A few years ago, a big pharmaceutical company entered into a joint development agreement for a large molecule therapeutic agent with a small biotech company. The formulation was to be freeze-dried, and formulation development, as well as early process development, was carried out by development scientists at the biotech company. At the time, the development scientists had no clear idea of where scale-up and, ultimately, production scale operations would take place. It was known that the formulation itself was very robust; that is, it could be freeze-dried under very aggressive conditions without compromising any quality attribute of the product, such as cake appearance, reconstitution time, recovery of original activity, or residual moisture level. The development scientists at the biotech company tried to take advantage of the robustness of the formulation by recommending aggressive cycle conditions that resulted in a relatively short freeze-dry cycle. A contract manufacturer was chosen and a scale-up batch was prepared using the suggested cycle conditions. The scale-up batch did not go according to plan. Pressure in the freeze dryer chamber could not be controlled, but rather oscillated between alarm limits. When the pressure reached the upper alarm limit, the power to the heating elements in the heat transfer fluid was cut off. As a result, the sublimation rate decreased and the chamber pressure dropped to the lower limit. In response to the pressure drop, the heating elements turned on again, resulting in a pressure rise to the upper limit, and the cycle repeated. The failed scale-up run caused a significant delay in the product development timeline.
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The underlying cause of the failed scale-up lot was a phenomenon known as choked flow [1, 6, 25, 26, 33], which we will not elaborate on here, but this event is a good example of the importance of understanding equipment capability. Any freeze dryer has performance attributes that limit the sublimation rate it will support—refrigeration capacity, condenser surface area, the upper temperature limit of the heat transfer fluid circulating through the shelves, system geometry such as vapor duct length and diameter, or the dynamics of vapor flow from the chamber to the condenser. It is important to know which factor, or factors, limits performance, as well as the maximum sublimation rate supported by a given freeze dryer. Understanding equipment capability or performance is a point of emphasis in the Quality by Design (QbD) regulatory paradigm [38], and has taken on increased visibility in light of the development of a graphical design space approach to optimization of the primary drying phase of a freeze-drying cycle [21]. One of the boundaries of the graphical design space is the equipment capability curve or the maximum sublimation rate supported by the equipment as a function of chamber pressure. This capability curve can vary widely between laboratory and production scale. Ideally, the optimized primary drying conditions should be based on the capability of the equipment intended to be used for the commercial manufacture of the drug product.
While the use of new process analytical technology has aided in freeze-drying process understanding, most processes are still run conservatively [20, 23, 24]. The conservative approach often taken is in part due to insufficient quantitative understanding of equipment capability. Unfortunately, the determination of the equipment capability curve is often not part of the traditional equipment qualification procedure. This limited equipment understanding has two negative consequences. First, drug products manufactured using an overly conservative freeze-dry cycle carry with them a “hidden cost” in the form of an excessively long process, and this cost stays with the product for its entire life cycle. Second, manufacturing management often has no idea of the true capacity of a freeze-drying plant because they do not know how long the freeze-dry cycles would be if the drug products were freeze-dried using more optimal conditions.
Thus, thorough equipment qualification data should be the link between laboratory and manufacturing scale freeze-drying operations, enabling seamless scale-up. Unfortunately, quite often, little time is set aside for performing thorough equipment characterization at the production scale. The performance qualification strategy should be designed to systematically identify characteristics of the equipment that not only test the limits of the equipment but also provide process relevant information using known, relevant product loads. Often, this exercise may be set aside for execution during equipment downtime which makes it even more expensive and, furthermore, limits the time needed for a systematic characterization.
The current work is aimed at summarizing the current best practices in performing pharmaceutical freeze-drying equipment performance qualification. The focus will be on disseminating a living guidance document that is updated periodically to incorporate the use of new technologies and challenges for understanding complex interactions between the freeze-dried product and the equipment used. The information is provided for use by development scientists, validation and operations engineers, technicians, and operators alike in the bio/pharmaceutical manufacturing industry, and the practices outlined in the documents are designed for voluntary use by anyone in the freeze-drying community. The recommendations presented here are based on experimental measurements supported by computational fluid dynamics and past experiences on (a) shelf temperature mapping requirements; (b) equipment capability testing; (c) condenser performance metrics; and (d) leak rate testing of the freeze dryer. Clean-in-place (CIP) systems, as well as sterilize-in-place (SIP) systems, are not in the scope of this document but may be covered in subsequent best practice documents.
Typical equipment testing strategy starts with design review/qualification and manufacturer internal testing. During this testing, non-conformance of required materials/finishes to surfaces, parts/assemblies, programmed sequence, and safety requirements is identified and corrected. This is followed by functional and documentation verification at the equipment manufacturer’s factory, commonly referred to as factory acceptance testing (FAT). Subsequently, the verification shifts to the end-user site first with the installation qualification (IQ) for conformance to design specifications, where documentation, blueprints, and drawing compliance are verified. The operational (OQ) and performance qualification (PQ) testing conclude the equipment testing strategy. Here, the characteristics of the equipment are tested first for operational requirements at no load and then under known, relevant product loads. The end-to-end process is time-consuming and can often take 4–5 years from supplier selection, procurement, and design review to installation with the end of performance qualification. It is estimated that 6–9 months could be saved in this end-to-end timeline, for example, by eliminating the need for customized protocol development requiring multiple working sessions with documentation and subsequent review cycles. Industry-wide consensus on the qualification process, standardized through a focus on scientific merit, could prevent unnecessary costs and delays in the timeline.
Standardized testing will undeniably benefit the industry in eliminating performance testing that (a) provides little process relevant information such as maximum heating and cooling rates for a shelf under no load and (b) is not based on a scientific rationale, but carried out merely for comparisons with legacy equipment. It is not uncommon to follow a test protocol merely because it was once executed on older equipment and has since erroneously become a benchmark for comparisons. Furthermore, industry-wide standardized consensus can reduce time lost in the unnecessary debate over appropriate test protocols often encountered today which in itself is a lengthy process. Here, we focus on three key areas of freeze dryer performance qualifications, the shelf mapping, the condenser, and the equipment vapor transport capabilities. These three areas are selected because of their importance to provide process understanding and control strategies for validation of pharmaceutical lyophilization [36].
Arnab Ganguly: overall leadership and direction for outline and completion of this paper; substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Lisa Hardwick: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Serguei Tchessalov: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Steven Nail: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Dan Dixon: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Frank Kanka: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Anthony Guidinas: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
TN Thompson: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Cindy Reiter: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Zakaria Yusoff: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Ted Tharp: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Joe Azzarella: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Prerona Sharma: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Petr Kazarin: responsible for consolidating the information contributed by all the authors and compiling it into a cohesive single document. He was also responsible for editing the contents of the contributions and discussing with authors regarding the information they provided for its clarity. He also worked with data to ensure all graphics meet publication requirements.
Alina Alexeenko: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Michael Pikal: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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