Best Practices – Injectable Packaging Lines

Manish Bhatkar Hyderabad 11th Nov. 2016

Best Practice A best practice is a method or technique that has been generally accepted as superior to any alternatives because it produces results that are superior to those achieved by other means or because it has become a standard way of doing things, e.g., a standard way of complying with legal or ethical requirements.

Best practices are used to maintain quality as an alternative to mandatory legislated standards and can be based on self-assessment or benchmarking. Best practice is a feature of accredited management standards such as ISO 9000 and ISO 14001.

Reference: https://en.wikipedia.org/wiki/Best_practice

Injections – USP <1> Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion.

Parenteral articles are prepared scrupulously by methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of the growth of microorganisms. An Injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration.

Injections Market – Trends & Drivers ¨  Industry Focus Shift (Oncology, Biologics)

¨  Novel Drug Delivery Systems (Gaining Prominence)

¨  $312 Bn. (2014) à $363 Bn. (2017)

Packaging Best Practices – Trends & Drivers

¨  Quality Expectations – WL’s, Import Alerts/ Bans

¨  Regulatory – Requirements (Dose Count, Needlestick Legislation)

¨  Regulatory Scrutiny – Approval Delays

¨  Cost Pressure – Margins (Standard, Simple & Robust Pkg. Solution)

¨  Drug Requirements – Complexity (Simple & Safe Administration)

¨  Self-Injection Technology – Patient Focused Care

¨  Supply Chain – Need for Risk Mitigation

Packaging Best Practices – Basis

Packaging Best Practices – Basis

Injectable Packaging Process

Checks Incoming Material

Formulation Filling

& Sealing

Labeling

Sterilization

Visual Inspection Packaging

Checks Finished Product

Washing &

Cleaning

Best Practices – Selection of PPM’s

q  Protection

Stability test conditions

q  Commercial Image Market requirements/trends Dosing/patient compliance Security/tamper evidence

Manufacturing Economics – COG

BASIC REQUIREMENTS

q  Legislation

E.g. EC Packaging and Packaging Waste Directive

q  Compatibility q  Regulatory

q  Corporate Global Quality Policies

Best Practices – Selection of PPM’s How the product will be used?

¤  Single-Dose Container (Vials, Ampoules & PFS)

¤  Multiple-Dose Container (Vials)

¤  Single-Patient-Use Container (Cartridges & Pens for Injection)

Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-

Use Containers for Human Use - Draft Guidance for Industry, Oct. 2015

Best Practices – Selection of PPM’s How the PPM’s will be sterilized? ¤  Saturated Pure Steam ¤  Gamma Irradiation

The sterilization process transfers a significant quantity of energy (heat or radiation) into the elastomer material that can initiate a variety of chemical reactions. These reactions have the potential to change;

¨  The quantity of compounds present in the closures and/or create new compounds, thus changing the extractable/leachable profile of the closure,

¨  Cross-linking reactions results in increasing the tensile strength, hardness, modulus, and compression set, while elongation is reduced.

¨  Sheds particles and yellowing on radiation.

Best Practices – Selection of PPM’s How the PPM’s will be sterilized?

Review Article - Reducing the Risk of Contamination of Sterile Parenteral Products via Ready-to-Use Closure Components by Wayne Curry, Samuel Conway, Clara Goodfield, Kimberly Miller, Ronald L. Mueller, and Eugene Polini. AAPS PharmSciTech, Vol. 11, No. 4, December 2010.

Best Practices – Selection of PPM’s Appropriate for the intended use (ideal fit between CC to ensure sterility throughout the product shelf-life)?

CPP’s: (1) Use of appropriate materials, (2) Matching dimensional fit, and (3) Validated assembly parameters

CQA’s: System fit

Basis: (1) Dimensional checks, (2) Visual verification, (3) CCIT – for presence of leak, leak rate & integrity over shelf-life

Establishes: (1) CC specifications, (2) Routine operating parameters, and (3) CCI over the product shelf-life

Best Practices – Selection of PPM’s Product & CCS Compatibility

CPP’s: (1) Use of appropriate materials, (2) Quality audits, (3) TA, (4) Trending of incoming CC items test results, and (5) Change control, (6) Management Reviews

CQA’s: Physico-chemical characteristics of the product

Basis: (1) USP 1660 – inner surface durability, (2) Product stability over shelf-life

Establishes: (1) CC specifications, (2) Routine QC test, and (3) CC & product compatibility over the product shelf-life

Best Practices – Selection of PPM’s Problem: Stoppers popped-up post stoppering on of the vials.

When: MF to support introduction of new vial (15mL, 20mm neck size, molded glass vial) to be combined with an existing elastomeric stopper (Chlorobutyl, 20mm, single leg Lyo. Stopper).

Root cause: (a) short neck of the molded vial in comparison to the same capacity tubular vial, and (b) single leg of the Lyo. elastomeric stopper

Same elastomeric stopper successfully used on 10mL, 20mm neck size tubular glass vials. Due to, comparatively short neck size of the 15mL molded glass vial the elastomeric stopper could not expand uniformly inside the vial neck.

A Case

Packaging Best Practices – Trends & Drivers

¨  Quality Expectations – Visible Particulate Matter

¨  Regulatory – Requirements

¨  Regulatory Scrutiny – Approval Delays

¨  Cost Pressure – Margins (Cost of Components Processing – Capex & Opex)

¨  Drug Requirements – Complexity (Custom Component Preparation Equipment)

¨  Self-Injection Technology – Patient Focused Care

¨  Supply Chain – Need for Risk Mitigation

Purpose: Reduction of Bio-burden, Pyro-burden and Particulate Matter

CPP’s: (1) Use of Appropriate Cleaning Agents – Final Rinse with WFI, (2) Quality of Cleaning Agents, (3) Trending of Incoming CC items for Bio-burden, Pyro-burden, Particulate Matter – Extent and Characteristics, and (4) Change Control, (5) Management Reviews

CQA’s: Validated In-process Control Limits

Basis: Washing/ Cleaning Process Validation

Establishes: (1) Washing Process Controls, (2) Routine In-process Checks, and (3) Process Capability Index

Best Practices – Washing & Sterilization of PPM’s

Best Practices – Washing & Sterilization of PPM’s

Purpose: Sterilization @ Desired SAL

CPP’s: (1) Use of appropriate Sterilizing Agent – Saturated Pure Steam, Dry Heat, Irradiation, (2) Quality Monitoring of Sterilization Agents, (3) Change control, and (4) Management Reviews

CQA’s: Sterilization Cycle Capability to achieve the desired/ validated Sterility Assurance Level – SLR

Basis: (1) Comparison of Each Cycle Chart with Standard Validation Cycle Chart, and (2) Comparison of Sterilization Cycle Lethality – F0

Establishes: (1) The Sterilization Cycle Specification, and (2) Sterilization Cycle Process Capability

Best Practices – Washing & Sterilization of PPM’s

A Case

The temperature and duration required for the heat sterilization method will damage the elastomeric closures and render them unusable.

Best Practices – Washing & Sterilization of PPM’s

A Case

Vial Washing Process Validation is Based on Capability to Remove:

¨  Salt

¨  Charcoal

Not a Risk Based Approach !!!

Packaging Best Practices – Trends & Drivers

¨  Quality Expectations – Visible Particulate Matter

¨  Regulatory – Requirements

¨  Regulatory Scrutiny – Approval Delays

¨  Cost Pressure – Margins (Cost of Components Processing – Capex & Opex)

¨  Drug Requirements – Complexity (Custom Component Preparation Equipment)

¨  Self-Injection Technology – Patient Focused Care

¨  Supply Chain – Need for Risk Mitigation

Reduction of Interventions & Aseptic Manipulations – Sterility Assurance, Particulates Matter, and Dose Accuracy

CPP’s: (1) Design & Selection of PPM’s – PPQ Studies, PST (2) Trending of Incoming CC items for Defects/ Dimensions, (3) Change Control, (4) Management Reviews

CQA’s: Continuous Verification: (1) PPM Specifications – Established Specifications, (2) Aseptic Interventions – Frequency

Basis: (1) PPQ Studies – Engineering/ Material Feasibility, (2) IP Checks – Fill Accuracy

Establishes: (1) Incoming Material Controls, (2) Routine In-process Checks, and (3) Process Capability Index

Best Practices – Filling, Sealing & Visual Inspection

Best Practices – Filling, Sealing & Visual Inspection

Future Trends – Injectable Packaging Line

¨  Reducing Contamination During Processing – (Pre)washed, sterilized, de-pyrogenated containers and closures

¨  Reducing Cost (capex & opex) – Avoiding multiple unit operations, such as washing, sterilization & de-pyrogenation

¨  Reducing Regulatory Review Time – Approval Delays

Future Trends – Injectable Packaging Line Open Close

Future Trends – Injectable Packaging Line

Blow/ Form Fill & Seal

Future Trends – Injectable Packaging Line Limited Versatile

Future Trends – Injectable Packaging

¨  Growth and competition in injectable markets ¨  Use of biologics drugs ¨  Global demand for vaccines ¨  Need of drug delivery in non-medical settings ¨  Focus on more efficient drug administration ¨  Ease of Administration ¨  Compliance – patient as well as regulatory ¨  Differentiaion

Future Trends – Injectable Packaging

Formulation Device

Future Trends – Injectable Packaging (Ease of Administration)

¨  Vetter’s dual chamber technology, LyoJect® syringe and dual chamber VLK® cartridge allows the differing ingredients and solvents to be prefilled and stored separately, then easily mixed and administered as needed just prior to administration. This help mitigate the residual risk of needle stick injuries allowing non professionals like patients and family members to safely use the device, in non-clinical setting.

¨  Watson Pharmaceuticals + West Pharmaceutical Services, Inc. developed a safe and convenient West’s MixJect® drug transfer device. This device provides ease of reconstitution with a diluent prior to injection by syringe. The entire process makes administration and disposal significantly easier and safer for patients and caregivers.

Future Trends – Injectable Packaging (Human Factor, Convenience)

¨  Integrating Human Factor in the Device Development

¨  Aptar Pharma ProJect® is a novel auto injector

¨  Confirmed benefits of ProJect in terms of ease of use, ergonomics, and design

¨  Features include push on skin activation, slow injection, hidden needle, highly visible indicator window, and audible feedback

Future Trends – Injectable Packaging (Human Factor, Needle Safety)

¨  Credence Companion offers the bio-pharm product manufacturers a new option to differentiate their products by delivering to their patients and caregivers the best technologies available.

¨  The cover allows easy attachment by dexterity-challenged users as well. Needle can be attached by holding the cover in a fist or in a thumb/forefinger wedge.

¨  Once attached the user receives audible, tactile, and visual feedback of a successful needle to syringe connection.

¨  At the completion of the injection, the needle automatically retracts into the syringe barrel and the syringe is automatically disabled.

Future Trends – Injectable Packaging (Patient Compliance & Self-use)

¨  West SmartDose® electronic wearable bolus injector.

¨  The single use, disposable system cGMP manufactured.

¨  Utilizies a Daikyo Crystal Zenith® polymer cartridge along with Flurotec® barrier filmcoated elastomers as the primary container.

¨  Designed for high volume (>1mL) and/or high viscosity protein formulations for subcutaneous bolus administration.

¨  The SmartDose injector can extend the time between dosing and may improve patient compliance (versus daily injections).

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