Container Closure Integrity Testing Method Development and Validation for Prefilled Syringes

Utilization of prefilled syringes as a preferred container closure system for biologics has been increasing [1]. As a primary container closure system, prefilled syringes must provide an integral barrier that protects drug product stability and sterility throughout its entire shelf life. Drug manufacturers are required to check and demonstrate the system is capable of maintaining its microbial barrier integrity [2, 3]. In 2008, FDA further promoted container and closure system integrity (CCI) testing as a component of the stability protocol for sterile products

In response to the increasing regulatory expectations, the pharmaceutical industry has driven and witnessed significant technical advancements in CCI testing [5]. Instrumentation-based technologies, such as high voltage leak detection (HVLD) [6], vacuum/ pressure decay [7], mass extraction [8], and tracer gas detection (helium, oxygen etc.) [9, 10], have emerged and demonstrated improved detection capabilities compared to conventional dye and microbial ingress methods. Many of the technologies have been used for on-line 100% inspection and/or drug product stability CCI testing. In this article, we highlight our current thinking in an attempt to devise a systematic approach for CCI testing method selection, development, and validation.

General Considerations

In order to function both as a container closure system and as a drug delivery device, prefilled syringes feature many unique design elements. They usually include multiple containment compartments that are sealed by numerous interfaces. For example, the current stake needle glass syringes (Figure 1) provide a syringe barrel compartment for drug product containment and a separate needle shield compartment for needle protection. The syringe barrel compartment is sealed by the plunger on one end and by the needle on the other with the needle tip embedded in the needle shield. The needle shield compartment, sealed by the syringe barrel head,protects the needle exterior surfaces from potential contamination. The potential failure modes associated with each compartment and seal interface need to be identifi ed, assessed, and taken into account during CCI testing method development.

“In order to function both as a container closure system and as a drug delivery device, prefilled syringes feature many unique design elements.“

Furthermore, the plunger in a prefilled syringe is allowed to move within a range along the syringe barrel. When experiencing lower pressure environment during shipping and distribution, plunger movements in response to pressure variations may potentially aff ect seal integrity. Therefore, it is essential to evaluate plunger seal integrity following these special conditions.

In addition to the complex designs of prefilled syringes, the drug products packaged therein should also be considered. For example, prefilled syringes have been widely used for biologics, some of which could require extremely low temperature storage (e.g. -70°C). Since seal property of syringe components, especially elastomers (e.g. needle shields and plungers), is temperature dependent, CCI testing under extremely low temperatures could be required if theoretical justifications based on elastomer property are not adequate [11]. Moreover, drug-package interactions may impact method sensitivity and selection. For example, proteinaceous products could prevent mass transfer through CCI defects and reduce the sensitivity of a vacuum decay method [12].

Figure 1. Illustration of a stake needle glass syringe

CCI testing strategy for development

Many distinct CCI failure modes can occur throughout the life cycle of a syringe, ranging from component manufacturing, drug product filling and sealing, device assembling and packaging, to subsequent distribution and storage. It is essential to develop an overarching strategy to apply a series of CCI testing throughout the entire syringe life cycle.

CCI testing strategy development started with thorough understanding of syringe construction, design, and manufacturing processes. The CCI failure modes and eff ects associated with each aspect were first identifi ed. Using a risk-based approach, we further determined whether CCI testing is required, and if so, the intended uses and testing frequencies needed. For example, knowing the needle shield compartment seal integrity was tested by the component supplier, we elected to apply a non-routine CCI test to confirm its seal integrity upon drug product filling and sealing, and upon being assembled into devices. In contrast, for the product-containing syringe barrel compartment, we incorporated an extensive set of CCI tests into the entire product development cycle, including initial design confirmation, machinability studies, and product stability testing, to ensure CCI was achieved and well maintained.

Method selection

Table 1 lists the major CCI testing technologies available for prefilled syringes and their key characteristics. Note all the technologies have major limitations. When selecting appropriate methods, the following key aspects should be considered.

  • Suitable for its intended use. The selected method(s) must be suitable for the intended use and scope of a specific CCI test. For example, microbial ingress testing, although a good selection for media-filled syringes for fil lling process validation, cannot be used for stability testing because it does not apply to drug product filled samples. If a single method cannot meet all the testing needs, complementary methods may be applied in tandem to achieve definitive and comprehensive testing conclusions.
  • Applicable to the specific drug product-package. As previously mentioned, drug products can interact with CCI defects in various ways and may further aff ect the eff ectiveness of CCI testing methods. The method applicability to the specic product-package must be evaluated and adequately demonstrated.
  • Detection capability and eff ectiveness. Recent technologies utilizing mass extraction [8], HVLD [5], vacuum decay [7], have demonstrated reliable detection of CCI defects of 5-10 microns or smaller. These technologies are based on quantitative measurement of certain sample characteristics that can be further correlated to presence and/or sizes of CCI defects. The superior sensitivity and reliability made them preferred CCI testing methods over conventional dye or microbial ingress tests.
  • Non-destructive CCI testing. Non-destructive methods enable 100% CCI testing. In addition, they allow for further analysis of the failure modes and root causes, which in-turn provides valuable feedback for continuous improvement.

Method development

Upon establishing a preliminary method following vendor’s recommendations or literature search, we further focused on optimizing testing parameters and determining the appropriate pass/fail threshold.

Optimize Testing Parameters

First, various defect standards of known sizes (Table 2) were tested along with intact samples under different testing parameters. The correlations were thoroughly explored between key method parameters and instrument responses to intact and defect samples, aiming to identify a set of parameters that yield optimized separation between defect and intact samples (i.e. signal-to-noise ratio).

Refine Pass/Fail Threshold

To establish the preliminary pass/fail threshold, the optimized method was used to test multiple lots of filled intact syringes representing relevant product variations, including various packaging component sources/lots, drug products batches, as well as packaging sites and lines. The testing results were statistically evaluated to define the instrument baseline and variation (σ) for intact samples. Ideally, the pass/fail threshold should be at 10σ above baseline (i.e. above limit of quantitation LOQ). Defect standards of known sizes were then tested to further finalize and verify the pass/fail threshold. In cases where the 10σ threshold did not provide the desired sensitivity (as illustrated in Figure 2), the threshold setting was further adjusted between 3σ above baseline (i.e. limit of detection LOD) and the 10σ LOQ to achieve the desired detection sensitivity while keeping false positive detection probability (i.e. intact sampled detected as Fails) within the acceptable level.

Verify Method Effectiveness

Although defect standards are essential for initial method definition and optimization, they do not necessarily fully represent natural CCI defects. Natural CCI defects are of a large variety and most of them are not simple orifices or tubes. Therefore, the method performance was further evaluated using “real-world” CCI defects.

A good “real-world” defect sample set should represent all major probable CCI failure modes. Actual CCI defects could be obtained from various sources, such as reject samples from incoming or inprocess controls. When actual defect samples were not available for a specific failure mode and defect type, simulated defects were used.

A few iterations of the steps above may be needed to finalize the method. For methods used for stability testing, additional studies were performed to verify the methods are capable of detecting “aged” samples. Usually it was demonstrated by placing a set of productfilled samples with known defects on a stability study and testing the defect samples at various time points.

Method validation

Table 1. Characteristics of Major CCI Testing Methods

Table 2. Commonly-used CCI Defect Standards

In general, ICH analytical method validation guideline [14] was followed to validate instrument-based CCI testing methods. The key method characteristics, such as detection limit, range, accuracy, precision and robustness, were evaluated and demonstrated during the validation stage. In order to demonstrate detection capability in size, micro-pipettes, microtubes, and laser drilled standards of known sizes were usually used, which also allowed direct comparison of testing capability of various methods.

CCI testing methods were validated for the specific drug productpackage. Because the drug product formulation and package design may change during early development phases, a phase-appropriate approach was implemented to validate methods in concert with product development phases. For example, we utilized scientifically sound methods to support packaging system qualification and development stability studies. Once the product formulation and packaging design were finalized, the methods were then fully validated in support of primary stability and process validation CCI testing. Additional long-term method robustness may be further validated prior to implementing the method in QC laboratories for routine testing.

Figure 2. Approach to establishing Pass-Fail threshold

Summary

Appropriately selected and validated methods are essential for demonstrating container closure integrity during package and drug product development and manufacturing. However, it should be realized that current CCI testing technologies do not off er an ideal method that satisfy all prefilled syringe CCI testing needs. An integrated approach incorporating CCI testing and other engineering and administrative controls must be taken to ensure overall container closure integrity.

 

Setting up a pharmaceutical cleaning strategy

Cleaning is an essential practice for any pharmaceutical activity. Difficulties can arise from the fact that the concept of ‘clean’ is not easily defined or can be related to non-evident residues.

 

Defining differences between sterilization and cleaning treatments, for example, is important to understand in-depth the main problems and peculiarities when setting up a cleaning strategy.

 

The kinetics of ordinary sterilization processes are well understood: to sterilize means to destroy or inactivate microorganisms. In this perspective, we know the target and we can define it in terms of a number (CFU/unit) and resistance (D, z). Though the definition of sterile product/ item is probabilistic (PNSU – Probability of Non-Sterile Unit or SAL – Sterility Assurance Level), it is universally accepted.

 

On the other hand, for a cleaning process, the “enemy” is not defined and, in any case, can vary on a case-by-case basis: residue of previously processed product, diluents, solvents, lubricants, microorganisms, etc. There is no absolute definition of cleanliness. The kinetics of the cleaning procedure are unknown. Consequently, also the definition of “cleaning dose” to be provided is undetermined.

 

In these conditions, even regulatory bodies struggle. Essentially, they allow manufacturers considerable flexibility in establishing their own cleaning specifications. The FDA, for example, does not define methods describing how a cleaning process should be validated. FDA inspectors have to assess the rationale used to set the cleaning limits, making sure that their basis are scientifically justifiable and grounded on adequate knowledge of the materials involved.

This is the reason why Fedegari have published a new e-book: to discuss the main challenges on taking the right decisions while developing a cleaning strategy. New requirements have been faced by manufacturers, new targets have been fixed and the evidence that these are met is shown through successful case studies. Our aim was to highlight the best practices and existing solutions to support your decision-making.

This is certainly a multidisciplinary issue that involves various company areas: from “Regulations” to Engineering, from Quality Control lab to Production department. Fedegari have collected contributions of all these areas together in order develop a robust and repeatable cleaning process.

In their new E-book you will find:

  • Aspects Distinguishing a Cleaning Process
  • Steps for Setting Up a Cleaning Procedure
  • Case Study I: Removal of Bacterial Endotoxins
  • Case Study II: Application of a Washer Sterilizer
  • Case Study III: Soil Removal From Smart Plate

 

Download it here for free. If you want to discuss your cleaning strategy with us give us a call at 800-829-5741.

 

 

Headspace Gas Analysis for Parenteral Manufacturing

Headspace content verification is a solution to ensure parenteral product stability and sterility maintenance. Integrity defects as well as failures in the aseptic manufacturing process, including unexpected variability in the nitrogen flushing or vacuum application, pose a risk to the product quality and patient safety.

 

Monitoring the maintenance of container headspace conditions is needed for sterile drugs such as oxygen sensitive liquid products and lyophilized or powdered products. Any modification to the headspace pressure, moisture or oxygen level may result in product degradation, reduce of potency, shelf life and safety.

The cGMP even regulates specific aspects of production of sterile drugs that also requires that Containers sealed under vacuum should be tested for maintenance of that vacuum after a predetermined time period.

To satisfy this segment of the market, Bonfiglioli Engineering has developed multiple products that can continuously perform such content integrity verification processes. The Laser Cube is a non-destructive, non-invasive laser-based inspection technology for measuring the headspace level of gases, such as oxygen and carbon dioxide, as well as monitoring moisture levels.

The inspection method is created to meet specific customer requirements offering extreme stability and accuracy in inspection even where the headspace is limited. Bonfig Laser Cube is a compact and lightweight system that is easy to use and set up via integrated PC and any wireless touchscreen tablet. HGA inspection process is based on the Tunable Diode Laser Absorption Spectroscopy (TDLAS) method which uses a laser beam to detect the target molecules within container headspace. HGA is therefore ideal for the accurate investigation of:
•    Headspace conditions for products packaged under modified atmosphere
•    Closure integrity in pharmaceutical finished containers

 

For more information or to schedule a Demo please give us a call 800-829-5741

Bellow Bottles and Filling Machine

LF of America is a reputable designer and manufacturer of single-dose containers for pharmaceutical, personal care, and OTC liquid products. Our services provide the cosmetic and pharmaceutical industries with innovative packaging options and contract filling services, including full turnkey solutions. The Bellow Bottle container is one of our most functional container designs and is popular for its high number of diverse uses.

Bellow Bottles deliver practical solutions and are especially favored by health and beauty cosmetic products. Ease of application, various size options, and durable packaging materials all make the Bellow Bottle an exceptional advancement in the world of innovative packaging.

The Bellow Bottle is an ideal container for serums, creams, and even powders. LF provides options for both long and short cannulas and the Bellow Bottle container ranges in size from 3 mL – 9 mL.

Clients can customize their container by choosing between a variety of caps, applicators, and bellow bottle sizes, all available in virtually any color. State of the art manufacturing technology coupled with a world-class team of experienced packaging design specialists created a unique and proficient design we are proud to now bring to you, too.

 

Bellow Bottle Machine

We also have a second hand Bellow Bottle Filling Machine to offer. It was pre owned and used by LF of America. This machine is designed to not only fill our Bellow Bottles but can even be modified to handle a variety of other containers. The machine has the production capacity of filling up to 1,500 units per hour (or 25 units per minute).

 

Here’s how it works:

  1. A vibratory feeder sources the star wheel with Bellow Bottles.
  2. A second feeder moves the cap to the opposite end of the star wheel.
  3. The filling size ranges from as little as 2mm to 10mm.
  4. The filling process is done with a piston filling system.
  5. After capping, the filled units are loaded onto a conveyor.
  6. Containers can be coded on the bottom once loaded onto the conveyor.

 

Give us a call to learn more.

Complete Production Line by Cozzoli

On specific client demand, Cozzoli has developed a complete production line that houses Filler, stopper, capper and unscrambler. The complete production line was installed at Biocor in Omaha, Nebraska. This is a very comprehensive production line solution since it meets all the FDA regulations regarding vaccines for veterinarian use.

 

OPERATIONAL LINE SEQUENCE:

Containers are placed on the unscrambling table, where they are automatically fed into the filler infeed conveyor. The containers are allowed into the filling station by a gating device, adjustable for different container sizes. After completion of the fill cycle, filled containers travel to the RS400 Stoppering Station, where full stopper insertion occurs. After stoppering, containers then travel to the CM200 Crimping Station, where aluminum crimp seals are adhered.

 

Containers enter the filling machine via the gating device and are filled using the diving nozzle system. The VR840 is a positive displacement liquid filler, operating on a 4″ pump stroke. This filler is equipped with a total of 8 stainless steel syringes for fill volumes up to 600 ml, and speeds up to 120 bottles per minute. After the fill is complete, containers cycle out of the filler and enter the Stoppering System.

 

BioCore’s RS200 Stoppering System is comprised of a vibratory sorting bowl, stopper feed chute, container feed screw and stoppper pressing foot. This machine is stoppering three container sizes with 20mm and 30mm stoppers. Sensors are located on the stopper chute for stopper make-up and on the conveyor for container make-up and back-up.

Traveling down the conveyor, the filled and stoppered vials are captured by an infeed starwheel for entry into the CM200 continuous motion rotary crimping machine. This machine also has a vibratory bowl; orienting the aluminum caps for placement into the feed chute. As the stoppered containers pass underneath, the containers strip-off the aluminum cap as it enters the infeed star wheel. The container then passes into the main star wheel, where the crimp head lowers. Contact with the cap activates the crimp head rollers to begin the progressive roll seal process.

CRIMPING OPERATIONAL SEQUENCE:

A fixed cup is used in each crimp head to prevent rotation of the container, and the crimping skirt height is easily adjusted for each size crimp. An automatic vial height adjustment is included with this machine for ease of container changeover. Simply place the container on the height gauge, and the height is measured and corrected automatically on the crimper. This machine will crimp 20 and 30 mm seals.

Popular New Liquid Packaging Trends in 2018

 

Contract filling and packaging solutions for liquids cover everything from food and non-food substances to over-the-counter (OTC) medications, pharmaceuticals, and more. The large size of different companies in need of these services has introduced new liquid packaging trends that are now being embraced by companies around the world.

Turnkey packaging solutions and multi-layer containers are two such examples commonly found in the current market. Both of these are direct responses to consumer demands and prove that the company selling the product is listening to their customers. Let’s examine all of the latest liquid packaging trends by covering the different benefits each individual trend offers.

The Rise of Turnkey Solutions

Turnkey solutions are becoming the norm for pharmaceutical companies in need of packaging their medications and OTC products. Contract packagers have evolved into a multi-billion dollar industry and their growth is only projected to increase year to year. This is a direct result of their all-in-one services that not only achieve the desired results but at a reduced cost. In other words, it is the better investment for growing companies.

Key benefits include:

  • Cost-reduction
  • Scalability
  • Quality assurance
  • More eco-friendly
  • Maximum value
  • Standard regulation compliance

Tip: Since turnkey solutions are among new liquid packaging trends, more companies are trying to quickly adapt. Choose your turnkey partner by verifying their history and looking for a proven track record of success first.

Creative Custom Packaging Designs

Knowing the consumer market is key when deciding on the package design. For example, organic items have been the preferred choice for consumers across most industries. This preference has revealed a simple pattern in labeling. In essence, the more modest and natural the packaging seems, the more appealing it is to customers.

Other packaging and label preferences include:

  • Functionality (Is it portable/ sealable/ recyclable/ etc.?)
  • Clear / transparency (Can you view the product through the container)
  • Eco-friendly (Does it reduce overall environmental impact)
  • Vintage labeling (Can you revive an older design for nostalgic appeal?)

Tip: The most important aspect to deciding on the packaging design and labeling is to know who you are marketing it to. Bold is not always better and a minimal design strategy can save you money.

Embracing New Technology

The improved capabilities of automated contract filling machines are equally economical and practical. Why potentially risk damaging your product during the filling process when it is unnecessary? The temperature when sealing can damage or negatively affect the product’s quality. Moreover, more companies are in need of small batch product sizes than ever before.

Contract filling services using injection molding technology during the blow, fill, seal process eliminate this risk and new, automated contract filling machines are capable of both full-scale and small batch production. What this means is you can eliminate paying excessive labor costs if you need to.

To learn more about the advantages of contract filling using injection molding, check out Contract Filling Equipment for more information.

 

To discuss these liquid packaging trends or to speak with someone about the advantages of using a turnkey partner connect with us or contact LF of America today.

A member of our team will be more than happy to find the perfect packaging solution that brings your company into its next phase of success.

 

JVNW Pharmaceutical Vessels

The processing of sterile and non-sterile liquids, such as blood plasma have specific purity requirements that can only be achieved with great technical skill and experience. Preparation and pressure vessels from JVNW are built to meet all standards and ensure that our customers ‘central process components’ have competitive advantages. The surfaces of JVNW’s preparation and pressure vessels are ground and polished, and as required, electro-polished. All welds are smoothed to the current GMP-/ FDA-standards and exclude even the smallest cleaning dead spaces.

All vessels can be supplied as stand-alone equipment (stationery or mobile) or as automated process units delivered as fully-functional modules installed on-site that include: agitators; homogenizers; metering and regulating technology; control units; valves and pipe connections. Options for hazardous environments are also available.

JVNW provides high quality storage and transportation vessels made of stainless steel. Each vessel is designed to the specific customer´s requirements. JVNW builds full scrape vessels with off-set turbines, dual motion full scrape tanks with counter-rotating turbine agitators and bottom sweep mix tanks. Fixed position spray-balls are custom drilled to match each tank and are tested for complete Sterilization-In-Place.

Bonfiglioli in Minnesota

 

We are delighted to announce that as of Monday June 25th we will be travelling around Minnesota accompanied by Bonfiglioli’s Product Specialist Piero Polastri.

Due to the opportunity of our Project Managers being in your close proximity, we strongly encourage you giving us a call and getting your name on our site visits calendar.

 

This Bofiglioli Demo Tour will uncover some insights on the just released new SAIL machine.

The Bonfiglioli Engineering SAIL puts Container Closure Integrity Testing, Visual Inspection and HGA all on one tabletop making it the ideal solution to ensure Quality and Safety of Parenteral Packages and verify:

– Presence of leaks

– Headspace gas content

– Absence of visible foreign materials.

It is suitable for in-process control, clinical trials and laboratory use without altering the container features. Testing is quick, reliable and repeatable, and gives consistent results for a comprehensive batch control.

 

SAIL stands for Smart Automated Inspection Laboraty meaning that the machine is an automated inspection laboratory especially designed to conjugate sensitivity performance, productivity as well as flexibility to inspect different container types, sizes and contents. A single machine designed to provide customers with a comprehensive set of benefits.

 

Based upon the Bonfiglioli Engineering state-of-the-art proprietary technologies, SAIL is fully customizable in order to best meet present and future user needs and cover a wide range of inspection requirements.

It is characterized by complete modularity and flexibility, including one or more stations for Automatic Visual Inspection to perform any kind of foreign particles detection, cosmetic analysis and cap control at 360°. Additionally, it can integrate stations for Vacuum-Decay based CCIT and Laser-Based HGA for Oxygen/Moisture/CO2/ Vacuum level control, thus making this product an all in one inspection solution suitable for various production facilities.

 

If you want to get some early insights on the SAIL machine as well as on other products off the Bonfiglioli Engineering product line get in touch with Joe Skorcz at JoeS@Lsi1.com or 312-545-2164.

 

Don’t miss out on the opportunity to be first in line to learn more about the newest innovation in the automation inspection for various containers.

Bonfiglioli Engineering unveiled the brand new SAIL – SMART AUTOMATED INSPECTION LABORATORY for pharmaceutical applications.

Earlier today, Bonfiglioli during the opening hours of this year’s Achema Expo in Frankfurt, Germany unveiled their latest product for the pharma applications. It is capable of performing multiple in line inspections on the same package container. By design it features in line leak detection, visual container inspection and laser analysis.

To learn more about the Smart Automated Inspection Laboratory – SAIL give us a call or contact MarkoV@Lsi1.com

Bonfiglioli Engineering will be attending ACHEMA 2018 trade fair.

 

What makes this year exceptional is the world premiere of a revolutionary product in the inspection field, which will enable the pharmaceutical companies and laboratories to reach an unrivaled competitive advantage never seen before, will take place during the exhibition.

You’ll just have to come and visit Bonfig at Booth C70 – Hall 3.1 by following the “Flexible Production” indications to discover the Bonfiglioli Engineering extraordinary innovation of 2018.

More teasers of the product that will be unveiled at the ACHEMA can be found here: http://www.bonfiglioliengineering.com/news/achema-2018

 

 

Fedegari will be exhibiting their latest developments on contamination control to help customers achieving cost-effectiveness with the best performances in pharma manufacturing.

You will be able to see the integration of different Fedegari processes and technologies, as Fedegari has developed fully integrated robotized solutions for different customers world-wide helping them to achieve the best performances and increasing cost-effectiveness.

Be prepared… you will be pleasantly surprised by this exclusive Italian manufacturer, that has prepared a show that you’ll cherish forever.

For this Achema, Bruno has created an exclusive menu for Fedegari. Bruno’s special dishes express his creativity through the quality of carefully selected ingredients: just as Fedegari does, everyday, when we build our engineered process equipment.

See more about Fedegari’s show roadmap at: https://www.achema.fedegari.com/

Curious? Come and visit Fedegari in Frankfurt, Hall 6.1 – Booth B6

 

Lameplast Group, the parent network of LF of America will be settling in Hall 1.1 D48.

Lot of innovations are waiting for you: new primary plastic containers, the brand new models of Pentafill Filling & Sealing Machines, the global services dedicated to pharmaceutical industries and the newest products ready for the distribution.

A great addition to Lameplast’s services is the new filling department for sterile products with fully-automated filling and packaging lines has been opened, set in Boca Raton Florida. The eco-friendly department has been built according to the best process technologies available, and is currently being reviewed for FDA compliance. The new US based camp should be an exact copy of the Italy based contract filling facility that houses a ISO 5 compliant cleanroom, suitable for aseptic automated filling in their COC Farmaceutici plant in Modena, Italy.

LF is an exceptional company and what makes them unique on the market is the fact that they offer Product Development as part of their services. The actual in lab product development main intent is to improve the flow and specification of the product by customizing it to fit the packaging and delivery method emphasized by LF & Lameplast.

Don’t’ miss them!

 

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