Extractable and Leachable Studies on Pre-Filled Syringes
This case study will focus on a drug manufacturer’s decision to change to newer co-polymeric and fluoro-polymer materials to replace current polymer and/or glass syringes. The article will examine key decision criteria in choosing a Contract Laboratory Service Organization (CLO) for the chemical compatibility studies with regard to extractables and leachables (E&L.) The use of comparative spread sheets matrices, project workflow charts with qualitative and quantitative analysis will be examined. And as required to be in conformance, a focus on meeting and/or exceeding current regulatory requirements/guidelines and industry standards will be included.
Some key decision parameters:
a) Investigating and selecting appropriate Contract Laboratory Organizations (CLO) for consideration.
b) Examining their analytical capabilities, skill sets and technical knowledge base.
c) Developing comparative spreadsheets and matrices focusing on these key decision points.
The overall objective is to make a more rigorous, effective and efficient decision making analysis in choosing the right CLO, who will be ultimately responsible for developing an appropriate protocol and executing the study.
The growing use of newer co-polymeric materials in pre-filled syringe applications has spurred further investigations into material extractable profiles and potential leachables that may adulterate the final filled drug product. Some important considerations in this process make it necessary to determine:
a) Key decision criteria for selecting an appropriate CLO,
b) Develop test study considerations and parameters, e.g., accelerated stability studies, and
c) Examine polymeric syringe specifications and materials of construction, e.g., chemical compatibility.
The newer co-polymeric materials included in this case study are the syringe materials, cyclic olefin polymer (COP), cyclic olefin co-polymer (COC) and the tip/cap plunger coating material, fluoro-polymer. The advantages of these materials for pre-filled syringe use are, but not limited to, clear glass-like transparency, rugged shatter-resistant construction, cleaner, lower potential contaminants, and highly moldable.
Pre-Filled Syringe Case Study
Concerns over contaminants leaching into the drug product post-filling were addressed by running an accelerated extraction study using Arrhenius and Q10 calculations and assumptions. The test study examined the interaction of the solvent system on these new polymeric materials and was used to establish a baseline extractables profile for the syringe/solvent system. An additional longer term Stability Study was initiated to determine leachables, if any, and to meet regulatory requirements for the NDA filing to demonstrate the drug maintained its safety, identity, strength, quality and purity.
Regulatory Requirements and Industry Standards
The regulations regarding container/closure and polymeric contact with drug product interaction apply for the various polymeric, glass and stainless steel materials. As there is heightened concern by regulatory bodies where polymers are used, a greater degree of scrutiny and resultant testing of the newer/novel polymers is needed. Although these materials may be well characterized by the suppliers, unique drug product and solvent systems demand additional examination. Typically the entire system up to downstream processes are candidates to determine where product contact situation will likely occur, e.g., liquid filtration application, storage in carboys/bags, fluid transfer via tubing sets etc. For this case study, the overarching concern focused on the component material change – the COP/COC syringe and fluoro-polymer tip cap and plunger coating. Many of the manufacturing processing components and materials had already been well characterized and qualified/validated.
Project Mileposts and Timelines
The next step involved establishing mileposts and associated timelines. This process helps to focus on key decision points and identify potential bottlenecks.
As the Milepost – Timeline Chart (Figure 1) illustrates, one must identify those key action items effecting the project’s progress and then assign timelines (target completion dates) and a reviewer. This individual or team, either manufacturer or CLO, will be ultimately responsible to oversee the completion of the task. This action item tabulating may quickly point to potential bottlenecks early on in the project to help anticipate and overcome the inherent delays. Once the charting has been completed these action items and target dates lend themselves to visualizing tables such as GANTT or PERT charting.
Figure 1: Action items chart
The mileposts may be identified as in this case study as ‘Stages 1, 2, 3.’ Each stage marks a Cardinal point in the project. As an example, in the chart various Action Items are highlighted in “orange’ indicating a sequential event that must be completed before proceeding to the next and therefore may represent a bottleneck. Those in ‘Green’ can for the most part be done concurrently once that Stage has begun.
Without many exceptions, the project bottlenecks are usually delays caused by the manufacturer due to internal routing issues, (vacations, travel, sick time, etc.) and/or management hierarchical issues, especially those involving extractable and leachable projects which can develop into the $100K+ test study category. Albeit, less significant in costs than human clinical trials, this still requires an upper management review and sign-off in most cases, thus adding to the timelines.
Typically the CLO well understands their internal workflow processes, controls, QA reviews, lab schedules and workload capacities. The CLO can therefore determine with a high confidence level the completion timelines for producing test results, preliminary analyses and final reporting. In summary, to make the project run smoothly and anticipate any potential project delays:
• Determine each Cardinal Stage early on in the project process.
• Determine which are concurrent (green) and which are sequential (orange.)
• Manufacturer timelines are generally the rate limiting factor.
• CLOs know internal scheduling and capacity – can delivery on-time.
Contract Laboratory Organization – Best Fit Analysis
Considering the high risk of successfully introducing a new drug product to market, an equally important aspect is the contractors hired to provide key information and testing data for the eventual drug filling. The aforementioned mileposts/timeline chart (Figure 1) can assist in choosing a CLO as the ‘Best Fit’ to provide these critical test studies. What are the key factors that enter the decision making process? How to determine the ‘Best Fit’ using qualitative and quantitative analysis of a CLO? What attributes should be examined? The following listing details these key factors for both processes:
• Analytical testing capabilities – instrumentation/chemistries
• Delivery timelines and promptness in scheduling
• Costs and pricing flexibility as project develops
• Long-term stability study capability – as needed.
• Turn-around timelines for proposal/protocol and report delivery. And:
• Extractable and leachable testing experience and knowledge base.
• Can provide a sample generic proposal/protocol.
• Level of analysis will be provided – simple raw date to in-depth assessment.
• Licensing and certification for facility and technical staff.
• Audit of lab and instrumentation – timelines/availability.
In addition to these key assessment factors, a good qualitative questionnaire evaluation by the manufacturer’s key management team will provide focus on those attributes as ‘perceived’ (scale of 1-10) by them as a good measure to distinguish amongst the CLO candidates.
Qualitative ‘Perceived’ Questionnaire-type Evaluation:
• Communications; clarity and conciseness, ease of dialogue
• Technical competence; technicians experience, competence, knowledge base
• Service support; project/business/technical competence and responsiveness.
• Proposal/Quotation; readability, accurately assess project parameters, timely.
The time and resources expended on these overall quantification and qualification assessments will prove well worth the expense and effort once the project begins. A hastily drawn decision based on ill-defined key capability factors and untested working relationships within both the CLO and manufacturer’s project teams would undoubtedly cause unforeseen setbacks costing the project lost time and added catch-up expenses.
Figure 2: P/PSS Form
Observations and Summary
The case study observations forms the basis for making key decision choices for a CLO as well as the material of construction for a critical drug delivery system, e.g., pre-filled syringes. These concepts could apply to most drug manufacturing process. Whether upstream or downstream, where polymeric single-use devices contact drug formulations, some form of comparability and compatibly assessment must be made to meet both regularly and industry expectations. Some key thoughts and factors that bear summation:
• Define at start-up:
o Key process components to study.
o Formatting and content in protocols and reports; raw data, notes, graphs.
o Method development.
o Depth of analysis expected from CLO.
• Know and conform to applicable regulatory requirements.
• Establish priorities for qualification test studies for extract/leachables.
• Establish mileposts/timelines priorities for each project Stage.
• Decision time: develop CLO decision matrices.
• Once contracted with the contract laboratory keep close and frequent communication between the mutual Project Teams.
In this case study, these well defined key decision parameters succeeded in making the distinction between many very capable and competitive contract laboratory service organizations. Price, timelines and analytical capabilities were paramount in the selection process. In the deciding choice between the final candidates, their lab service capabilities were considered equivalent. The final definitive factor was people-based; the interaction between the manufacturer and the CLO became the key decider. This human factor made the qualifying difference.
US Pharmacopeia monographs: <87, 88, 381, 661, 1031>)
CFR 211.65 Equipment Construction
CFR 211.94 Drug Product Containers and Closures
ICH Q7A Guidance for Industry: Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (8-2001)
BioPharm International, December 2002, page 28.
BPSA - White Paper, Bioprocess International January 2008
About the author: Mr. Trotter, President and principal consultant of Trotter Biotech Solutions, provides consulting services and training programs in the pharmaceutical, biologics, & bioprocessing industries.