On 24 & 25 March, Nelson Labs Leuven hosted its first virtual symposium on Large Volume Parenteral Packaging. The PDFs of the presentations from this two-day seminar are now available. Contact [email protected] for more information.
Session 1 – Introduction to LVPS and LVP packaging
An introduction to large volume parenterals (LVPs) as a pharmaceutical dosage form and an E&L challenge
Speaker: Dennis Jenke Phd, Principal Consultant
Company: Nelson Labs
Pharmaceutical dosage forms are differentiated primarily by their route of administration and secondarily by other dosing parameters. Parenteral dosage forms are those dosage forms that are injected through the skin or other external boundary tissue, or implanted within the body, to allow the direct administration of the active drug substance(s) into blood vessels, organs, tissues, or lesions. Large-volume parenteral drug products (LVPs) are liquid parenterals that are packaged in unit doses of greater than 100 ml. LVPs are typically packaged in flexible (i.e. plastic) packaging, opening the possibility of substances that leach from the packaging and become drug product impurities. Due to their large volume and sometimes complex composition, LVPs can be difficult to test (screen) for unspecified leachables. This presentation introduces LVP’s as a pharmaceutical dosage form and introduces the concept of the AET Challenge.
Download the presentation slides here.
The development of a large volume parenteral packaging system: Things to keep in mind
Speaker: Philippe Chanson, Associate Director, Head of Materials Platform
Company: B. Braun
Administration of large volume parenteral fluids to the patient has not really changed over the past 150 years. LVP has become a commodity product distributed in large quantities around the world. This has drastically changed the way to develop and produce LVP. Low price combined with complex and high regulatory requirements make development challenging. We will present an overview of LVP development, focused on selection of packaging raw materials and components, taking into account migration requirements.
Download the presentation slides here.
Session 2 – Building an LVP from resins to commercial product
LVP polyolefin solutions addressing different packaging and regulatory requirement
Speaker: Anja Gottschalk, Application Development Engineer Healthcare
Company: Borealis
LVP can be packed in different packaging formats made from polyolefins: pouches, bottles produced in blow-fill-seal process or Injection stretch blow molding. The different packaging options drive the need for different raw materials and depending on the material, different key regulatory requirements.
This presentation will look at the different packaging formats, the materials that can be used, and their specific regulatory requirements; as well as the regulatory support available for regulated “Medical Grade Plastics.” A short overview will be given on sustainable materials to be used in such applications.
Download the presentation slides here.
The production process and qualification of film: A film manufacturer perspective
Speaker: Dr. Bianca Schweiger, Quality Control / Christian Kunz, Head of Sales
Company: PolyCine
What is needed to qualify primary packaging materials for Large Volume Parenterals? And what to consider when selecting the right material? Dr Bianca Schweiger and Christian Kunz from PolyCine, a pharmaceutical film manufacturer, give insights on the requirements for IV-solution primary packaging materials. They will discuss how these materials are produced and the regulatory requirements that apply to these materials during their presentation regarding “Production and qualification process for pharmaceutical films”.
Download the presentation slides here.
The design, manufacturing and qualification of a large volume parenteral packaging system
Speaker: Dominique Saint Ellier, QA/RA Director
Company: Technoflex
Large Volume Parenteral systems can be sold empty to pharmaceutical companies that will fill the bags with solution. The qualification of such container closure systems must conform to pharmaceutical market regulations and take into account various aspects of the product. This presentation describes the steps followed by Technoflex for validating empty flexible bags—taking into consideration the product to be placed in the bag and the applicable regulations.
To be in conformance from a physical, chemical, and biological point of view, all the components of the bags should be qualified separately before assembly and constitute the primary packaging. The manufacturing process also is an important input in qualification as is sterilization validation. The finished bag will be tested according to the ISO 15747 standard.
Finally, the sum of testing will constitute the demonstration that the LVP system is suitable to its use and the documentation package will support customer registration dossier.
Download the presentation slides here.
Blow-fill-seal technology in large volume parenteral packaging
Speaker: Michael Spallek PhD, Director Research & Development
Company: Rommelag
Blow-fill-seal is the advanced aseptic technology for the efficient production of containers (e.g. bags or bottles) for large volume parenterals /1/. It allows compact and fast production of LVP containers ranging from 50 to 1000 ml. The favored practice when administering an infusion is to avoid venting the container to minimize patient risk /2-5/. This can be accomplished by using low density polyethylene (LDPE) containers that collapse as the solution is withdrawn. However, if terminal sterilization at 121°C / 20 min is preferred, the use of polypropylene (PP) is required. Well suited for this application are new, so called soft PP materials with bottle geometries that support easy folding during administration.
Some insight into the development process of LVP-PP bottles will be given including design optimization from an intuitive approach, to Finite-Element-Analysis (FEA), as well as the method development to characterize the administration / discharge behavior.
/1/ FDA guidance for Industry: Sterile drug products produced by aseptic processing – current GMP Annex 2 –
September 2004
/2/ N. Barsoum, C. Kleemann: Now and then, the history of parenteral fluid administration, American journal
of Nephrology 22, 2-3, 2002, p 284-289
/3/ C.M. Thorpe, D.H.T. Scott: Air inlets for infusion bottles Anaesthesia 1994, 49: 610-612
/4/ N. Graves, A.G. Barnett, V.D. Rosenthal: Open versus closed IV infusion systems…
BMJ Open 2011;1: e000188 doi:10.1136/bmjopen-2011-000188
/5/ G.A. Sacha, M.J. Akers et al. Practical fundamentals of glass, rubber, and plastic sterile packaging
systems Pharmaceutical Development and Technology 2010; 15:1, 6-34
Download the presentation slides here.
Design and qualification process for a LVP packaging system from a user perspective; case study nitrosamines
Speaker: Rawaa Ammar PhD, Senior Research Associate III / Extractables & Leachables Lead
Company: Baxter
To meet the increasing patient need for LVP, more complex packaging systems are required to be designed and further qualified to house different solutions. The high maximum daily dose of the multi-components of the packaging system present challenges when evaluating extractables and leachables (E&L). Controlling E&L levels in LVP is vital for the safety, quality, and efficacy of the finished product. Leveraging existing regulations (Pharmacopeial and food compliance) and effective collaboration with the suppliers of the raw materials will provide the required knowledge to design accurate E&L assessments.
E&L testing of LVP dictates a low detection limit due to the long LVP treatment duration and high volumes. Thus, impurities with ppb levels such as Nitrosamines trigger great analytical challenges. Approaching LVP based on E&L risk assessment at an early stage of the product’s life cycle, namely material selection, will allow the E&L strategy to succeed in ensuring patient safety and product compliance.
Download the presentation slides here.
Notified body perspective on CE-marked medical devices versus article 117 MDR combination products
Speaker: i. A. Dr. Katharina Weidmann, Expert Biocompatibility / Dr. Christiana Hofmann, Team lead Non-Active Medical Devices
Company: Tüv Süd
With the implementation of the MDR, the Marketing authorization holder (MAH) must also show compliance for the device part of the combination product with the applicable GSPRs as outlined in Annex I. acc. Article 117.
During this presentation we will highlight the differences for you as a manufacturer between the approach for a CE-marked medical device and the Notified Body Opinion for an Article 117 device. We will focus on general obligations for the manufacturer, as well as on biocompatibility and sterility aspects.
Download the presentation slides here.
Session 3 – Safety qualification of LVPS, E&L
Challenges and considerations for complex LVP drug products
Speaker: Mike Hodgson, Senior Manager of Extractables & Leachables team
Company: Baxter
The technical challenges associated executing a strategy to address the toxicological risk associated with patient exposure to leachables vary depending on the unique characteristics of the dosage form. For Metered Dose Inhalers (MDIs), widely regarded as the highest risk dosage form from an E&L perspective, often contain leachables at levels that require a strategy to be put in place to control leachables in commercial batches of the drug product after approval. Topical drugs have complex formulations that present unique analytical challenges to analyze the topical drug product and/or justify an appropriate surrogate solvent system to generate extracts of the container closure system.
Large Volume Parenteral (LVP) drug products are similar to Small Volume Parenteral (SVP) drug products in the sense that most are aqueous based, however the increased daily dosage volume present analytical challenges that are pushing the boundaries of science and the capabilities of the state of the art analytical instruments that are available today. The talk discusses some of the complexity associated with deriving the Maximum Daily Dosage (MDDs) of LVP drug products and how this can impact the AET.
Furthermore, the challenges associated with detecting and identifying extractables/leachables in line with evolving Safety Concern Thresholds (SCTs) is discussed along with when it is appropriate to consider the value of incorporating risk based concepts into a leachable study to ensure the level of effort (i.e. extent of testing) is commensurate with the level of risk.
Download the presentation slides here.
Use of auxiliary information to support the development and qualification of flexible LVP packaging
Speaker: Dennis Jenke PhD, Principal Consultant
Company: Nelson Labs
Although leachables data is the gold standard, and extractables data is arguably the silver standard; toxicological safety risk assessment of packaging, extractables and leachables profiling, may not be possible or appropriate at every stage of the packaging’s development and registration. In such situations, “safe for use” can be inferred through a “preponderance of evidence” approach, where the preponderant evidence is auxiliary information.
In this presentation, the types of auxiliary information are explained. Also, the use of auxiliary information to evaluate and choose candidate materials during material selection and how to manage the AET gap during extractables and leachables safety assessments is discussed.
Download the presentation slides here .
Testing of the packaging: Extractable study design and challenges
Speaker: Karen Pieters, Senior E&L Expert
Company: Nelson Labs Europe
Large volume parenteral applications are characterized by high volume doses of a drug product, which are administered intravenously. Flexible bag systems, which contain a combination of different materials, are often used as container/closure systems. Definitions and regulatory requirements for extractables and leachables testing of large volume parenteral products, will be highlighted. Next, typical sources of extractables and leachables in flexible bag systems for parenteral use will be listed. Emphasis will be put on the specific challenges associated with large volume parenteral applications. Finally, some case studies regarding different designs of extractable studies will be discussed.
Download the presentation slides here.
The value of simulation studies for LVP packaging systems
Speaker: Dr. Dennis Jenke
Company: Nelson Labs
Testing of the drug product, stored in a large volume parenteral packaging system: Leachable study design and challenges
Speaker: Pieter Van Wouwe PhD, Senior E&L Expert
Company: Nelson Labs Europe
Large volume parenteral drug products are characterized by high dose volumes administered to the patient. This results in challenges in extractable and leachable study approaches. This presentation highlights the expected challenges, which are characteristic for large volume parenteral leachable studies and introduces strategies to resolve and deal with these difficulties. Furthermore, a clear vision will be outlined, as well as an emphasis on differences with the more “classic” leachable studies.
Download the presentation slides here.
The need for high-end analytical technology to support the need for a higher level of identifications in large volume parenteral packaging qualifications
Speaker: Ward d’Autry PhD, Senior E&L Expert
Company: Nelson Labs Europe
Inherent with the high maximum daily doses encountered in large volume parenteral applications, screening results have to be evaluated at a low concentration level, often close to the lower limits of the analytical methods. The reported list of extractables or leachables is often extensive, where a correct identification for each of the reported compounds is key to allow an accurate and comprehensive toxicological assessment.
In this presentation, we will touch on some key aspects of good identification practices in first-pass evaluations and how to increase the identification level of unknown or only partially identified compounds using high-end analytical techniques in second-pass evaluations.
Download the presentation slides here.
Session 4 – Additional Connsiderations
The challenges in tox assessments for large volume parenteral packaging system applications
Speaker: Koen Van Deun PhD, External Toxicologist
Some typical toxicological challenges in LVP E&L will be presented, such as difficulties in exposure evaluations due to low AET. On the other hand, typical difficulties in hazard and risk evaluations relate to data-poor substances typically seen from rubber stoppers on glass bottles and the variety of substances from polymer materials containing several sources of E&L. Based on these settings, some E&L examples were selected to discuss the critical toxicological endpoints and were evaluated by means of various methods, in terms of deriving appropriate safety limits.
Download the presentation slides here.
Common themes and challenges in LVP qualifications and submissions: Time for an “Interest Group”?
Speaker: Piet Christiaens PhD, Scientific Director
Company: Nelson Labs Europe
In addition to reviewing the most common themes and associated challenges that have been discussed during the 2-day symposium on Large Volume Parenteral Packaging Qualification, this presentation will explore if moving forward to an LVP “Interest Group” could create value for all stakeholders working on and with LVP packaging systems, where this value could come from, and what the value of participating in a broader “LVP Interest Group” could bring.
Download the presentation slides here.
Looking for more information on these subjects? Make sure to take a look at our website to find the most recent research, including numerous whitepapers and brochures on Extractables and Leachables:
Brochures:
Whitepapers:
- Errors in screening, PDA article 1 & article 2
- White Paper series (4parts) on “Good Identification Practices” ( PART I, PART II, PART III, PART IV)
- Establishing the Proper PH Range for Aqueous Simulating Solvents Used in Extractables Profiling
- Use of Exaggerated Surface Area to Solution Volume Ratios in Extractables Studies; Equilibrium Case
- Establishing the Proper Alcohol/Water Proportion for Simulating Solvents Used in Controlled Extraction Studies
- Use of Accelerated Conditions in Extractables and/or Leachables Studies
