Filling Line Improvements to avoid the Defect of Product on the Stopper for Sterile Syringes
Author: Emeris Rivas Rodríguez
Advisor: Dr. José A. Morales
Industrial and Systems Engineering Department
Abstract Methodology Results and Discussion Conclusions
This research aims to optimize the syringes filling line at the facility The filling manufacturing process of the sterile solutions for The stopper setting parameter has an impact on the Air Bubble size of the The lots manufactured after these findings/corrections were monitored and
to not exceed the action limits because of the defect of syringes with subcutaneous administration (syringes) was evaluated to determine what syringe. Stopper setting parameter has a relation with the ABS, if the value complied with the alert control limit requirement of not more than 1.0% of
product on the stopper. The product or liquid on the stopper of the conditions contribute to the product's defect or liquid on the stopper. changes, the Air Bubble will change. If the stopper setting parameter is units with the defect of product on the stopper. Based on the satisfactory
results, it is concluded that the root cause of the events included in this report
syringe is one of the defects that can be encountered in sterile solutions Data was gathered from six (6) manufacturing lots that exceeded the higher, the air bubble will be higher and if the stopper setting is lower, the was identified as a combination of the described elements.
for subcutaneous administration. This defect is classified as major, and control limit of 1.0% because of product or liquid on the stopper, ABS will be lower. An adjustment to the parameter more negative side can
The data of % of product on the stopper per lot was analyzed in stages per
the established control limit is not more than (NMT) 1.0%. including: result in the insertion tube getting more introduced on the syringe, reaching
month from 06/01/22 to 08/12/22 (Refer to Figure 3). After the
The project implementation will reduce the defect of syringes with the product and leaving product on stopper during the insertion tube implementation of the improvements in the filling line (August 2022), it is
• Atypical situations reported during the manufacturing activities. retraction causing the defect of product on the stopper.
product on the stopper to ensure the manufacturing of the product observed that the control limits are significantly closer and the center line
• Start-up air bubble size In-Process ABS values below 2.00 mm throughout the filling process can (individual value/moving range) reduced significantly, closer to the control
according to the quality standards and lowest customer risk.
• In-process air bubbles in the filling hoses during filling
create the defect of product on stopper by inserting the insertion tube deeper limit of NMT 1.0%.
Furthermore, will reduce re-inspection lots, the product cost, and • Filling needles work orders (e.g., misalignment, clogged)
Work orders because of the malfunction of the insertion rods that needed to place the stopper, causing it to reach the product. If the•
Quality Events.
• Work orders for the stoppering system insertion tube reaches the product, the stopper will “clean” the walls of the
Key Terms ⎯ Product on the stopper, sterile solutions, sterile solutions
insertion tubes and the stopper will have product on the ribs when placed on
filling line, syringe defect.
The DMAIC methodology will be followed for the data analysis. the syringe.
Introduction There were 4 corrections made to the filler:
Define
On June 2022, the control limit of not more than (NMT) 1.0% was 1. The insertion tube holder from set #2 was replaced with a new one.
In the define phase was described the defect of product on the stopper
exceeded for the total major defects because of high incidences of Figure 32. Syringes X/Y table slide plate stop mechanism was adjusted so that the
on the pre-filled syringes. Also, was included a process flow map with the I-MR Chart of % Product on Stopper by Month
syringes with product on the stopper. syringes have less movement without creating damage to the syringes.
process steps for the pre-filled syringes manufacturing.
3. Fine-tuned the tub transfer positions for stoppering, checking to make Future Work
sure that the insertion tubes will not rub on the inside of the syringes
This research includes recommendations for filling line optimizations Measure
when stoppering. Stoppers dimensions can affect the insertion of it on the syringe, creating a
to avoid the defect of syringes with product on the stopper. Optimizing In the measure phase was included the data gathered related to the 4. Changed the stopper plunger home position from -4.5 to -4.9 and probability of over insertion. As part of the vendor feedback, Beckton
the filling line will decrease the defect of syringes with product on the identified lots that exceeded 1.0 % of pre-filled syringes with the defect of insertion tube home position from -2.7 to -2.9 in order to place the Dickinson (BD) acknowledge the “Barrel to Barrel and Barrel to Machine
stoppers higher in the syringes during startup with a -33mm stopper 
stopper to ensure the product's manufacturing according to the quality the product on the stopper. In addition, historical data of pre-filled Contact” during the syringe forming, printing, and assembly process step asposition. 
standards and lowest customer risk. syringes inspection results (% defects of product on the stopper). (https://myplace.bms.com/personal/emeris_rivas_bms_com/Documents/E potential cause for syringe breakage.
Gathered data includes evaluating the filling sets, work orders, and batch meris/Personal/Manufacturing%20Competitiveness/Design%20Project% Based on the information provided by BD, it is understood that the
Background records. 20Fall%202022/Project%20Presentation/Mechanical_stoppering_%20sta additional printing process that undergoes syringe material could reduce thendard%20Video.avi)
strength of the barrel making the syringes prone to breakages during the
Analyze The three lots filled after the implementation of the improvements were
handling at the filling process. For future research, it is recommended to
Filled syringes contain a sterile solution for subcutaneous
A surrogate run assessment was executed to assess the filling process monitored to assess the inspection results. The three monitored lots complied assess the printed syringe barrel process and identify opportunities for
administration. with the control limit of product on the stopper defects less than 1.0%.
and identify any area of improvement to avoid product on/over the improvement.
The product on the stopper defect is illustrated in Figure 1. The improvements to avoid the product on the stopper were implemented
stopper.
on 08/03/22 at the Filling line. It is observed in the time series plot (Figure 2)
The data from inspected lots from 01/01/22 to 08/01/22 was assessed to Acknowledgements
that the lots manufactured from 08/05/22 to 08/12/22 complied with the
determine if the process was in control. The I-MR control chart was My sincere gratitude to my professor of Design Project for his valuable
control limit of less than 1.0% of defects because of product on the stopper.
generated to identify if the process demonstrates control regarding the guidance and feedback. I also could not have undertaken this journey
defective units because of product on the stopper inspected. without the support of my company of work who financed my graduate
A one-sample-t-test was performed at a significance level of 0.05 to studies.
Figure 1
Product on the Stopper Defect determine if the % of defects because of product on the stopper seems to I am also grateful to the company engineering, manufacturing, and
Product on the stopper is a condition that originates during the be less than 1. technical team because of the teamwork efforts for the completion and
filling process. The most common causes for this defect are: implementation of the filling line improvements.
Improve
Lastly, my husband and my daughters because of motivation during this
The filling line was improved based on the analyzed data, implementing process.
• Air bubble size (below the criteria of 2.00 mm)
controls to avoid product or liquid on the stopper for the pre-filled
• Air bubbles in the filling hoses during filling
syringes. References
• Dried product at the filling needles’ tip
Handbook
• The stopper position is too low because of air bubble size is below Control Figure 2
1. Andrew, W. V. (2004). On-line inspection ensures needle quality. Vision Systems Design,
the criteria of 2.00 mm The control phase includes the monitoring of the inspection results of Time Series Plot of % Product on Stopper 9(10), p37-42. 5p.
• Misalignment of the filling needles the pre-filled lots manufactured after the implementation of controls to
It was demonstrated that there was a shift in the mechanical reference of the
Standards
avoid product or liquid on the stopper for the pre-filled syringes. insertion tubes and insertion rods axis. This in turn caused the value of 1. ASQ. (n.d.). ANSI Z1.4.
Problem Implementing the process controls will minimize the risk of adversely -33mm to not represent the same position as previously set. This shift was 2. ISO 11040. (2012). Plunger Stoppers for Injectables. Prefilled Syringes, Part 5.
corrected by adjusting the stoppering system home position to place the stopper
The control limit of not more than (NMT) 1.0% was exceeded for the total impacting the quality attributes of sterile solutions for subcutaneous 3. United States Pharmacopeia (USP). (n.d.). Visual Inspection of Injections. U S P < 1 7 9
higher on the syringes during the initial startup position.
0 >.
major defects because of high incidences of syringes with product on the administration because of product or liquid on the stopper. The The cost per unit is of approximately $1,250.00. The total units rejected
stopper. manufacturing process was monitored for three (3) consecutive lots to
Report
because of product on the stopper from June 2022 to July 2022 (prior
The project implementation will reduce the defect of syringes with product assess the effectiveness of the implemented controls to not exceed the
1. Caballero Rodríguez, A. (2013). Risk Prevention in Syringe Filling Line in a
improvements) was of 17,025 ($21,281,250). The total units rejected because of
Pharmaceutical Manufacturing Plant. San Juan.
on the stopper to ensure the manufacturing of the product according to the action limits because of the defect of syringes with product on the stopper. product on the stopper on August 2022 (after improvements) was of 524
2. (2017). Prefilled Syringes Market 2016-2026. NEW YORK 4th: Edition., PR Newswire.
quality standards and lowest customer risk. Furthermore, will reduce re- In addition, statistical analysis was performed with the inspection results ($655,000). When the costs of rejected units prior the improvements and after
3. (2022). Parenteral Drug Product Visual Inspection Defect Harmonization, Classification
inspection lots, the product cost, and Quality Events. of the pre-filled syringes after the implementation of control in the the improvements are compared, there is a financial benefit of $20,626,250.
and Risk Assessment. Puerto Rico.
manufacturing process.