Importance of Container Closure Integrity in Autoinjector

Minuk Kim, Samsung Bioepis 2

Drug? Device? Combination Product! - Combinations of drugs, devices, and/or biological products device (FDA) - Drug-device combinations (EU MDR)

➢ Combination Product (FDA)

Single entity Co-packaged Cross labelled (Combined into one) (Solid together) (Dependent)

➢ Drug-Device Combinations (EU MDR) Pre-filled syringe Needle safety device Autoinjector Syringe pre-filled with drug Automatic needle cover Automated needle insertion and injection

FDA QSR (Quality System Regulation) ❖ FDA has provided two options for manufacturers to comply with 21 CFR Part 4 ➢ Option 1. Establish a quality system to comply with both 21CFR211 & 21CFR820 ➢ Option 2. Establish a quality system to comply with cGMP requirement

If cGMP system is based on 21 CFR 211 (Pharmaceuticals), If cGMP system is based on 21 CFR 820 (Medical Devices), then also demonstrate compliance with: then also demonstrate compliance with:

§820.20 Management responsibility §211.84 Testing and approval or rejection of components, drug product containers, and closures

§820.30 Design controls §211.103 Calculation of yield

§820.50 Purchasing controls §211.132 Tamper-evident packaging requirements for over the counter (OTC) human drug products

§820.100 Corrective and Preventative Actions (CAPA) §211.137 Expiration dating

§820.170 Installation §211.165 Testing and release for distribution

§820.200 Servicing §211.167 Special testing requirements

§211.170 Reserve samples

EU MDR (Medical Device Regulation): May 2021

❖ Device Related Module in EU CTD (As-Is) ❖ Device Related Module in EU CTD (To-Be)

Module 3.2.P Drug Product (Device) Module 3.2.P Drug Product (Device) 3.2.P.7 Container Closure System 3.2.P.2 Pharmaceutical Development 3.2.P.7.1 Pre-filled Syringe 3.2.P.2.3 Manufacturing Process Development 3.2.R.7.2 Pre-filled Pen 3.2.P.3 Manufacturer

Module 3.2.R Regional Information (Device) 3.2.P.3.1 Manufacturers 3.2.R.2 Medical Device 3.2.P.3.3 Description of Manufacturing Process and Controls 3.2.R.2.1 Introduction 3.2.P.3.4 Control of Critical Steps and Intermediates 3.2.R.2.2 Description and Composition of PFP 3.2.P.3.5 Process Validation and/or Evaluation 3.2.P.5 Control of Drug Product 3.2.R.2.3 PFP Development 3.2.P.5.1 Specifications 3.2.R.2.4 Manufacture 3.2.P.7 Container Closure System 3.2.R.2.5 Control of PFP 3.2.P.8 Stability 3.2.R.2.6 Stability Module 3.2.R Regional Information (Device) 3.2.R.2.7 Attachments 3.2.R Regional Information Article 117 GSPR checklist and Notified Body opinion

*Reference: Draft guideline on the quality requirements for drug-device combinations_29 May COPYRIGHT © PDA 2018 2019_EMA/CHMP/QWP/BWP/259165/209_Committee for Medicinal Products for Human Use (CHMP) 5

Autoinjector Development

Autoinjector development process in compliance with ISO 13485, ISO 14971, 21CFR820.30, and MDR Article 117

Design & Concept Planning Engineering Validation Commercialization Development Post- Implemen Design Design Process Concept Planning Design Development Launch Production -tation Verification Transfer Validation Support

Design Control Waterfall Model Human Factor Engineering Design History File (DHF)

Autoinjector Development

FINISHED MEDICAL DEVICE

❖ Design Verification according to ISO 11608-1 ISO 11608-1 Table 3. Test matrix

ISO 11608-1 Table 1. System designations

Benepali™ (SB4) Autoinjector

Imraldi™ 2 (SB5) Autoinjector 1

3 6

4,5

1. Thakur K, Biberger A, Handrich A, et al. Patient Perceptions and Preferences of Two Etanercept Autoinjectors for Rheumatoid Arthritis: Findings from a Patient Survey in Europe. Rheumatol Ther. 2016; 3:245-256. 2. Pachon J, Kivitz A, Heuer K, et al. Assessing usability, label comprehension, pen robustness and pharmacokinetics of a selfadministered prefilled autoinjector pen of methotrexate COPYRIGHT © PDA 2018 in patients with rheumatoid arthritis. SAGE Opne medicine. 2014; 1-12. 3. Brazeau G, Cooper B, Svetic K, et al. Current Perspectives on pain upon injection of drugs. Pharmaceutical Sciences. 1998; 87(6): 667-77. 4. Glenski S, Conner J. 29 gauge needles improve patient satisfaction over 27 gauge needles for daily glatiramer acetate injections. Drug, Healthcare and Patient Safety. 2009; 1: 81-6. 5. Berteau C, Filipe-Santos O, Wang T, et al. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Medical Devices: Evidence and Research. 2015; 8: 473-84 6. Wu M, Mcintosh J, Liu J. Current prevalence rate of latex allergy: Why it remains a problem?. Occupational Health. 2016; 58: 138-44. 10

Aseptic Manufacturing Non-Aseptic Manufacturing : Drug Substance & Drug Product : Secondary container – Autoinjector

Autoinjector Assembly

Thawing + + = Syringe filling

DS bags

Sterile Filtration Device component + Drug Product + Device component = Final assembled (Front part) (Rear part) Combination product

• How to ensure that the drug product has not been exposed to non-sterile condition? Pooling & mixing → Container closure integrity test (CCIT)

Definition of CCIT

• Container Closure Integrity Testing (CCIT) is an assay that evaluates the adequacy of container closure systems to maintain a sterile barrier against potential contaminants.

• Contaminants that could potentially cross a container closure barrier include microorganisms, reactive gases, and other substance.

• CCIT is commonly referred to as leak detection.

• Leak: There are many risks associated with glass, including issues such as breakage, delamination, leachable, and physical and chemical compatibility with the drug product itself that can affect the safety and efficacy of a pharmaceutical product.

*Reference1: USP <1207>, Sterile Product Packaging – Integrity Evaluation COPYRIGHT © PDA 2018 *Reference2: FDA Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products 12

Leak test methods

• Bubble test • Residual gas ionization • Helium mass spectrometry • Tracer gas leak detection • High voltage leak detection (HVLD) • Ultrasonic detection of gas flow • Lid deflection • Ultrasonic imaging • Liquid tracer • Vacuum/pressure decay • Microbial challenge, aerosolization • Vacuum/pressure retention • Microbial challenge, liquid immersion • Visual inspection • Package headspace analysis • Volumetric gas flow • Particulate transmission • Weight loss/gain

CCIT Methods

Leak Detection Range Test Method Measurement Outcome (For reference only) Bubble emission Bubble by visual inspection N/A Microbial challenge Growth promotion by visual inspection > 0.2 μm Probabilistic Gas tracer (sniffer mode) Gas detection by visual inspection N/A Minimum detectable dye concentration by Dye ingress > 20 μm visual inspection

High-voltage leak detection (HVLD) Electrical current 10-40 μm

Gas tracer (vacuum mode) Helium or Hydrogen loss 0.01-20 μm Vacuum decay Pressure rise 0.01-20 μm Deterministic Pressure decay Pressure drop 0.01-20 μm Mass extraction Mass flow > 1 μm Laser-based gas headspace analysis Gas composition or gas pressure > 0.01 μm

*Reference 1: PDA technical report No.27, Pharmaceutical package integrity (1998) COPYRIGHT © PDA 2018 *Reference 2: USP <1207>, Sterile Product Packaging – Integrity Evaluation *Reference 3: https://www.pharmaceuticalonline.com/doc/ccit-solutions-for-the-pharmaceutical-industry-0002 14

Main CCIT Method Used in Industry for Autoinjectors

Test Method Advantages Disadvantages Probabilistic Dye ingress test • Regulator familiarity • Poor sensitivity • Many samples tested at once • Not effective for PFP due to potential of trapped pockets of air in the device and difficulty in rinsing Microbial challenge test • Regulator familiarity • Long test – 2 weeks for results • Many samples tested at once • Poor sensitivity • Requires careful rinsing to avoid false positives • Not effective for PFP due to potential of trapped pockets of air in the device Deterministic Vacuum decay test • Test commonly used for PFS in production • May not be effective with viscous drug because • Good sensitivity leak may be blocked • Not effective for PFP due to potential of trapped pockets of air in the device Gas tracer test • Good sensitivity • Requires careful set up to avoid false negatives or • Same method suitable for both PFS and PFP positives • Many samples tested at once • PFP may need to be modified to allow probe access to the drug container • Location of leak can be identified

CCIT Method Selection

• Package contents (Drug product) • Package design and construction (Device design) • Seal type and location • Maximum allowable leakage limit (Sensitivity) • Method outcome • Regulatory and validation requirement • Cost versus benefit

→ Considering the above factors, Choose the most appropriate CCIT method.

*Reference 1: Parenteral Medications, Fourth Edition, Chapter 24. Parenteral Product CCIT COPYRIGHT © PDA 2018 *Reference 2: Container Closure Integrity Testing Sensitivity - D. Guazzo, “Package Integrity Testing” Chapter 4, Parenteral Quality Control, 2nd Ed.,Marcel Dekker, NYC, 19941 *Reference 3: PDA technical report No.27, Pharmaceutical package integrity (1998) 16

CCIT (Container Closure Integrity Test)

• The most important factor for Autoinjector CCIT ➢Choose the most appropriate CCIT method ➢CCIT method must be properly developed, qualified, and fit for its intended purpose ➢According to USP <1225>, valid methods should exhibit up to eight key attributes as situationally applicable; Accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness

• CCIT in Autoinjector development ➢Autoinjector assembly ➢Shipping process ➢Shelf-life

*Reference 1: Parenteral Medications, Fourth Edition, Chapter 24. Parenteral Product CCIT COPYRIGHT © PDA 2018 *Reference 2: Dye Ingress Methods for Container Closure Integrity Testing: An Industry Position Paper 17

Importance of Container Closure Integrity in Autoinjector

• Autoinjector (Pre-filled pen) is a combination product developed through compliance with Design control considering Risk management, Design verification, Design validation (Assembly performance qualification, Human factor), and etc. • Autoinjector itself is considered as a secondary container which is not in contact with drug product. • Autoinjector is assembled in a non-aseptic manufacturing condition. • During Autoinjector development, CCIT should be considered to ensure the integrity at each manufacturing simulated situation & Shelf-life. • CCIT is the easiest and the most reasonable approach to set-up non-aseptic manufacturing process of the autoinjector.

Thank You

Passion for Health

Samsung Bioepis is a biopharmaceutical company

focused on increasing patient access to high-quality medicines through the development of biosimilars.

Address : 107, Cheomdan-daero, Yeonsu-gu, Incheon, 21987 Republic of Korea

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