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Welcome! Our goal is to provide you with industry updates on a routine bases. Each update of "In The Know" will bring you news of industry presentations, conferences, and educational information.
We hope you enjoy Lyophilization Technology's (LTI) "In The Know". Just in case you missed any of our wonderful updates, here are some important highlights that we accomplished in 2018!
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Highlights from the 2018 CPPR Freeze Drying of Pharmaceutical
Conference
s & Biologics
The 2018 Freeze Drying of Pharmaceuticals and Biologics conference on September 18th through the 21st in Garmisch-Parkirchen Germany was again a successful international event. There were twenty podium presentations and a large assembly of poster presentations. Samantha Singer of LTI presented a poster on "Differences in Sublimation Rates and Relative Partial Pressures Measured by a Residual Gas Analyzer". LTI also supported Valeria Gervasi from the School of Pharmacy at University College Cork to attend the conference and present a poster on her work, titled "Investigation into the impact of Arginine in Lyophilized High Concentration Protein Formulations". There were also tributes to Michael Pikal given by Steve Nail and Alan MacKenzie given by Ed Trappler. Both Mike and Alan were part of the conference organizing committee, and they will be greatly missed by the lyophilization community. Discussions have already started for the conference in Breckenridge, Colorado for 2020. Robin Bogner of the University of Connecticut and Alina Alexeenko of Purdue University are the newest members of the committee. We look forward to another successful conference.
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R
ecent Indu
stry C
ontributions
"RGA Use for Sublimation Endpoint Determination in Lyophilization"
Samantha L. Singer,Carrie A. Shults and Edward Trappler
Lyophilization, or freeze drying, is a process by which nearly all the water is removed from a frozen product under vacuum by sublimation, causing the ice to change directly from a solid to vapor without
passing through a liquid phase.
Sublimation endpoint determination in Primary Drying is crucial to the development of a robust lyophilization process as it directly impacts the critical quality attributes of the absence of collapse and residual moisture.
Current technologies that determine the endpoint of primary drying include direct product temperature measurement and combining chamber pressure readings of a Capacitance Manometer with a Thermocouple Vacuum Gauge. There is a growing interest in measuring the composition of the atmosphere within the lyophilizer using a Residual Gas Analyzer (RGA), a Process Analytical Technology, to ensure achieving the sublimation endpoint. This poster compares and contrasts data from conventional methods with the use of the RGA using quadrupole mass spectrometry. The effectiveness of the RGA for defining the completion of the sublimation of ice in Primary Drying is demonstrated.
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"Lyophilization in Pre-filled Syringes: Evaluating the Influence of Primary Container Material and Loading Device"
Timothy S. Dutill, Hideaki Kiminami, Yoshihiko Abe, and Kevin
Constable
Lyophilization in pre-filled syringes is a growing interest in the field of parenteral lyophilized products particularly for biological materials. These studies evaluated the influence of container construction on lyophilization by sublimation rates and finished product attributes of model systems in plastic and glass syringes.
The studies showed a direct comparison of the effects of the heat transfer characteristics of plastic versus glass syringes. Sucrose and mannitol based formulations were used as model systems to evaluate processing while using conservative and aggressive processing parameters. The sublimation rates were compared for plastic and glass syringes based on location, loading device, and average. The rates were also assessed relative to the conservative and aggressive processing parameters. Finished product attributes of a lyophilized preparation were also evaluated.
The processing data and finished product attributes will be presented. Evaluation of the data shows the impact on sublimation rates and uniform finished product characteristics for both plastic and glass syringes. The behaviour during processing will be compared for both model formulations processed using conservative and aggressive processing conditions. The resulting finished product attributes of the sucrose model formulation under conservative conditions will demonstrate the impact of both the container closure material and the loading device.
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"Particle Formation of a Freeze-Dried
Monoclonal Antibody"
John M. Stewart and Samantha L. Singer
The slow freezing rate (0.1°C/min) appears to have significantly influenced the appearance of the reconstituted solution of the mAb drug product. Despite the use of a presumed amorphous (sucrose) formulation, crystalline particles formed within the freeze-dried cake as identified by Polarized Light Microscopy and Raman Spectroscopy.
Aggregation appears to be the primary mechanism of crystalline protein particle formation as suggested by Dynamic Light Scattering.
It is likely that the freezing ramp rates during the lyophilization process play a critical role in the creation of crystalline particles upon reconstitution of the lyophilized cake. However, more work will need to be completed to determine which parts of the freezing process impact the formation of
particles. Results from this study highlight the need for cycle optimization for each drug product.
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"Comparison of Product Behavior During Lyophilization When Processed in Dual Chamber Syringes and Tubing Vials"
Michael S. Thomas
Product behavior and the influence of the lyophilization process parameters for material processed in a vial are generally well understood. Product behavior and process parameters suitable in a cartridge or, even furthermore in a syringe can be considerably different for the same material processed in a vial. This often warrants unique assignment of the critical independent variables of shelf temperature, chamber pressure and time to process with success and robustness against the challenges of the extraordinary device. The influence of the novel container/closure system of a syringe compared to the more traditional vial and stopper combination was evaluated in this series of studies. Product behavior during processing and finished product attributes from both container types were compared.
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"Particulate Detection and Location for Lyophilized Products"
Carl F. Ventura, Carrie A. Shults, and
Edward H. Trapple
r
Particulate matter in sterile parenteral products is regarded as a critical quality attribute. Due to the nature of a parenteral products being essentially free of particulates is paramount in meeting the requirements of a product for injection, as listed in the USP, Sections <1>, <788>, and <790>. Inspection of any parenteral product should detect any particles or other foreign material. Particles can arise from many sources intrinsic, inherent to the product, or extrinsic, the latter arising most often from materials shed during processing. Inspection of lyo products can be extrinsic only. Inspection of lyo products occurs after lyophilization is already complete. For a lyophilized product, there is greater exposure to potential contamination due to subsequent processing. The lack of complete visibility of any particulate material within a dried cake imposes unique challenges in the inspection of lyophilized materials. This poster provides insight into the ability to detect and the behavior of particulates during the lyophilization process, this study assessed the impact of the type of particle; the material, size, and density, as well as, the influence of the nature of the solution; density, surface tension, and viscosity.
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"Differences in Sublimation Rates and
Relative Partial Pressures Measured
by a Residual Gas Analyzer"
Alison K. Mutchler, Samantha L. Singer, Carrie A. Shults and Edward H. Trappler
Lyophilization, or freeze-drying, is a process by which nearly all the water is removed from a frozen product under vacuum by sublimation, causing the ice to change directly from a solid to vapor without passing through a liquid phase.
Sublimation endpoint determination in Primary Drying is crucial to the development of a robust lyophilization process as it directly impacts the critical quality attributes of the absence of collapse and residual moisture.
Current technologies that determine the endpoint of primary drying include direct product temperature measurement and combining chamber pressure readings of a Capacitance Manometer with a Thermocouple Vacuum Gauge. There is a growing interest in measuring the composition of the atmosphere within the lyophilizer using a Residual Gas Analyzer (RGA), a Process Analytical Technology, to ensure achieving the sublimation endpoint.
During lyophilization, measured process data indicate that the critical process parameters of shelf temperature, chamber pressure and time are within acceptable ranges. Boundary studies are performed with the intent to establish a proven acceptable range for the process. These studies also demonstrate the robustness of the process by addressing the potential impact of processing deviations that could occur unavoidably, unknowingly or unintentionally, at conditions other than the target parameters, during routine processing.
This presentation compares and contrasts data from conventional methods with the use of the RGA using quadrupole mass spectrometry while demonstrating the effectiveness of the RGA for defining the completion of the sublimation of ice in Primary Dry
ing and its ability to detect differences that occur when there is a deviation from the target cycle.
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"Parenteral Drug Manufacturing Challenger: It is mandatory to drive future progress and remove barriers to implementing innovative technology, focusing on a real application of quality by design"
Edward H. Trappler
There has been a significant expansion in the number of parenteral products. According to Genetic Engineering News (www.genengnews.com), of the 10 best-selling drugs in 2016, with sales totaling $60.9 billion, 7 were parenterals, of which 3 are self-administered. The top seller totaled $16 billion, and is available as a prefilled syringe and an auto-injector. The industry faces new and different challenges in moving from developing products to treat prevalent ailments, to less common conditions having orphan designation, to personalized therapeutics. In addition, the steady increase in parenteral products has led to the investigation and use of alternative drug delivery devices for ease of administration and improved patient compliance. These include a prefilled syringe and an auto-injector, or "pen". For products requiring a greater dose, large volume wearable injectors (LVWI) are under development as a new delivery system. The rapid growth demands an increased focus on better integration of product, quality, and manufacturing method development.
"Residual Moisture Testing Methods for Lyophilized Drug Products"
Amy M. Bosch and Edward H. Trappler
Lyophilization is a way to preserve products that are unstable in the presence of water. Removing the water from the product decreases the potential for degradation by hydrolysis, and therefore improves the shelf life. Residual Moisture content is a critical quality attribute (CQA) of lyophilized finished products as it can have a significant impact on the stability of a lyophilized product upon storage in the dried state.
There are a number of different methods to measure residual moisture content in lyophilized materials. Understanding the advantages and suitability of each method and its respective limitations surrounding the method aids in choosing the most appropriate method for testing. The goal of this paper is to review the common methods for residual moisture testing. The methods covered are Loss on Drying, Thermogravimetric Analysis, Karl Fischer Coulometric Titration, and Near Infrared Spectroscopy. Considerations when using each reach respective method will be presented. Compendial requirements in the USP, EU and JP will be highlighted as well.
Identifying TPPs and CQAs for a Lyophilized Parenteral Product"
Denise L. Miller, Carrie A. Shults and Edward H. Trappler
Quality by design (QbD) highlights product and process understanding and control, integrating quality risk management, and is also considered a quality system for managing a product's lifecycle.
A Target Product Profile (TPP) also referred to as Quality Target Product Profiles (QTPPs), is a summary of the proposed quality characteristics of a finished drug product. A TPP is a useful guide to bring focus to desired quality, safety, and efficacy. The goal of pharmaceutical development is to design and create a quality product and process to achieve delivery and performance, suitable for its intended use. A TPP forms the basis of design for the development of the product. The TPP is dynamic; to be updated as new knowledge is gained over the product lifecycle. The TPPs result from enhanced product knowledge and as such, aid in discussions with drug discovery, product development teams, clinical groups, manufacturers, as well as regulatory agencies. This allows for ease of risk-based decisions, and product and process improvements. To guide in the development process, potential Critical Quality Attributes (CQAs) are derived from the TPPs. Typical CQAs for solid dosage forms are aspects affecting purity, strength, and stability. Unique CQAs specific for a lyophilized product include aspects leading to solution and dried state stability, as well as reconstitution time, appearance of the constituted solution, and residual moisture. This is an essential application of quality by design principles and parallels those reflected in the Guidance for Industry Q8 (R2) Pharmaceutical Development. Among the benefits are increased focus during development and understanding of the unique lyophilized product quality attributes. The result is an increased level of assurance that a product meets the needs of the end user and suitability for its intended use.
This article was published in the June 2018 Issue of Pharmaceutical Technology. To
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Recent Press Releases
Lyophilization Technology, Inc. provides improved access to lyophilization resources through their new website launch.
Philadelphia, PA January 31, 2018 - Lyophilization Technology, Inc. (LTI) officially announces the launch of a new website which coincides with an expanding role as a global leader in lyophilization solutions through scientific and technical services for the healthcare industry! The new site is accessible through
https://www.lyotechnology.com.
For the full press release,
click here
.
Beyond 10 years of successful use, Lyophilization Technology targets a new generation of dedicated disposable isolators.
Philadelphia, PA March 13, 2018 -
Leveraging on more than 10 years of utilizing dedicated, disposable, soft wall, negative pressure isolators (NPIs), Lyophilization Technology Inc. (LTI) incorporates advanced design features into the next generation isolators. The new design will be based on the extensive experience in conducting both development studies and clinical material batches of sterile product.
For the full press release,
click here
.
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Upcoming Industry Events
LTI wants to meet with you! Stop by our booths at any of the following events to discuss your lyophilization needs with one of our expert staff members. We look forward to meeting with you!
CHI PepTalk 2019 - "18th Annual PepTalk Protein Science Week"
January 14-18, 2019 * San Diego, CA
PepTalk: The Protein Science Week is one of the largest annual gatherings of protein science researchers in the world. Now, in its 18th year, PepTalk features renowned speakers from academia, biotech and pharma who bring global expertise and perspective to the forefront. The international delegation of over 1,300 participants convene for intensive learning and networking to discover new opportunities, apply alternative solutions, and develop promising partnerships. LTI will be exhibiting! Stop by Booth 507 for your lyophilization needs!!
March 20, 2019 * Boston, MA
Information TBA closer to event date. LTI will be exhibiting! Table number TBA at event.
Oligonucleotide & Peptide Therapeutics (OPT)
March 26-28, 2019 * Cambridge, MA
CHI is delighted to announce a new and improved Oligonucleotide & Precision Therapeutics (OPT) Congress for 2019. To complement our 4th annual Oligonucleotide Discovery and Delivery conference we are introducing a 2 day program dedicated to Oligonucleotide CMC and Regulatory Strategies. In addition, we deliver two in-depth symposiums focusing on Drug Discovery for Rare Diseases and New Frontiers in Gene Editing and Repair. Bringing together leading discovery scientists, developers, CMC experts, regulatory specialists and technology providers, OPT Congress provides a unique opportunity to discuss advances in next-generation oligonucleotide therapies throughout the drug development process. Attend in 2019 to optimize your drug design, delivery and performance, accelerate time to market and achieve commercial success. LTI will be exhibiting! Stop by Booth 15 for your lyophilization needs!!
LEARN MORE
AACR Annual Meeting
March 29 - April 3, 2019 * Atlanta, GA
The AACR Annual Meeting program covers the latest discoveries across the spectrum of cancer research - from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy - and highlights the work of the best minds in research and medicine from institutions all over the world.
LTI will be exhibiting! Stop by Booth 2452 for your lyophilization needs!!
LEARN MORE
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