to the Government, upon the Government’s request, at any time, or from time to time, during the performance of the contract and for a period of three years after expiration of the supplies to which such records relate.

3.1.2 Raw materials and components

No company supplying any raw materials or injector components to the contractor or injector manufacturer will be considered an acceptable facility for the performance of any inspection requirements specified herein. Inspection and test requirements not specified herein but referenced by applicable documents in 3.1 may be performed at the option of the contractor or injector manufacturer.

3.2. Quality conformance inspection

3.2.1 Lot

3.2.1.1 Medication Lot for Inspection

For purposes of this specification, a lot, batch or control is that single, uniform, and homogenous quantity of the medication produced from one formulation, subjected to the same compounding and manufacturing operation, and filled into final containers.

Sterility sub-lots may be defined, sampled, and tested in accordance with USP definitions.

3.2.1.2 Pharmaceutical Lot for Finished Injectors

A lot shall consist of those ATNAA produced from one lot of Atropine and one lot of Pralidoxime Chloride at one plant, under essentially the same manufacturing conditions. Retain samples of each sterility sub lot will be held; 40 minimum from each sterility sub lot.

Page 12 of 31 Pages

3.2.1.3 Lot for Water for Injection, USP

Water for Injection shall meet the requirements of the USP.

3.2.2 Sampling

Where possible the sample may be used for two (2) or more tests.

Sampling for examination shall be conducted per ANSI/ASQ Z1.4, as specified in Tables 3 - 12.

Retain samples for stability testing shall conform to cGMP sampling requirements.

Reserve samples shall conform to cGMP sampling requirements.

4. QUALIFICATION TESTS

The lot size shall be between 10 – 100% of a full product batch. Samples for Initial Qualification Testing will be pulled as if the lot is a full production batch size.

Table 3 describes the functional testing performed during the Initial Qualification Process.

4.1. Table 3: Functional and Attribute Testing at Initial Qualification

Functional and Attribute Tests Specification

Activation Force (AF)

Requirement:

Subsequent to arming, the auto-injector shall activate on application of not less than 2 pounds and not more than 8 pounds of force applied axially to the end housing the needle (the green end). The front end of the injector shall not become dislodged during activation.

Test:

Remove the Gray Safety Release from the injector. Place the injector in a suitable device capable of applying and measuring required loads. Apply a load axially to the injector with the least possible impact and increase the load until the injector is activated. Examine the injector to determine if the front end has become dislodged during activation.

2.0 – 8.0 lbs

Dispensed Volume (DV)

Requirement:

When activated the auto-injector shall deliver 2.43 – 2.97 mL in a single injection while keeping the drug solutions separate in the injector and allowing minimal mixing within the injection site. The auto-injector shall be capable of delivering its combined volume through combined layers of chemical protective clothing, the BDU and undergarments during a test

2.43 – 2.97 mL

Page 13 of 31 Pages

Functional and Attribute Tests Specification period of not more than 7.0 seconds from the time of activation.

Test:

Using a suitable apparatus, activate the injector and determine the Dispensed Volume dispensed by weight, corrected for specific gravity.

Dispensing Time (DT)

Requirement:

The auto-injector shall dispense 2.43 – 2.97 mL of medication during a test period of not more than 7.0 seconds from the time of activation.

Test:

While measuring volume, measure, to the nearest second, the time between start of flow and the stop of the flow of medication from the needle.

NMT 7.0 seconds

Needle Extended Length (NEL) after Dispensing

Requirement:

The auto-injector needle extended length after firing at room temperature shall be 18 to 23 mm.

Test:

Using a suitable apparatus, activate the injector. After the medication has stopped flowing from the needle, measure the length of the needle protruding from the injector to the nearest millimeter.

18-23 mm

Rub Test (RT)

Requirement:

Each auto-injector shall be durably and legibly marked or labeled as specified herein. Labels shall be durable and waterproof. Marking shall remain entirely legible; labels shall be unaffected and shall remain firmly affixed to the auto-injector.

Test:

Rub the labeling on the auto-injector ten times with fingers using moderate pressure. Examine for legibility and permanency of marking or labeling.

Marking shall remain entirely legible and label shall remain firmly affixed.

Compression Load Test (CL)

Requirement:

Each auto-injector shall not activate when a load of twenty pounds is applied axially to the injector with the gray safety release in place.

Test:

On appropriate test equipment apply an axial load of twenty pounds to the auto-injector. The injector should not activate.

Injector does not activate

Page 14 of 31 Pages

Leak Test (LT)

Requirement:

The auto-injector shall retain the contained solution when subjected to a simulated altitude of 15,000 ft.

Test:

Visually examine the injector for evidence of medication leakage

No leakage evident

AF=Activation Force, DV=Dispensed Volume, DT=Dispensing Time, NEL= Needle Extended Length, RT=Rub Test, CL=Compression Load Test, LT=Leak Test

Table 4 describes the MIL-STD-810E testing performed during the Initial Qualification Process in accordance with various conditions prior to testing. Where noted, testing will include activation force (AF), Dispensed Volume (DV), Dispensing Time (DT) and Needle Extended Length (NEL) after Dispensing, as described above in Table 3. These MIL-STD-810E testing requirements may be waived if the same auto-injector and packaging configuration has been shown to meet specifications through performance qualification testing performed by the manufacturer.

For release testing of qualified products, see Tables 7 – 11.

4.2. Table 4: Conditions for MIL-STD-810E Testing at Initial Qualification

Conditions Prior to Testing Packaging Condition

AF

Test

DV

Test

DT

Test

NEL

Test

RT

Test

CL

Test

LT

Test

AQL

Level

ANSI/

ASQ

Z1.4

Reliability

Requirement:

The auto-injector shall activate and deliver a combined solution in a range of 2.43 mL to 2.97 mL with a minimum reliability of 99.5 percent as demonstrated by performance qualification testing by the manufacturer when tested at Room Temperature.

Test:

Functionality Test

No CHP

No Label x x x x n/a n/a n/a n/a n/a

Temperature Range Operability

Requirement:

Auto-injector shall be operable in an ambient temperature range of 0 - 50°C.

No CHP

No Label x x x x n/a n/a n/a 0.65 Level I

Page 15 of 31 Pages

AF

Test

DV

Test

DT

Test

NEL

Test

RT

Test

CL

Test

LT

Test

AQL

Level

ANSI/

ASQ

Z1.4

Test:

Auto-injectors shall be stored at 0oC ± 2oC for 24 hours and tested in accordance with Method 502 (I) of MIL-STD-810E. Auto-injectors shall also be stored at 50ºC ± 2ºC for 24 hours and tested in accordance with Method 501 (I) of

MIL-STD-810E.

Temperature Shock

Requirement:

The auto-injector shall be operable after being stored at -21.1°C for 24 hours, and then being stored at 54.4°C for 24 hours.

Test:

Auto-injectors shall be tested in accordance with MIL-STD-810E, Method 503. The low temperature extreme shall be -21.1°C ± 2ºC and the high temperature extreme shall be 54.4°C ± 2ºC.

No CHP x x x x n/a n/a n/a 0.65 Level I

High and Low Temp Storage (Accelerated Aging)

Requirement:

The auto-injector shall meet the requirements on activation force, dispensed volume, dispensing time, and needle extended length.

Test:

Auto-injectors shall be subjected to low temperature of -51°C ± 2ºC for 24 hours, and then shall be subjected to a high temperature of 71°C ± 2ºC for 24 hours. Auto-injectors shall be exposed to both temperature conditions prior to testing.

No CHP

Page 16 of 31 Pages

AF

Test

DV

Test

DT

Test

NEL

Test

RT

Test

CL

Test

LT

Test

AQL

Level

ANSI/

ASQ

Z1.4

Rough Handling: Vibration Test/Secured Cargo

Requirement:

The auto-injector shall meet the requirements on activation force, dispensed volume, dispensing time and needle extended length.

Test:

Unit shall be tested in accordance with MIL-STD-810E, Method 514, Test Procedure I, Cycled Sinusoidal Vibrations. Frequency of 10-200- 10 Hz, 12 minutes/cycle, 7 cycles.

Total test time 84 minutes.

Labeled

In CHP x x x x n/a n/a n/a 0.65 Level I

Rough Handling: Vibration Test/Loose Cargo

Requirement:

The solution shall meet the requirements on activation force, dispensed volume, dispensing time and needle extended length.

Test:

Intermediate package shall be subjected to the vibration test (loose cargo) in accordance with MIL-STD-810E, Method 514, Test Procedure III: Package Tester. 5 Hz (300 rpm), duration 3 hours (0.5 h/side), amplitude 1 inch (25.4 mm), double amplitude, circular motion.

Labeled

In CHP

In Inter-mediate Package x x x x n/a n/a n/a 0.65 Level I

Rough Handling: Shock

Requirement:

The solution shall meet the requirements on activation force, dispensed volume, dispensing time and needle extended length.

Test:

Unit shall be subjected to the shock test performed in accordance with MIL-STD-810E, Method 516. At height of 48 inches (122 cm), the injector shall be dropped 3 times on

Labeled

In CHP

Page 17 of 31 Pages

AF

Test

DV

Test

DT

Test

NEL

Test

RT

Test

CL

Test

LT

Test

AQL

Level

ANSI/

ASQ

Z1.4 needle end and on side onto a 2 inch thick wood surface.

Rough Handling and Safety Mechanism

Requirement:

The auto-injector shall not activate with the Gray Safety Release in place when a force of 20 to 22 pounds is axially applied.

Test:

Drop unit onto a 2 inch thick wood surface from a height of 4 feet.

Repeat the drop 3 times. Examine the auto-injectors for evidence that they would be unusable. Without removing the Gray Safety Release, attempt to activate the injectors by applying an axial force of 20 to 22 lbs.

Labeled

In CHP n/a n/a n/a n/a n/a X n/a 0.65 Level I

Ability to Withstand High Altitude (Low Pressure)

Requirement:

The auto-injector shall retain the contained solution when subjected to a simulated altitude of 15,000 feet.

Test:

Place the unit in a suitable vacuum chamber and reduce the pressure to 400 mm mercury absolute and maintain the pressure for at least one hour. Return the pressure to normal for at least one hour.

Repeat the pressure cycle 3 times (total of 4 cycles). Remove the injector from the chamber and visually examine for evidence of medication leakage.

Labeled

In CHP n/a n/a n/a n/a n/a n/a X 0.65 Level S-4

Page 18 of 31 Pages

AF

Test

DV

Test

DT

Test

NEL

Test

RT

Test

CL

Test

LT

Test

AQL

Level

ANSI/

ASQ

Z1.4

Permanency of Marking

Requirement:

Each auto-injector shall be durably and legibly marked or labeled as specified in Section 2.7. Labels shall be durable and waterproof.

Marking shall remain entirely legible; labels shall be unaffected and shall remain firmly affixed to the auto-injector.

Test:

Rub the marking or labeling on the injector 10 times with fingers using moderate pressure. Examine for legibility and permanency of marking or labeling.

Labeled

No CHP n/a n/a n/a n/a X n/a n/a 0.65 Level I

AF=Activation Force, DV=Dispensed Volume, DT=Dispensing Time, NEL= Needle Extended Length, CL = Compression Load Test, RT=Rub Test, LT = Leak Test

Table 5 describes the tests performed during the Initial Qualification Process to ensure the chemically-hardened pouch (CHP) meets all required specifications.

4.3. Table 5: CHP Functional and Attribute Testing at Initial Qualification

Page 19 of 31 Pages

Protection from Light with Readability of Label (LP)

Requirement:

Each auto-injector shall be packaged in a chemically-hardened pouch (CHP), which is capable of protecting the drug solutions from light while allowing the label to be read from the outside.

Test:

Light exposure tests will be conducted per ICH guidelines. Labels will be visually examined for readability.

Drug Stability Specification.

Flexibility of Pouch (PF)

Requirement:

The CHP shall be sufficiently flexible durable to maintain integrity under operational conditions

Test:

CHP will be moderately flexed and twisted 10 times in appropriate controlled apparatus. CHP will be inspected for tearing or de-lamination.

No signs of tearing or de-lamination.

Ease of Tear and Tamper Evidence (ET)

Requirement:

The CHP shall be tamper-evident, and shall be easily torn open by gloved hands.

Test:

Government Evaluation of Final Product.

As demonstrated through Government conducted

Testing

Pouch Integrity and Waterproof Test (PI)

Requirement:

All edges of the CHP shall be completely sealed. The package shall be waterproof.

Test:

Immerse final sealed CHP with auto-injector included in a suitable container of water that will allow for complete coverage. Check for seal integrity and bubbles.

No bubbles or evidence of leakage.

Decontamination Test

Requirement:

It shall be capable of being decontaminated with standard decontamination agents and shall be sufficiently durable to maintain its integrity while being carried by the service-member.

Test:

Government Conducted Testing.

As demonstrated through Government conducted

Testing

Dimensional Testing (DT)

Requirement:

The CHP shall measure 22 cm by 8.5 cm. The CHP shall have a 19 mm by 12 mm

Current drawing/specification at Quality Control Incoming

Page 20 of 31 Pages rectangular orientation tab on the Gray Safety Release end of the package. The CHP shall have 8 V-shaped tear-notches, located approximately 1.5 cm from each corner (a slight variation in the placement of the notches is acceptable provided that there are still 2 notches on each of the 4 sides of the package (a total of 8 notches), that the placement does not affect the functionality of the tear-notch, and that the placement does not interfere with the placement of the rectangular orientation tab on the Gray Safety Release end of the package.

Test:

Dimensions will be measured in accordance with the specifications and tolerances on the currently approved drawing/specification. Visually look to see if orientation tab is present.

inspection lot acceptance.

LP=Light Protection, PF=Pouch Flexibility, PI=Pouch Integrity, DT=Dimensional Testing, ET=Ease of Tearing

Table 6 describes the MIL-STD-810E testing performed during the Initial Qualification Process of the CHP in accordance with various conditions prior to testing. These MIL- STD-810E testing requirements may be waived if the same auto-injector and packaging configuration has been shown to meet specifications through performance qualification testing performed by the manufacturer.

Sampling for tests shall be in accordance with ANSI/ASQ Z1.4, Level and AQL as listed.

4.4. Table 6: Conditions for Testing the CHP at Initial Qualification

LP

Test PF

Test PI Test DT

Test ET Test AQL

Level

ANSI/

ASQ Z1.4

Room Temperature

Requirement:

The CHP shall measure 22 cm by 8.5 cm.

The CHP shall have a 19 mm by 12 mm rectangular orientation tab on the Gray Safety Release end of the package. The CHP shall have 8 V-shaped tear-notches, located approximately 1.5 cm from each corner (a slight variation in the placement of the notches is acceptable provided that there are still 2 notches on each of the 4 sides of the package (a total of 8 notches), that the placement does not affect the functionality of the tear-notch, and that the placement does not interfere with the placement of the rectangular orientation tab on the Gray Safety Release end of the package.

Test:

Dimensional and Visual Analysis

Pouch as Received n/a n/a n/a X n/a Current drawing/specifi cation at Quality Control Incoming inspection lot acceptance of

CHP

Current drawing/specifi cation at Quality Control Incoming inspection lot acceptance of

CHP

Page 21 of 31 Pages

LP

Test PF

Test PI Test DT

Test ET Test AQL

Level

ANSI/

ASQ Z1.4

Room Temperature

Requirement:

Each auto-injector shall be packaged in a chemically-hardened pouch (CHP), which is capable of protecting the drug solutions from light as demonstrated through an ICH light test while allowing the label to be read from the outside and light blockage verification.

Test:

Tested per ICH guidelines and MMT protocol.

Tested for UV light (%T) Black Print (<15% at 200-800nm) Amber Print (45-65% at 800nm)

X n/a n/a n/a n/a n/a n/a

Temperature Range Operability

Requirement:

The CHP shall be operable in an ambient temperature range of 0 - 50°C.

Test:

Unit shall be stored at 0ºC ± 2ºC for 24 hours and tested in accordance with Method 502 (I) of MIL-STD-810E. Auto-injectors shall also be stored at 50ºC ± 2ºC for 24 hours and tested in accordance with Method 501 (I) of MIL-STD-810E.

Test performed as a unit n/a X X n/a n/a 0.65 Level I

Temperature Shock

Requirement:

The CHP shall meet specified requirements after exposure.

Unit shall be tested in accordance with MIL-STD-810E, Method 503. The low temperature extreme shall be -21.1°C ± 2ºC and the high temperature extreme shall be 54.4°C ± 2ºC.

n/a X X n/a n/a 0.65 Level I

High and Low Temp Storage (Accelerated Aging) n/a X X n/a n/a 0.65 Level I

Page 22 of 31 Pages

LP

Test PF

Test PI Test DT

Test ET Test AQL

Level

ANSI/

ASQ Z1.4

The CHP shall meet specified requirements after exposure.

Test:

Unit shall be subjected to low temperature of -51°C ± 2ºC for 24 hours, and then shall be subjected to a high temperature of 71°C ± 2ºC for 24 hours.

Rough Handling: Shock

Requirement:

The CHP shall meet specified requirements after exposure.

Test:

Unit shall be subjected to the shock test performed in accordance with MIL-STD- 810E, Method 516. At height of 48 inches (122 cm), the injector shall be dropped 3 times on needle end and on side onto a 2 inch thick wood surface.

n/a n/a X n/a n/a 0.65 Level I

Rough Handling: Vibration Test/Loose Cargo

Requirement:

The CHP shall meet specified requirements after exposure.

Test:

Intermediate package shall be subjected to the vibration test (loose cargo) in accordance with MIL-STD-810E, Method 514, Test Procedure III: Package Tester. 5 Hz (300 rpm), duration 3 hours (0.5 h/side), amplitude 1 inch (25.4 mm), double amplitude, circular motion.

n/a n/a X n/a n/a 0.65 Level I

Ability to Withstand High Altitude (Low Pressure)

Requirement:

The CHP shall maintain integrity when subjected to a simulated altitude of 15,000 feet.

Test:

Place the unit in a suitable vacuum chamber and reduce the pressure to 400 mm mercury absolute and maintain the

. n/a n/a X n/a 0.65 Level S-4

Page 23 of 31 Pages

LP

Test PF

Test PI Test DT

Test ET Test AQL

Level

ANSI/

ASQ Z1.4

pressure for at least one hour. Return the pressure to normal for at least one hour.

Repeat the pressure cycle 3 times (total of 4 cycles). Remove the unit from the chamber and visually examine for leakage of CHP.

LP=Light Protection, PF=Pouch Flexibility, PI=Pouch Integrity, DT=Dimensional Testing, ET=Ease of Tearing

5. RELEASE TESTS

Table 7 describes the chemical and microbiological testing performed during the Release Process.

5.1. Table 7: Chemical and Microbiological Specifications at Release of Basic Units

Test Pralidoxime Chloride Release Limits

Requirement:

The solution shall be tested in accordance with the Assay, Identification, Color, Clarity, and pH tests for Pralidoxime Chloride Injection specified in the NDA.

Pralidoxime Chloride Assay 300.0 – 360.0 mg/mL

Benzyl Alcohol Assay 18.0 – 22.0 mg/mL

Total Impurities Per the NDA

Clarity Clear, Free of Visible Particles

Color Yellow Solution pH at 25o C 2.2 – 2.8

Identification (Pralidoxime) Conforms

Page 24 of 31 Pages

Test Atropine Release Limits

The solution shall be tested in accordance with the Assay, Identification, Color, Clarity, and pH tests for Atropine Injection specified in the NDA.

Atropine (Base) Assay 2.84 – 3.14 mg/mL

Phenol 3.0 – 4.2 mg/mL

Clarity Conforms

Color Conforms pH at 25o C 4.0 – 5.0

Identification (Atropine) Conforms

Total Impurities Per the NDA

Test Combined Solution Release Limits

The solution shall be tested in accordance with the Particulate Matter, Bacterial Endotoxin and Sterility tests for ATNAA Injection (combined solution) specified in the NDA.

Particulate Matter NMT 6,000 ≥ 10µ NMT 600 ≥ 25 µ per container

Sterility

Requirement:

A certificate of sterility listing all lot or control numbers shall state that samples from each sterility lot have been tested in accordance with the USP method and found to be sterile.

Sterile

Bacterial Endotoxin NMT 43.2 EU/mL

Page 25 of 31 Pages

Table 8 describes the functional testing performed during the Release Process.

Sampling for tests such as Activation Force, Dispensed Volume, Dispensing Time and Extended Needle Length (NEL) after Dispensing, for the purpose of manufacturing lots release, shall be done on a lot per lot basis.

5.2. Table 8: Functional Testing at Release

Functional Tests (each lot) at Room Temperature Specification AQL

Level

ANSI/

ASQ Z1.4

Activation Force (AF)

Requirement:

Subsequent to arming, the auto-injector shall activate on application of not less than 2 pounds and not more than 8 pounds of force applied axially to the end housing the needle (the green end). The front end of the injector shall not become dislodged during activation.

Test:

Remove the Gray Safety Release from the injector.

Place the injector in a suitable device capable of applying and measuring required loads. Apply a load axially to the injector with the least possible impact and increase the load until the injector is activated. Examine the injector to determine if the front end has become dislodged during activation.

2.0 – 8.0 lbs 0.65 Level I

Dispensed Volume (DV)

Requirement:

When activated the auto-injector shall deliver 2.43 –

2.97 mL of the drug solutions in a single injection while keeping the drug solutions separate in the injector and allowing minimal mixing within the injection site.

Test:

Using a suitable apparatus, activate the injector and determine the Dispensed Volume dispensed by weight, corrected for specific gravity.

2.43 – 2.97 mL 0.15 Level I

Dispensing Time (DT)

Requirement:

The auto-injector shall dispense 2.43 – 2.97 mL of medication during a test period of not more than 7.0 seconds from the time of activation.

Test:

While measuring volume, measure to the nearest second, the time between the start of flow and the stop of the flow of medication from the needle.

NMT 7.0 seconds 0.65 Level I

Page 26 of 31 Pages

Functional Tests (each lot) at Room Temperature Specification AQL Level

ANSI/

ASQ Z1.4

Needle Extended Length (NEL) after Dispensing

Requirement:

The ATNAA needle extended length after firing at room temperature shall be 18 to 23 mm.

Test:

Using suitable apparatus activate the injector. After the medication has stopped flowing from the needle, measure the length of the needle protruding from the injector to the nearest millimeter.

18-23 mm 0.65 Level I

AF=Activation Force, DV=Dispensed Volume, DT=Dispensing Time, NEL= Needle Extended Length

Table 9 describes the defect testing performed at Release.

5.3. Table 9: Classification of Defects at Release

Defect Testing (each lot) at Room Temperature

Specification AQL Level

ANSI/

ASQ Z1.4

Needle Gauge

Requirement:

The needle through which medication shall be delivered shall be 23 gauge, AISI 304 stainless steel. The needle shall be siliconized using Medical Grade Silicon Oil.

23 gauge NA Per Supplier

Certification upon

Incoming QC Testing

Sampling for Missing Needle Conforms 0.065 Level I

Sampling for Missing Medication Conforms 0.065 Level I

Sampling for Missing or Illegible Label or Markings

Conforms 0.065 Level II

Workmanship

Requirement:

Workmanship shall be first-class throughout.

The auto-injector shall be free from defects which detract from its appearance and impair its serviceability.

Conforms 2.5 Level II

Clarity Solution is essentially clear and free from undissolved or foreign particulate matter

1.0 Level II

CHP Characteristics 4.0 Level II

Page 27 of 31 Pages

Table 10 describes the testing required to ensure labeling and marking requirements are met at the time of Release.

5.4. Table 10: Labeling and Marking Requirements at Release

Labeling and Marking Testing (each lot) Specification AQL

ANSI/

ASQ Z1.4

Unit

Requirement:

Each auto-injector shall be marked as specified in 2.7.

In-process QC Visual Inspection

Conforms

0.04

Level II

Unit Container (CHP)

Requirement:

Markings identifying the contents are not required on each tamper-evident bag (see 2.5), provided all markings on the auto-injector are legible, except the statement "TEAR OPEN AT ANY NOTCH" shall be printed on each bag. Placement of this statement shall not interfere with visibility of the auto-injector markings through the bag.

Intermediate Package

Requirement:

Each intermediate package shall be marked as specified in Medical Marking Standard No. 1. Marking shall include the lot (control) number and expiration date and the legend:

“STORE AT 25ºC (77ºF); EXCURSIONS PERMITTED TO

15º - 30ºC (59º - 86ºF) (SEE USP CONTROLLED ROOM

TEMPERATURE). KEEP FROM FREEZING. PROTECT

FROM LIGHT.” or other similar commercial legend, may appear.

Exterior (Shipping) Container and Unitized Load

Requirement:

Each exterior (shipping) container and unitized load shall be marked as specified in Medical Marking Standard No. 1.

Marking shall include the lot (control) number and expiration date and the legend: “STORE AT 25ºC (77ºF);

EXCURSIONS PERMITTED TO 15º - 30ºC (59º - 86ºF) (SEE

USP CONTROLLED ROOM TEMPERATURE). KEEP FROM

FREEZING. PROTECT FROM LIGHT.” or other similar

Page 28 of 31 Pages

Labeling and Marking Testing (each lot) Specification AQL

ANSI/

ASQ Z1.4

commercial legend, may appear.

In-process OC Visual Inspection

Table 11 describes the testing required to ensure packaging requirements are met at the time of Release.

5.5. Table 11: Packaging Requirements at Release

Packaging Testing (each lot) Specification AQL

ANSI/

ASQ Z1.4

Unit

Requirement:

One auto-injector, in CHP, constitutes one unit. Each auto-injector shall be packaged as specified.

Instructions for use (see IFU specs) shall be supplied with each auto-injector.

4.0

Contents Per Exterior Shipping Container Not As Specified

Conforms 4.0 Level II

Exterior (Shipping) Container Damaged Conforms 4.0 Level II

Intermediate Package

Requirement:

100 individually packaged ATNAA auto-injectors, together with 100 copies of the instructions for use, shall be packaged in a box of appropriate size conforming to ASTM D 5118, class weather resistant.

Closure shall be as specified in ASTM D 1974, Closure Method 1D. Each fiberboard box shall be water-resistant as specified in ASTM D 1974.

Test:

In-process QC Visual Audit or Weight Check

Conforms 4.0 Level II

Exterior (Shipping) Container

Requirement:

Packing shall be level M10. Two intermediate packages (200 units) shall be packed in an exterior container designed for a type 2 load and conforming to ASTM D 5118, class weather-resistant. Closure shall be as specified in ASTM D 1974, Closure Method 1D. Each fiberboard box shall be water-resistant as specified in

4.0

Page 29 of 31 Pages

Packaging Testing (each lot) Specification AQL

ANSI/

ASQ Z1.4

ASTM D 1974.

If the required number of units to be shipped is less than the number of units specified to be over-packed in an exterior (shipping) container, such units shall be packed in an exterior (shipping) container of suitable size and design, conforming to the requirements above.

Material shall be unitized as specified in the contract or order.

In-process QC Visual Audit

6. STABILITY TESTS

Table 12 describes the chemical and microbiological testing performed during the Initial Qualification Process.

6.1. Table 12: Chemical and Microbiological Specifications During Stability Testing

Test Pralidoxime Chloride Solution Stability Limits

Requirement:

The solution shall be tested in accordance with the Assay, Identification, Color, Clarity, and pH tests for ATNAA Injection specified in the NDA.

Pralidoxime Chloride Assay 270.0 – 360.0 mg/mL

Total Impurities Per the NDA

Clarity Clear, free of visible particles

Color Yellow Solution pH at 25o C 2.0 – 3.0

Test Atropine Solution Stability Limits

The solution shall be tested in accordance with the Assay, Identification, Color, Clarity, and pH tests for ATNAA Injection specified in the NDA.

Page 30 of 31 Pages

Atropine (base) Assay 2.69 – 3.44 mg/mL

Total Impurities Per the NDA

Clarity Clear, free of visible particles

Color Not darker than color std pH at 25o C 4.0 – 5.0

Test ATNAA (Combined Solution) Stability Limits

The solution shall be tested in accordance with the, Sterility, Particulate Matter and Bacterial Endotoxin Tests for ATNAA Injection specified in the

NDA.

Particulate Matter NMT 6000 ≥ 10µm size

NMT 600 ≥ 25µm size

Bacterial Endotoxin Content NMT 43.2 EU/mL

Sterility

Requirement:

A certificate of sterility listing all lot or control numbers shall state that samples from each sterility lot have been tested in accordance with the USP method and found to be sterile.

Passes Test

7. RE-QUALIFICATION TESTS

Re-qualification is defined as any qualification activity performed to demonstrate compliance with the MPID after Initial Qualification has been demonstrated by the contractor.

Re-qualification can be demonstrated on reduced batch sizes. Sampling plans and sampling sizes for re-qualifications will be based on reduced batch size stated in re-qualification protocol documents (not less than 25 units per test).

Re-qualification activities will concentrate on only the item, component, assembly or package subject to change. The contractor will determine and justify the appropriate testing and rationale needed for each change in a formal Validation/Qualification document. A full re-qualification will be performed on an interval not to exceed 5 years

Page 31 of 31 Pages from previous full qualification.