ABSTRACT

The design of extractables and leachables studies for Pre-Filled Syringes depends on the intended application. Therefore, every specific case requires a tailor-made study set-up.

This presentation will initially discuss the basic definitions of extractables and leachables, before going over the most important regulatory guidelines, on to the actual design of the E/L studies.

It will focus on the most important variables to consider (type of extraction solvents, material-to-solvent ratio, temperature, extraction times…) and how to obtain correct and useful extractable information for further assessments.

Subsequently, it will demonstrate how the list of obtained extractable compounds can be narrowed down to a list of target compounds that can be subjected to a toxicological assessment or be used in a targeted leachable study. In a last part, the set-up and time line of leachable studies for pre-filled syringes will be explained and illustrated.

The editorial activities of new ISO standards and the revision of existing are continuously on going.

With his presentation, Andrea Salmaso, member of the ISO TC76 WG2 (Rigid container systems and related accessories for Parenterals and injectables) for several years, updates on the latest news about applicable ready to use ISO standards for glass syringes, cartridges and vials.

Starting from the analysis of the contents of the ISO 11040-8 published in 2016 the aim of the speech is to take a look on the general requirements of the standard and on the test methods listed in it by reference to other ISO standards (ISO11040-4, ISO80369, ISO7886)

Will be discuss the contents of the new ISO Working Draft (ISO/WD 21881 and ISO / WD 21882) respectively related to "Sterile packaging for ready for filling Cartridges" and "Sterile packaging for ready for filling vials" that are being prepared and that will be published over the next few years.

Pharmaceutical manufactures recognize that the drug primary packaging is not a background decision to take just before the market launch: the rationalized selection of the proper container-closures system can make the difference in terms of drug stability, safety and efficacy.

Improved manufacturing processes as well as new coating concepts and materials are some of the keys to successfully develop and offer high quality and high performance primary packaging.

At the same time, research efforts are spent to detect, mitigate and reduce the potential risk linked to the interaction between the packaging components and the drug product.

-To take care of what is inside our product- is a quality milestone of OMPI mission, therefore glass delamination should be considered one of the critical topic having a concrete influence on the final quality of the drug product.

Data Integrity Assurance is becoming an urgent and hot topic in the pharmaceutical industry.

The recent updates from regulatory authorities have indicated the future trend of inspections, which will be globalized and much be focus on Data Integrity issues.

We are going to discuss the following topics:

• Data Integrity and Computerized System Validation: its regulatory background;
• Comparison between US 21 CFR PART 11 vs. EU GMP ANNEX 11;
• Data Integrity by US:
  • Concepts and Interpretation
  • FDA Draft Guidance – Data Integrity and Compliance with cGMP
• Data Integrity by EU:
  • Concepts and Interpretation
  • MHRA Guidelines (March 2015) Analysis
• WHO International Guidance
• Recent Inspections and Observations Excerpts

Furthermore, we will bring some thoughts in how to achieving good Data Governance and maintaining the quality units aligning with the ever-growing requirement from regulatory authorities and future global coalitions of the inspectors.

Even though we might create more questions and concerns before our audience walking into this symposium, we wish to plant a seed that every attendee can consider Data Integrity is a MUST thing on their prioritized To-Do-List.

Implementation of a structural solution will be the top choice instead of putting in place of some interim actions, which can be and will be challenged time by time.

• Current and future market requirements for fill&finish CDMO’s from development to mid size commercial quantities
• Product/process requirements
• Regulatory and safety requirement

The ISO standard 11040-8:2016 was published 2016-11-04.

The standard presents test methods used for prefilled syringes that are already available for the sub-assembled pre-fillable syringes as components. However, the recent publication focuses on the filled syringe.

The tests should be carried out with the actual drug and the actual rubber plunger. The tests should include system characterization where critical dimensions are mentioned. Importantly, the rubber plunger changes its dimensions when placed into the syringe barrel.

Placement of the plunger is important as it is an interface between the syringe and the needle based injection system, so the backside of the plunger should be measured using the relevant datum surfaces. The ISO 11040-8:2016 gives examples of this in notes.

The presentation will show how extrusion forces and extrusion times can be measured and the theoretical equation of Hagen–Poiseuille can be used to visualize the data.

For performance requirements, the break loose and extrusion forces shall be measured using the method described in ISO 11040-4:2015.

The Glide force test method should be used to evaluate syringe lubrication. In the informative annex one test speed of 100 mm/min is mentioned, but this slow speed might not be relevant for the behavior during the actual use.

The visualizing will also include the effect of the power pack forces and one point measurement as release specification of syringe batches.

Importance in understanding Extractables and Leachables (E&L) associated with packaging and container systems for parenteral drugs.

Regulatory guidances and the recommended approach for an E&L evaluation: Pre-planning and component selection, gap assessment and evaluation, Risk assessment and leachable analysis.

The pharmaceutical demands on machine manufacturers are steadily increasing. In the recent past, clean room classifications (RABS / isolators) and sterilization processes (UV / H2O2 / Plasma / e-beam) were the main focus.

Today dosing systems (rotary piston pump, time pressure, peristaltic pump) and stoppering are of great importance. Another trend of prime importance is the demand for automatic and 100% IPC.

Nested syringe machines must thereby provide a wide variety of performance options. Established syringe manufacturers are now offering nested cartridges and vials. Machine manufacturers need to act on such trends with sophisticated and flexible solutions.

All these objects are supplied pre-sterilized in trays. Multi use filling machines for ready-to-use components are the new trend in the pharma industry.

Today smaller batch size and higher value products are used compared to previous larger batch sizes.
The big challenge when developing a syringe processing line is the handling of different objects such as syringes, vials and cartridges on a single machine.

Optima pharma has realized the demands and has established a high flexibility to process ready-to-use components on one machine (Multi use filling machines).

In order to successfully construct the MultiUse Filler and to secure the machine concept, simulation of airflow conditions (virtual application) were used. Through this, the high development costs were saved.

The improved collection of data and targeted analysis increasingly helps improve the technical developments in the area of sterile rooms and isolators in which the airflow plays a key role.

The high level of complexity and dynamics of these processes alleviates the predictions of the airflow in such highly complex MultiUse fillers.

Weaknesses in design or problematic areas can be found early on due to the visual depiction of the airflow. The future lies in the virtual representation of machines within this industry.