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.

 

Fedegari Washing Solutions

Washer-Sterilisers (independent and combined use)

One of the most inovative solutions in the Fedegari washer range is also a unique and original. Combined Washer-Sterilisers have the ability to operate in three ways, they can be bought to be independent washing machines, operate as back up sterilisers when washing is not required or perform as a hybrid washer/sterilisers which allow you to wash, sterilise and dry machine parts, vessels and other materials in a single cycle.

 

Steam Washers

Fedegari high performance GMP Steam Washers capitalize on the experience acquired with the Combined Washer-Steriliser series within the pharmaceutical market. These machines represent a cost-effective solution for the highest performances. Fedegari steam washers use an integral steam generator to optimize performance and reduce operational costs. The state-of-the-art modular customizable rack can be adapted to every specific load configuration.

 

Free Standing Washers

The Fedegari laboratory glassware washer combines excellent washing and drying performances with first class materials, economical consumption, safety and operating ease. With its dedicated process controller and its integrated steam generator that allows steam injection directly in the chamber, this machine is suitable for use in many different applications.

 

Later this month we have prepared a special webinar broadcast with Fedegari that will focus on The Key Factors of an effective Pharmaceutical Cleaning Strategy.

For more information on the washing solutions by Fedegari, give us a call and we’ll be happy to assist you.

 

Bahnson Environmental Specialties Products and Services

Bahnson Environmental Specialties offers a large selection of environmental chambers with proven quality construction and innovative technology, serving a variety of industries.

Temperatures range as low as -84°C (-120°F) with high temperatures to +350°C (+662°F) and humidity ranges from 10% to 98% RH.

Test chamber sizes That BES produces, range from small benchtop chambers for testing small components to full walk-in/drive-in rooms large enough to accommodate a semi-truck and trailer or larger, suitable for more comprehensive storage needs.

BES offers a complete line of temperature and humidity control solutions for today’s demanding research needs. These units combine reliable performance with a range of advanced features that make them a superior choice for a diverse array of applications.

BES offerings include:

  • WRST
    Optimum uniformity for cold and warm stability chamber studies
  • WRS Series
    A single chamber, a wide range of testing conditions
  • CRS Series
    Low-temperature precision and dependability
  • FAS Series
    Exceptional cleanroom capabilities with optimum temperature and humidity control
  • DRS Series
    Dry rooms tailored for specific pharmaceutical and industrial applications
  • LT Series
    Ultra-low temperature, high-volume freezers
  • ES2000 Series
    Reach-in chambers for your low-volume pharmaceutical and industrial test applications

 

Bahnson Environmental Specialties offers intensive preventive maintenance and calibration programs for most major brands of laboratory equipment, including environmental chambers.

Call us today and let us tailor a program designed to satisfy your complex equipment needs and demanding schedules.

Dryer designed and built by VETROMECCANICA

EOLO DRY is a drying system designed and built by VETROMECCANICA S.R.L.

 

EOLO DRY is characterized by a manual adjustment system of the air blades that allows the ideal positioning for any format (bottle or can) and also for the neck. This drying system allows to obtain optimal results in the various phases and types of labeling, sealing and coding.

EOLO DRY is composed of blowers that feed the specifically designed manifolds to obtain the right balance between pressure, flow rate and temperature of the air that is warmed up by the compression.

The Eolo Dry System is AVAILABLE IN:

  • MODULAR SYSTEM
  • STAND-ALONE SYSTEM

 

MAIN CHARACTERISTICS of the EOLO DRY:

  • AISI304 STAINLESS STEEL STRUCTURE with polycarbonate opening doors
  • MODULAR SYSTEM: quick & easy installation on pre-existing lines
  • HIGH EFFICIENCY LATERAL CHANNEL MOTORS

§  4 ADJUSTMENTS TYPES OF THE AIR BLADES by: ·        DEPTH, ·        HEIGHT, ·        LONGITUDINAL INCLINATION, ·        BLADE INCLINATION

  • ANODIZED ALUMINUM AIR BLADES: aluminum treatment that assures lifelong guarantee of the blades
  • INVERTER ON EVERY BLOWER: allowing to optimization of the speed of the air leaving the blades according to needs of the product that’s supposed to be dried
  • ENERGY CONSUMPTION OPTIMIZATION
  • Waste water and drop collection
  • NOISE LEVEL COMPLIES WITH SAFETY RULES
  • COMPLIES WITH EC REGULATIONS, NEMA and CSA

 

Technical data:

 

Here is a video demonstration of the Dryer system

https://www.youtube.com/watch?v=xv–10AuUr0

 

For more information regarding the EOLO Dry systems please call our HQ at 800-829-5741

How to Properly Calibrate Your Torque Analyzer

 

Cap torque analyzers are an extremely refined set of products that need to be cared for and calibrated on a regular basis to ensure accurate and consistent results. Calibrating these complex machines can be an intimidating process, however there are tried and true steps to follow to improve not only the calibration process, but also the end results.

Why is calibration important?

Regular calibration ensures that you’re getting the most accurate results which can greatly improve your ROI and avoid production loss and costly recalls. We recommend calibration be performed at least every 12 months.

 

The Five steps to calibrate your torque machine include:

  1. Before beginning calibration, be sure to attach the frame with 1-2 screws to ensure stability.
  2. Insert the pulley into the chuck and rotate the chuck. Make sure the screw is facing a direction that allows the wire to twist 90 degrees and lock the shaft.
  3. “Zero out” any offset and hang the weight slowly and deliberately.
  4. Make sure the weights are still and are not touching anything.
  5. Be sure to calibrate both sides of the machine. This will give you the proper torque read out.

 

To make sure you are consistently getting the most accurate results from your SureTorque products, Mesa Labs recommends yearly calibrations.

To meet your needs, we currently offer 3 different ways to manage your calibration:

  1. On-site calibrations
  2. Send your lab equipment to us
  3. Laboratory calibration kit

Call our offices now to inquire about Mesa’s calibration services.

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.

FOWS The power of steam: a cost-effective cleaning

 

 

 

Fedegari Lab Division latest innovation is a Lab Glassware Washer that capitalizes the experience done with FOWS-series of washers in the pharmaceutical industry.

 

The new FGW Lab Glassware Washer uses a steam generator to improve washing performances: steam has an optimized emollient effect on greasy and sticky dirt.

Moreover the use of steam can significantly reduce operating costs: this true eco-friendly solution allows to minimize the need of detergents as well as water consumption, lowering the running costs per cycle. In addition, steam is able to access hard-to-reach areas and therefore clean thoroughly. A conductivity meter placed on the FGW drain is capable to detect the water purity, helping to terminate the process as soon as the desired set-point is reached thus further reducing water and other utilities consumption of the washer.

The cleaning process is constantly supervised:

  • Dedicated probes monitoring the temperature of the air/water and of the steam in chamber
  • A dedicated trasducer controls the pressure of the circulating water.

 

Fedegari Glassware Washer has an internal LED lamp that remains operative during the whole cycle: in case of alarm evident signals are displayed by color change.

 

The piping, as any other equipment manufactured by Fedegari, has a rigorous sanitary finishing. The machine is loaded by a modular rack which could be standard or customized for adapting to all loads configurations and is directly connected to the piping.

 

As all Fedegari laboratory process equipment, the FGW is easy to use specially thanks to ergonomic loading height, a friendly process controller and the interchangeable external trolleys compatible with Fedegari FOB5 lab sterilizers.

 

As all Fedegari lab equipment, the FGW series is compliant with cGLP standards.

The FGW series is equipped with Thema4lab process controller, engineered and pre-validated by Fedegari according to GAMP5. Thema4lab is the most advanced process controller for lab applications, based on a wide library of phase groups, developed by Fedegari thanks to its experience with the highest standards in the pharmaceutical industry.

Having doubts about the Thema4, please see this podcast we did a couple of months ago for our Lunch and Learn Webinar Series.

 

On demand you can also integrate the FGW Lab Glassware Washer with your FOB5 Horizontal Steam Sterilizer.

 

For more information on this or any other Fedegari products please give us a call 800-829-5741

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.

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