Serialization: Don’t Wait Until the Last Minute

By Kevin Swartz and Tina Gushue, IPS-Integrated Project Services

A reminder to pharma manufacturers, the Drug Supply Chain Security Act (DSCSA) deadlines are quickly approaching. Have you planned for the implementation of Transaction Documents for your packaged products and how to introduce them into your supply chain? Have you developed a strategy for implementing packaging serialized data and infrastructure?

With the coming New Year, the Drug Supply Chain Security Act (DSCSA) requires Transaction Information, Transaction History and a Transaction Statement be forwarded to your distributors with the finished packaged product. Most wholesalers have specific requirements for how to do this. Have you spoken with them? Do the right people in your organization know the requirements?

We’re only a few months out. Documents should be going through your quality departments and vetted out with dry runs to ensure you’re not only compliant, but well versed in the process.

Once you’ve got the Transaction Documents squared away, it’s time to create a strategy to implement serialization into your packaging lines by November 2017. This may seem far away; however don’t underestimate the amount of time required to develop and execute a solid, well-thought plan. There are many steps that need to be taken before these systems can go live.

First, put together an internal team that understands your corporate culture and processes to learn about the requirements for DSCSA compliance. Then, contact and interview serialization solution vendors. These include machine level printing and vision up through line control, plant data management and enterprise systems to communicate with your ERP system. Once you’ve got a solid understanding of vendor requirements for time and cost, put together your budget and capital requests quickly. As you know, the approval phase of these budgets takes time (sometimes significant time) away from your implementation and troubleshooting. Also note that it’s critical to pick the right partner-vendors. Remember thousands of other companies are speaking with those vendors too. As the deadline approaches, your first choice(s) may have lead times that exceed your timeline and costs that exceed your budget.

As you learn more about what is required from a compliance level and from a resource and education level, you may decide that 100% internal resources for the project are not available. We all have other daily responsibilities.

Now that you’ve been reminded, let’s get started!

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Manual Cleaning in an OSD Facility – Will it ever go away??

By Michael Vileikis

Manually executed cleaning techniques and procedures have been utilized to wash small change parts and equipment since the inception of oral solid dosage manufacturing. As processes, procedures and perceptions have matured the apparent risks associated with manual cleaning have become a frequently discussed topic throughout the pharmaceutical industry.

Why haven’t companies completely transitioned to automated parts washing? Capital cost is a consideration that limits some companies from an upgrade to a cabinet style parts washer. Along with the cost of the equipment and the facility modifications, specific washing racks must be designed and maintained for each set of designated components. Another consideration is that cleaning validations must be performed as new products and materials are introduced into the facility. And after your capital investment and your time and effort to complete a cleaning validation, there is still a manual element of loading the washer, which can be considered a risk.

There are many challenges and risks associated with manual cleaning, including but not limited to: Cross Contamination, Consistency, Quality and Material Handling. Consistency, or the ability to demonstrate control of your cleaning procedure, is the largest challenge associated with a manual cleaning operation.

To ensure a repeatable washing operation, all potential operators must be trained to execute the same scrubbing patterns, soap/detergent application, cleaning procedures and drying procedures. They must consistently execute required soaking or rinsing for a designated length of time, and under the same temperature of water. Also, all operators need to be trained and continually monitored to identify “visually clean” surfaces accurately.

In addition to the inherent variability in human performance, the risk of cross-contamination during manual cleaning is highly dependent on the suitability and effectiveness of the room design and material handling methods employed. Operators must physically segregate soiled components from areas in the room used for cleaning and drying to ensure that clean, dry materials will not be contaminated by dirty equipment. Manual cleaning operations in multiproduct facilities should be performed in segregated washing paths to prevent mix-up and product-to-product carry over.

A trend is emerging in the industry showing movement towards semi-automated cleaning methods. This is mainly driven by the demands of cleaning potent compounds. The total elimination of manual cleaning is not anticipated in the near future. If implemented correctly, manual cleaning can be effective and repeatable. To provide their operators with the best chance to succeed, organizations must develop sound procedures, define cleaning goals, train personnel, optimize wash room design and select proper material handling methods.

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Rapid Microbiology Methods (RMM), an alternative for traditional microbiology?

By Vilma Bonilla, MMC, President-BPTS Learning Center

Much has been published about the limitations of traditional microbiological culture-plate methods and the need of rapid methods to solve these limitations.

Traditional methods tend to be labor-intensive and take several days to obtain results. As per FDA, Rapid Methods are methods designed to provide performance equivalent to the traditional testing methods while providing results in significantly less time. Manufacturers should show that an alternative method will provide assurances of the safety, purity, potency and effectiveness of the product equal to or greater than the assurances provided by the method specified in 21 CFR Parts.

RMM include identification, qualitative and quantitative methods. Identification methods provide the name or species of the microorganism in a sample. Qualitative methods provide a presence or absence result in a sample. Quantitative methods provide a numerical result (number of microbes present in the sample.) Common technologies used in RMM include nucleic-acid-based detection, which uses DNA or RNA targets; antibody-based detection; biochemical and enzymatic detection methods, among others. Some of the benefits of RMM are shorter production cycles and shorter release time of finished products to market; also, reduction of inventory requirements, among others.

Comparison of both methods:

Microorganisms growth in media.

Cultures are visually check for microorganisms.

Microbes can only been seen when growth reaches a high number of colony-forming unit.

Use markers that can be detected by an instrument.

Many instruments detect those markers even at a low number of colony-forming units which reduces time for detection

It is slow, labor-intensive, and subjective It is easier to use and provide a much faster time to result. Are sensitive and objective in detecting bacteria and fungi compared with the traditional methods

BPTS Learning Center will be providing one-hour conference and demonstration on “Advanced Methods for Detection and Identification of Microorganisms in Controlled Environments?

Traditional and RMM methods will be compared using Genotypic Identification Method-Micro SEQ Microbial Identification System for detection and identification of a fungi. It will be held Th (4:30pm-5:30pm); Fr (3:30pm-4:30pm) @ Booth 1231. Spaces are limited.

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Part Four – Container Integrity Testing – Capping, Residual Seal Force & Laser Diffraction| Whitehouse Laboratories

PartFour_Thumbnail(1)Part Four – Container Integrity Testing – Capping, Residual Seal Force & Laser Diffraction | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

In part four of this series on CCIT, two commonly used methods – Residual Seal Force and Laser Diffraction – will be reviewed.

Parenteral Vial Capping and Residual Seal Force Testing

Residual seal force testing of parenteral vials is often performed in conjunction with helium leak testing or vacuum decay testing. Residual seal force is not a leak test, but is an indirect measure of the compressive force exerted by the stopper on the vial’s land surface. A slow, constant rate of strain is applied to the top of a capped vial and the resistance to compression is monitored and reported. The appropriate amount of compressive force is required to ensure a quality seal. Vials capped at an insufficient force may leak from the sealing surface. On the other hand, vials capped at an excessive force may experience cracking and bulging, also risking the integrity of the closure system. When used in conjunction with leak test methods such as helium mass spectrometry or vacuum decay, an optimal range of residual seal force values may be determined that correlate to a reduced risk of leakage resulting from improper capping force.

This type of testing is of value to clients aiming to establish optimal sealing parameters or those who wish to implement a sampling procedure during product production.

Laser-Based Headspace Analysis

Gas headspace analysis via laser-based analysis techniques provides a quantitative, nondestructive measure of oxygen content, nitrogen content, water vapor content, or low internal pressure in a nonporous, rigid or non-rigid package headspace.

A near-infrared diode laser light is passed through the gas headspace region of the sealed package. Light absorption, measured using frequency-modulated spectroscopy, is indicative of gas concentration and pressure. Gas headspace analysis, as a function of time, provides a quantitative measure of the total leakage rate of the test sample.

This technology is especially applicable when verifying the integrity of packages that must maintain a specific gas headspace content such as low oxygen, low water vapor, and/or low pressure. For testing, packages only need be either transparent or semi-transparent material, either amber or colorless; test samples require a minimum headspace volume and headspace path length. Vials, syringes, cartridges and bottles are all amenable to this approach.

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Part Three – Container Integrity Testing – Helium & Mass Extraction| Whitehouse Laboratories

PartThree_Thumbnail(1)Part Three – Container Integrity Testing – Helium & Mass Extraction | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

In part three of this series on CCIT, two commonly used methods – Helium and Mass Extraction – will be reviewed.

Helium Mass Spectrometry

Helium mass spectrometry, based upon ASTM F 2391-05 “Standard Test Method for Measuring Package and Seal Integrity Using Helium as the Tracer Gas” is applicable to non-porous packaging such as vials, syringes, and cartridges. Even flexible packages can be tested by helium mass spectrometry using appropriate test fixture.

Helium-filled samples are placed in a test chamber, where a vacuum is created by the instrument’s internal pumps. Leaking samples allow helium to escape, enter the test system, and be detected by an analyzer cell. The stream of helium ions hitting the analyzer cell target is proportional to the partial pressure inside a sample. From this, a specific leak rate can be calculated and reported to the user. Results can be reported quantitatively (as a leak rate), or qualitatively (Pass or Fail) if method development is performed.

This type of testing may be of interest to clients looking to accurately assess the performance of an established package or analyze the effect of processing variables, such as capping force, closure materials, etc., on the performance of a package system.

Mass Extraction

Mass extraction leak detection operates by drawing vacuum on a sample enclosed in a chamber. Once vacuum is established, the instrument monitors the amount of airflow required to sustain a specific vacuum level. The amount of flow required to keep the vacuum steady is equal to the amount of flow escaping from leaks in sample under testing. Specific test parameters must be set after adequate method development. Results are reported quantitatively, as flow rates, as well as qualitatively (Pass or Fail) according to acceptance criteria established in method development.

Mass extraction testing is applicable to any package containing headspace, including parenteral vial packages, screw-capped bottles, and flexible bags or pouches. In some cases, liquid-packages can also be leak tested by this approach if the product formulation poses no threat of clogging leak paths.

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Part Two – Container Integrity Testing – Vacuum Decay and HVLD | Whitehouse Laboratories




Part Two – Container Integrity Testing – Vacuum Decay and HVLD | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

In part two of this series on CCIT, two commonly used methods – Vacuum Decay and High Voltage Leak Detection – will be reviewed.

Vacuum Decay

Vacuum Decay leak testing is based upon ASTM F 2338-09 “Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method”. This nondestructive test facilitates the identification of package leaks that may not be visibly detectable. It operates on the principal of vacuum decay. A test package is placed into a chamber that is subsequently exposed to vacuum. Sensitive pressure transducers monitor changes in chamber pressure; a result of package headspace being drawn through any leaks present. Using acceptance criteria established through method development, quantitative test results are qualitatively judged as pass or fail.

This type of testing is applicable to any package containing headspace, including, but not limited to, parenteral vial packages, screw-capped bottles, auto-injectors, and flexible bags or pouches. Vacuum decay is generally not recommended for liquid filled packages, as proteinaceous product has the potential to clog and mask leaks. However, if vacuum decay is the preferred method, alterations can be made to the method development and validation process to accommodate liquid filled packages.

Electrical Conductivity (HVLD)

The electrical conductivity leak test, also called high voltage leak detection (HVLD), or “the spark test”, is an approach for detecting leak presence and potentially the location of a leak(s) in the wall of a nonporous package, rigid or flexible, containing liquid product. The principle of leak detection is based on quantitative electrical conductance measurements. The presence of a leak path in the proximity of electrically conductive liquid results in a drop in test sample electrical resistance, as evidenced by a spike in current above a predetermined pass/fail limit. This highly sensitive method even works to detect package defects clogged by product formulation proteins or salts. Stability studies by clients have supported the use of this technology for nondestructive leak testing a variety of product formulation types. This should be considered, however, on a product-by-product basis.

Package systems that may be tested by HVLD include parenteral vials, pre-filled cartridges and syringes, plastic containers, and plastic bags or pouches.

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Part One – Current State of Container Integrity Testing | Whitehouse Laboratories


Part One – Current State of Container Integrity Testing | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

This series of articles will review the state of Container Closure Integrity Testing (CCIT) today and the various methods currently available, the factors for choosing the most optimal method and current regulatory guidelines under development.

Dye and microbial ingress testing have long been employed for assessing the integrity of container closure systems. However, research and experience as shown such tests are limited in their ability to provide accurate, sensitive and reliable data for definitive container closure integrity verification, especially for packages that demand the highest degree of product protection.

With the advent of new technologies, various sensitive and data-producing test methods have been developed to bring package integrity testing into the 21st century. The development of these new and improved methods over the past 10 years has led to regulatory agencies taking a fresh look at how to best guide industry. Within the next few months the United States Pharmacopeia will publish new General Chapter 1207 that deals specifically with container integrity and will outline in detail the various methods that industry can use. These new and improved Container Closure Integrity Tests have been successfully used to

  • characterize packages and materials,
  • optimize sealing parameters,
  • evaluate package storage temperature impact,
  • replace sterility tests for product stability batches,
  • screen production lots for faulty packages, and
  • support regulatory submission applications for product commercialization around the world.

The new USP 1207 chapter will prove to be a useful guide for companies that are in need of CCI testing. As this area of qualification is often misunderstood, the initial draft of the general chapter has taken a basic approach and will dedicate a section to each of the methods that may be employed. In addition, the chapter will discuss all the factors that must be considered when choosing the most optimal method. Key factors test method selection include package type, chemical make-up of product, type of seal and storage conditions.

With so many variables under consideration, there will not be one method that will satisfy all the CCIT needs of a company. Over time, the industry will need to have the ability to employ all the various methods if they are to insure that their products and package systems meet the stringent GMP regulatory requirements.

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