Lab Study The Impact of Plunger Stopper Movements on Prefilled Syringe Container Closure Integrity 7th PFS & Injectables Summit 2017 Xu Song MS&T Bristol-Myers Squibb 11
Prefilled Syringe Container Closure Integrity (CCI) CCI must be maintained at all times During manufacturing process Filling and plunger stopper insertion Plunger rod insertion During transportation and storage High altitude shipping 22
Prefilled Syringe Container Closure Integrity 33
Syringe Filling and Stopper Insertion Process H: Insertion tube insertion depth h: Stopper position inside the syringe 44
Syringe Filling and Stoppering Process Syringe Filling A fixed volume of liquid is dispensed into the syringe barrel Plunger Stopper Insertion Process with Insertion Tube Plunger stopper is inserted into syringe barrel. The insertion depth is controlled to avoid stopper touching liquid while at the same time minimizing the air bubble size between stopper and liquid. 55
Plunger Rod Insertion Process e.g. A Generic Mechanical Cam Driven Process Note: Shown as an example for a generic insertion dynamics Different equipment and process would result in different dynamics 66
Plunger Rod Assembly Process Plunger Rod Insertion Process Initial plunger stopper position inside syringe is based on plunger stopper insertion process (nominal, maximum and minimum positions). Plunger rod is mechanically inserted and connected to plunger stopper. Plunger Rod Insertion Parameters e.g. Mechanical Cam Driven Step 1: Plunger rod is inserted into the plunger stopper targeting the expected lowest plunger stopper position. Step 2: Plunger rod & plunger stopper are pulled back toward syringe flange, in order to decompress the head-space gas. 77
Potential Stopper Movement during Shipping When shipping at high altitude, the pressure difference between the air bubble and the external environment pushes the stopper toward flange. 88
Summary - Syringe Stopper Movements Movement 1: Linear Plunger stopper is pushed during plunger rod assembly process. Movement 2: Rotational Plunger rod/plunger stopper rotational movement during plunger rod assembly process Movement 3: Linear Plunger stopper is moved toward flange intentionally during the plunger rod assembly; or due to higher pressure of compressed air bubble with respect to environment; and then again during high altitude shipping because of lower environmental pressure. 99
10 Syringe Plunger Stopper Movements and CCI Risks The plunger stopper movements (linear and rotational) during plunger rod assembly may breach the Seal #1 (formed between the plunger stopper and syringe barrel internal diameter) by exposing the sterile side of the stopper to a non-sterile environment. When a plunger stopper is moved toward the syringe tip, it compresses the air bubble inside the syringe. The increased pressure may force liquid through needle - breaching the Seal #2 (formed by embedding the needle tip inside the rubber needle shield).
11 Lab Study by Simulating Plunger Stopper Movements CCI Test Methods Dye Leak Detection e.g. Methylene blue dye or Fluorescein Dye Microbial Incursion Detection e.g. Inoculating suspension solution containing Brevundimonas diminuta Detection of Liquid leak at needle e.g. through a pierced hole on needle shield
12 Study Procedures Pierce a hole in the syringe needle shield (e.g. using a soldering iron) Place dye or inoculating suspension solution above stopper Assemble a plunger rod Move plunger rod & plunger stopper (in Step -1, -2 and -3), with a micrometer Dye leak/microbial incursion into syringe a breach of CCI between stopper/barrel Leak through the hole in needle shield a breach of CCI at the needle tip
13 Conclusions A simple and repeatable lab study methodology to evaluate PFS CCI by simulating the plunger rod assembly process and high altitude shipping. The lab study does not require commercial line time. Study can be modified to suit various process parameters. Enable faster decision making by understanding the CCI risk. BMS successfully conducted lab studies by simulating a commercial plunger rod insertion process and high altitude shipping No Dye Leak and No Microbial Incursion were observed.
14 Acknowledgement to BMS Team Members Chuck Dahlheim, Drug Product Science and Technology (DPST) Andre Karotki, Biologics External Manufacturing (BExM) Quality Lavanya Uppugonduri, Global Quality Kris Knutsen, Analytical and Bioanalytical Operations (ABD) Casey Tyrrel-Pawlowic, ABD Janet Perezbrown, ABD Greg Brotske, ABD Peter Heyman, DPST Device Development Steve Richard, DPST Device Development Frank Berardocco, DPST Device Development Jens Hetzel, Manufacturing Science and Technology (MS&T) Anthony Economou, MS&T Lei Ling, MS&T Manasa Parakala, MS&T