Developing a Best Practice Guide for Leachables Risk Assessment, Study Design, and Analytical Methods

Transcription

1 Developing a Best Practice Guide for Leachables Risk Assessment, Study Design, and Analytical Methods Single-use systems (SUS) offer biopharmaceutical manufacturers significant gains in process flexibility, speed, and efficiency. Implementation of Single-Use Systems and components in biopharmaceutical manufacturing processes has increased rapidly in recent years. SUS are comprised of polymers, and their manufacturing process can utilize a variety of chemical processing aids (i.e. wetting agents, slip agents, plasticizers, antioxidants, blocking agents). In this manner, any polymeric processing component that has product or process fluid contact can contribute chemical entities to the fluid or product. Generally, these entities include oligomers, plasticizers, antioxidants, slip agents, or degradation products. The potential for these entities to be introduced to the product or process fluid is an inherent risk when implementing SUS into biopharmaceutical manufacturing processes. Potential additive entities may be in the form of extractables or leachables. Extractables are organic or inorganic chemical entities that can migrate from a material under aggressive conditions such as elevated temperature, extreme surface exposure, and/or aggressive solvent systems. Leachables are organic or inorganic chemical entities that can migrate from a material under normal processing conditions. Leachables are often, but not always, a subset of extractables. As knowledge about extractables and leachables grows, biopharmaceutical manufacturers and regulatory bodies are taking notice and trying to implement strategies to ensure that appropriate evaluations can be completed to adequately protect patient safety. Presently, there are no specific regulations for extractables testing for SUS. In contrast, there are regulatory guidelines and regulations from FDA (21 CFR ), and EMEA (EMEA/ CVMP/205/04) for leachables in drug product. 21 CFR (a) specifically states that Equipment used in the manufacture of drug product shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, strength, quality, or purity of the drug product beyond the official or other established requirements. The BioPhorum Operations Group (BPOG) Extractable Work Group is composed of subject matter experts from 20 biopharmaceutical manufacturers. In 2014, the Extractables Work Group established and published a standard protocol for extractables testing of SUS components. The standard extractables protocol provides information on: extractables testing methods, sample preparation, extraction conditions, Kathryn McGohan Scientist I Bristol-Myers Squibb Kathryn McGohan is a Scientist I within the Materials Science group of the Global Manufacturing Sciences & Technology organization at Bristol-Myers Squibb. Kathryn is responsible for the selection, qualification, and validation of single-use products for use in late stage development and commercial biopharmaceutical manufacturing processes (U.S. and ex-u.s.). Kathryn also supports the authorship of CMC regulatory filing sections, new product launches, and continuous improvement efforts. Kathryn currently represents Bristol-Myers Squibb on the BioPhorum Operation Groups (BPOG) Disposables Workstream. and guidance for reporting extractables data. Adoption of the standard extractable protocol by suppliers would ensure that a comprehensive and consistent set of extractables data is available to the end users for assessment. Availability of these data would also benefit suppliers, as it would allow end users to more readily implement new SUS into their manufacturing processes. Another working group has been formed to address the topic of leachables. The BPOG Leachables Work Group is composed of subject matter experts from 22 biopharmaceutical manufacturers. The BPOG Leachables Work Group has been working collaboratively toward developing an industry best practice guide to ensure a robust and streamlined approach to understanding the materials used in the process, their impact on the process, and eventually the API. Regulators and biopharmaceutical manufacturers agree that a risk-based approach to assessing the issue of extractables and leachables is appropriate. Per ICH Q9 guideline, Quality Risk Management offers guidance on Drug Product, It is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of the drug (medicinal) product remain consistent with those used in the clinical studies. 6 BioPharma Asia July/August 2016 Augmented Reality powered by Aurasma 4

2

3 Biopharmaceutical manufacturers must assess the various materials used in their respective manufacturing processes. This assessment should begin with a thorough review of the extractables data available for each component. Once the extractables data has been reviewed, further assessment is required to ensure that the components used are compliant with the CFR requirement. Performing an effective assessment requires an understanding of the conditions under which the SUS components will be used in the actual manufacturing process. Consideration must include: Toxicological Risk: Final Drug Product safety Product Quality: Impact on final drug product quality i.e. stability, activity Process Performance: Impact on process performance, i.e. cell growth The regulations and guidelines that are currently in place do not provide details on how to assess risks, how to design a test plan, how to perform analyses, or how to interpret the extractables and leachables profiles. The BPOG leachable work group proposes that a scientific approach be used, whereby process knowledge and experience gained during manufacturing of batch lot(s) during different phases of drug development is leveraged towards a comprehensive process understanding and associated risks. BPOG supports using the principles of risk management / assessment to better identify, evaluate, communicate and mitigate extractables / leachables risks to product quality and patient safety. To this end, the BPOG Leachables team is developing a Leachables Best Practices Guide. This Best Practice Guide is comprised of three main sections described below: The Risk Assessment Model, Leachables Study Design, and Analytical Methods. The Risk Assessment Model: The Risk Assessment Model will guide the user through an assessment which considers various aspects of any polymeric materials used in the drug manufacturing process as well as the conditions under which the SUS are used within the process. The BPOG leachable work group Risk Assessment Model Best Practice guide is aligned with the ICH Q9 guidance on Quality Risk Management (QRM). The QRM guidance indicates that the evaluation of risk to quality should be based on scientific principles and ultimately link to the protection of the patient. The BPOG Risk Assessment model aims to allow for science and risk based assessments of leachables that are built upon a foundation of comprehensive process knowledge, which is key to quality by design principles. The comprehensive process knowledge required include, but is not limited to: understanding of data that has been gathered through Related Product Focus - Finesse Leverage cutting-edge automation and maintain flexibility in system operations The Finesse SmartFactory platform integrates and automates process control, batch automation and data management for your bioprocess facility. SmartFactory features an open architecture that lets you choose the equipment best suited and priced for your unit operations regardless of manufacturer. SmartFactory provides seamless integration and control of vessels and skids from top bioprocessing equipment vendors at a commercial scale. Mix and match equipment or add intelligence to your existing infrastructure to get more out of your facility network. SmartFactory lets you select the level of automation required for each unit operation. You can also focus simultaneously on the compatibility of single-use materials between upstream and downstream for global process yield optimization. And in the case of multi-product facilities, the ability to reconfigure the process train, depending on the campaign of the molecule being produced is extremely important. Process flow can be designed in a modular and scalable manner while maintaining quality and regulatory compliance in electronic batch records at the same time. With a SmartFactory, you leverage cutting-edge automation, enabling you to produce higher yields, significantly reduce labor and capital expenses, and maintain flexibility in your system operations. 8 BioPharma Asia July/August 2016

4 research and development studies, process descriptions, batch records, standard operating procedures, technical reports, data trending, and operating parameters. The BPOG Risk Assessment Model provides key material, process, and operating attributes to consider for Extractable/Leachable assessments. The properties of the solution in contact with the component of interest is a key consideration. Solutions with higher solvation power, such as organic solvents, can increase penetration into polymeric materials, which increases the propensity for leachables to be contributed into the fluid from the component. Based on this, solutions with lower relative solvation power represent a lower risk for leachables. Similarly, higher temperatures and/or longer durations of contact increase the likelihood of leachables to be added. Therefore, processes that occur under high temperatures or over longer periods of time represent a higher risk of leachables than do low temperature or short duration processes. Another important consideration is the volume of solution in contact with the component relative to the solution contact surface area. Solutions that have high volume relative to surface area provide some dilution of potential leachables, reducing the potential for impact as a result of those leachables. Another important risk factor is the distance along the production stream. A leachable compound that is introduced into a process stream prior to purification or clearance steps is less likely to be forward processed and persist into the API. Therefore risk increases from Vial Thaw and Upstream steps through Drug Substance Filling, and up through Drug Product Fill /Finish Steps. Using these key factors, the BPOG leachables team is developing a tool to perform a risk assessment that is quantitative or qualitative, based on the preference of any given individual company. The tool is standardized in that it provides key parameters, but it is also flexible to fit a wide variety of end user quality systems/approaches. Within each attribute, individual companies have the ability to customize the levels of risk and cutoff points, as deemed appropriate based on their process knowledge and risk tolerance. Another important consideration for any extractable or leachable evaluation include: pre-treatment steps, such as autoclaving, gamma irradiation, water for injection or buffer flushes, etc. These pre-treatment steps have the potential to impact the extractable/leachable profile for a given component, and as such should be considered in the overall evaluation. Using the risk assessment model, SUS applications can be ranked into High, Medium, and Low Risk categories. This ranking allows the company performing the assessment to determine whether extractables data is sufficient to support a given SUS application, or whether further evaluation and/or leachables testing will be required. This also allows prioritization of evaluations and leachables studies to ensure that the higher risk applications can be identified and thoroughly evaluated. Leachables Study Design Once a process is well understood, and the SUS applications requiring leachables testing have been identified through use of the risk assessment model, a leachable study will be developed to support the application. The leachable work group Leachable Study Design Best Practice Guide is in development with the goal of providing users with the key parameters to consider when designing a study to ensure robustness and efficiency. A robust study will support the full range of possible manufacturing or storage conditions, which increases overall efficiency. In addition to being robust and efficient, it is important that a study be designed appropriately for the component type and application that will be supported. The Best Practice Guide will provide recommendations for customizing study design based on the type of component (e.g. filter, storage, processing) and application under consideration. With a well thought out study design, a user can design and execute a study once and be able to leverage the results from that study for other similar process steps (technical transfer, similar applications, etc.) where applicable. The Leachable Study Design section will present parameters to consider when designing a study. As a result, an end user can efficiently design a study to support the full range of their manufacturing process conditions to more thoroughly understand the potential leachables that may be present in their in-process streams and products. This will allow maximum value to be garnered from the data generated. Several key design parameters described in the Best Practice Guide are the same as considerations which increase the risk to process. Since contact duration and higher temperatures increase the risk of leachables, the leachables study design should be developed in order to bracket the longest possible duration of contact as well as the highest potential temperature. Also, the guide presents options for studies that will need to be carried out over long periods of time ( 6 Months) to support storage. For example, when designing a long-term study, users should consider interim time points. For each time point, a separate control and test sample should be used in order to mitigate any risk of contaminating a pooled sample during aliquoting. This will also reduce the possibility for inaccurate results due to varying surface area to volume ratios over time due to aliquot removal. Other considerations described in the guide will include: sample handling, i.e. using a scale down approach and developing an appropriate surface area to volume ratio for testing, pretreatment of samples (gamma irradiation or steam sterilization), and appropriate storage of samples as well as control materials. The guide will also provide information on selecting an appropriate solvent for testing. In most cases it is best to select actual process streams/fluids. At times, this not possible due to availability or analytical interference concerns. In these cases, users can use a worst-case solution or other alternate solution and present an appropriate justification for July/August 2016 BioPharma Asia 9

5 that choice. In addition to providing a framework for designing an appropriate and robust leachables study, the Leachables Study Design section of the BPOG Best Practice Guide is intended to provide regulatory agencies with information. The information can be used to bolster the agency s ability to evaluate the strength of data packages which have been provided to them by manufacturers in support of their manufacturing operations. Ultimately, by helping companies to develop appropriate study parameters, and facilitating strong Health Authority evaluation, the Best Practice Guide will benefit patients through an increased assurance of safety. This goal is paramount in the mind of both drug manufacturers, and health authorities. Analytical Methods Once the parameters of the leachable study have been established, users must determine what analytical methods will be used to detect any leachable compounds present in the samples. The leachables work group Analytical Methods Best Practice Guide is in development to provide industry with key considerations that users are able to identify and to assess any leachables detected through a leachables study. The Analytical Method section is designed to provide recommendations to users for the selection of methods, method parameters, and method performance indicators so that the maximum amount of information can be gathered from samples generated through well-designed leachables studies. Enhanced detection, identification, and quantification of leachables will ultimately lead to a better understanding of Single Use Systems and components through availability of more accurate and reliable data. This will allow toxicologists to generate well informed conclusions about the impact anticipated to the patient from the leachables species that may be present in a formulation. The Analytical Methods Best Practice Guide is being developed under the assumption that an acceptable extractable study has been conducted, and therefore information on the potential leachables is available - see BPOG Standard Extractables Protocol for Biopharmaceutical Single Use Systems and Components. Based on the Standard Extractables Protocol, the Analytical Methods Best Practice Guide will recommend a robust approach that includes the use of analytical techniques that can screen for potential unknowns or unexpected entities. The guide also provides options for a more targeted approach to be used when applicable. The main analytical methods recommended are listed for each analyte class, and are not limited to: Organic Volatiles o Headspace Gas Chromatography with Mass Spectrometric o Headspace Gas Chromatography with Flame Ionization Organic Semi-Volatiles o Gas Chromatography with Mass Spectrometric o Gas Chromatography with Flame Ionization Organic Non-Volatiles o Liquid Chromatography with Mass Spectrometric o Liquid Chromatography with Photo Diode Array Inorganic (Trace Elements and Heavy Metals) o Inductively Coupled Plasma Mass Spectrometry o Inductively Coupled Plasma Optical Emission Spectrometry In cases where other techniques have been used in an extractables study, those techniques should be utilized in the leachables study as well. Also, other techniques may be used for leachables studies where applicable and necessary to supplement the data generated through the main analytical techniques. For each analytical method, appropriate internal standards and reference materials are recommended to monitor the performance of the analysis, as well as to establish the level of the determined leachable species. The Analytical Method Best Practice Guide will also provide users with recommendations for instances when a specific compound reference material is not available. In addition to recommending the analytical methods used, the Best Practice Guide will provide users with information to assist in developing appropriate Analytical Evaluation Thresholds (AETs) and Safety Concern Thresholds (SCTs). The SCT can be based on Product Quality Research Institute (PQRI) recommendations proposed for parenteral drug products and accepted for orally inhaled and nasal drug products (Ball D, Blanchard J, Jacopson-Kram D, et al. Development of safety qualification thresholds and their use in orally inhaled and nasal drug product evaluation. Toxicol Sci 2007; 97(2):226-36). Specific recommendations are detailed in the Analytical Method Best Practice Guide. The Best Practice Guide will also provide recommendations for validation of leachable methods where necessary following the ICH Q2 guidelines. Validation of quantitative methods may include the characteristics of: accuracy, precision, specificity, detection limit, quantitation limit, linearity, and range depending on the intended use of the method. Validation of limit test methods may include specificity and detection limit. Furthermore, unexpected compounds observed in the analysis may need to be validated into the method if they reach an established SCT level. Leachables data reporting recommendations will also be described in the Analytical Methods Best Practice Guide. 10 BioPharma Asia July/August 2016

6 The BPOG Leachable Working group suggests summarizing data into a report inclusive of representative chromatograms and raw data tables. Additionally, the report should include analytical conditions for each technique. Specific suggestions for analytical parameters and method performance criteria are also detailed in the Analytical Methods Best Practice Guide. Summary The protection of the safety of our patients is the foremost responsibility of any biopharmaceutical manufacturer. The BPOG Leachables Working Group team has been working collaboratively to develop a Best Practice Guide that provides an end to end strategy for handling the complex issue of Single Use System components and their potential process additives. The Best Practice Guide includes the following three subsections: Risk Assessment Model Leachables Study Design Analytical Methods. Adoption of the BPOG Leachables Best Practices will enable biopharmaceutical manufacturers to develop a customized strategy to perform a risk assessment that enables efficiency through knowledge based prioritization of required work. It will also facilitate development of well-designed and robust leachable studies which rely on appropriate analytical methodologies to detect, identify, and quantify any leachable species present. In turn, this will enable enhanced accuracy and reliability of leachables data. Accurate data supports more precise toxicological understanding of the potential impact of the leachable profile to patient safety, maintaining product quality. The Best Practice Guide will also assist regulatory bodies in assessing the strength of data packages presented by biopharmaceutical manufacturers. This ultimately benefits patients through increased assurance of safety. Acknowledgement This article is based on the work of subject matter experts from 22 BioPhorum Operations Group member companies. The guide - BEST PRACTICES FOR MITIGATING RISK FROM LEACHABLES IN SINGLE-USE SYSTEMS - will be freely available on the BPOG website ( biophorum.com/) when it is published in November Related Product Focus - GE Healthcare Life Sciences Reliable supply, predictable performance GE Healthcare s ReadyToProcess chromatography columns help you plug right into today s challenges. The columns are supplied prepacked and ready for use to simplify and accelerate bioprocessing, reduce time-consuming routines, and ultimately increase your manufacturing agility. With a robust column design and validated packing methods, the columns exhibit high lot-to-lot consistency. ReadyToProcess columns are available with a range of BioProcess chromatography resins in five different sizes. Reliable supply Reliable and predictable supply of manufacturing tools under all circumstances is key to meet your goals. A standardized column format allows off-the-shelf availability of ReadyToProcess columns, for short delivery lead times. As a supplier of both resins and prepacked columns, GE Healthcare takes responsibility for the complete supply chain, from chromatography resin production to the final prepacked ReadyToProcess column. ReadyToProcess columns are covered by our extensive security of supply program for chromatography resins. Predictable performance ReadyToProcess columns are delivered presanitized, prequalified, and ready for use. With a robust design and a validated packing method for each resin, the columns offer a predictable performance. Each individual ReadyToProcess column is qualified by efficiency testing against its validated specifications, and every column is supplied with a certificate of analysis and a customer reference sample. July/August 2016 BioPharma Asia 11