Disposable Technology and Single-Use Systems. Regulatory Perspective, Best Practices and Future Trends of Extractables and Leachables

Master's Thesis, 2015

51 Pages, Grade: 1.1


Table of Contents


List of Figures Tables

List of Acronyms

1. Introduction

2. Literature Review
2.1 Overview
2.1.1 History
2.2 Single-Use Technology (SUT)
2.2.1 Advantages of SUT
2.2.2 Concerns with SUT
2.3 Regulatory Outlook
2.4 Primary Data

3. Current Methodologies for EL testing
3.1 Extractable and Leachable studies
3.1.1 Solvent selection
3.1.2 Worst-case conditions
3.2 Extraction Techniques
3.3 Analytical techniques
3.4 Evaluation of Data
3.5 Leachables Studies
3.5.1 Application-specific evaluation

4. Regulatory Perspective
4.1 Official guidance documents
4.2 Industry groups contributions
4.3 Current Regulatory Outlook

5. Risk Assessment Current Best Practice
5.1 Risk Identification
5.2 Risk Analysis
5.2.1 Quality by Design
5.3 Risk Control
5.4 Risk reduction

6. Conclusion
6.1 Discussion
6.2 Future trends and improvements

7. Bibliography

8. Appendices
8.1 Appendix – A
8.2 Appendix – B
8.3 Appendix – C
8.4 Appendix – D
8.5 Appendix – E


First and foremost, I would like to take this opportunity to express my thanks to Dr Sarah Hehir, my project supervisor for your guidance and support throughout the completion of this dissertation. I would also like to extend my thanks to my work colleagues for their continued support, constructive criticism and friendly advice during this project. To the many industry professionals working in this field that gladly participated in my research questionnaire and willingly shared their expert knowledge with me on a number o f issues related to the project, I am very grateful. Finally, I would like thank my family and boyfriend, Emmet for their continued support and encouragement throughout the past two years completing this master’s course.


With the adoption of Disposable and Single-use manufacturing equipment on the rise, it is logical there is an industry push to develop a standardised set of testing requirements to thoroughly evaluate the impact of extractable and leachable (EL) contaminants on patient safety. The main objectives of this work are to critically evaluate the preliminary research previously undertaken on the subject area of Single-Use Systems (SUS) with emphasis on the data currently generated from vendors of single-use systems, the need for harmonised supplier data, current methodologies and best practices employed for EL testing, and also identification of key areas that warrant further study.

This will be accomplished using both quantitative and qualitative research methods where primary data is sourced directly from interviews with experienced professionals in the field. The secondary information is obtained from the critical analysis of scientific publications, scholarly articles, databases, and use of statistical data generated from recent surveys on the challenges EL present and how industry have addressed this matter thus far.

From an extractables and leachables viewpoint the regulatory outlook is still quite uncertain. Some SUS suppliers deliver a very strong data package which satisfies the needs of the drug product manufacturer while others fail in this regard. So, in that sense the evaluation of extractables and leachables remains a grey area at present. The challenge for the industry now is to achieve uniformity of data across multiple single-use vendors to facilitate end user risk assessment and compliance for future regulatory submissions and better patient care.

List of Figures & Tables

Figure 1: Schematic of the WAVE bioreactor

Figure 2: Composition of Sartorius Stedim Biotech Flexel 3D disposable bioprocessing container

Figure 3: Pharma IQ survey 2014 - The main drivers for implementing SUT

Figure 4: Venn diagram illustrating the relationship between Extractables and Leachables

Figure 5: Safety Assessment Triad

Figure 6: Example of packaging concerns for common classes of drug products

Figure 7: Establishing an EL study through partnership

Figure 8: Quality by Design (QbD) Model

Figure 9: Role of change control in polymer supply chain

Figure 10: Flowchart illustrating the various options of leachables testing using the actual drug formulation

Figure 11: Extractables and Leachables evaluation flowchart

Table 1: Example of Solvent selection for an extraction study

Table 2: Model of Analytical package used for full leachables study

Table 3: Common extractables in materials used to manufacture disposable assemblies

List of Acronyms

Abbildung in dieser Leseprobe nicht enthalten

1. Introduction

The application of Disposable and Single-Use Systems is currently in a state of remarkable growth, as this revolutionary technology continues to rule as a hot topic in the Biopharmaceutical industry (Kapp et al., 2010). In recent years, the subject area has generated considerable interest, where the adoption of Single-Use Systems (SUS) across the manufacturing process has produced significant benefits compared to the use of traditional stainless steel equipment. Amongst the many advantages SUS offer, the most evident benefits include a substantial reduction in long-term financial costs, reduced risk of cross- contamination, shorter time to market, elimination of cleaning procedures together with improved safety and lower environmental impact.

Until recently, biomanufacturing facilities have heavily relied on the use of classical technology which largely consists of inflexible, hard-piped equipment and stainless steel tanks (Shukla and Gottschalk, 2013). However, since the evolution of single-use systems, it has led to the development of improved key capabilities and technological advancements in the field. As a result, it is now possible to exploit disposables for almost all stages of upstream and downstream processes. The end-to-end processes of a manufacturing facility has steadily evolved to potentially become fully disposable assemblies (Shukla and Gottschalk, 2013). While much progress has been made in this field, there still remain some significant challenges ahead where single-use technology is employed.

One of the key areas of growing interest, and indeed concern is the topic of Extractable and Leachable (EL) contaminants, and the potential risk they pose to the safety and efficacy of the final drug product. For many companies, the evaluation of single-use systems for extractables and leachables is unfamiliar territory (Bestwick and Colton, 2009). As a result, the introduction of this technology has not been entirely welcomed across the industry, as many have expressed concerns in relation to these specific challenges facing end users (Ding and Martin, 2010). In contrast to traditional stainless steel equipment, disposable processing material consists of various polymeric substances which over time have been shown to leach out foreign material. This raises uncertainty over the safety, efficacy, and stability of the pharmaceutical drug product, potentially rendering it unsafe for use, and so it is for this reason that these degradation products continue to be a major focal point in the implementation of disposable systems (Yu et al., 2008).

Extractable and Leachable substances are generally recognised as potentially toxic, carcinogenic, mutagenic, teratogenic, or harmful to reproductive organs. It therefore, becomes essential to evaluate the safety of these compounds during the research and development process of a new drug [9]. Much of the debate surrounding the issue of EL testing resides in the fact that a standardised set of requirements for the assessment of EL in support of a drug product for regulatory approval does not yet exist. This situation becomes even more complex for end users with increasing pressure from regulators to demonstrate product safety [2].

Thus, the purpose of this research is to deliver a comprehensive account of the existing challenges facing suppliers and end users in relation to the assessment of Extractable and Leachable compounds. This will be achieved through the critical evaluation of research previously undertaken in the subject area of Disposable technology. This dissertation also aims to highlight the growing concerns surrounding appropriate testing requirements for EL regulatory submissions, with emphasis on the data currently generated from vendors of SUS, the need for harmonised supplier data, the role of risk management, and current best practices employed for EL evaluation.

Another objective of this research is to examine the current methodologies and best practices used to model a single use system and drug product, with a view to generating an EL profile through a mimic or modelling approach. Also, to consider the current regulatory landscape, role of suppliers, industry group contributions, and how risk management tools are key to designing an EL programme in such challenging circumstances. Lastly, to propose recommendations for continuous improvement, and to highlight the growing trends that will ultimately enhance the performance and market penetration of disposable manufacturing in the future.

2. Literature Review

2.1 Overview

The last two decades has seen Disposable Technology and Single-Use Systems emerge as state-of-the-art polymeric platform solutions, which have attracted much attention from research teams globally. So what exactly is it about single-use technology that makes it so innovative? An industry report issued by Pharma IQ claim that single-use systems have radically transformed New Product Development (NPD), as it demonstrates the key capabilities to completely replace conventional stainless steel equipment. From its use in clinical trial studies, Single-Use Technology (SUT) has now expanded to meet the demand for commercial manufacture of novel biotechnology products [3].

(Kapp et al., 2010) explain that due to the low probability of drug products going from concept to full commercialisation, there is now a large niche in the market for a manufacturing platform such as SUT which is adaptable, cost effective, and provides the key capabilities required to test a variety of potential drug concepts. This avoids the long-term commitment of a substantial investment on a production facility that may never produce a commercial product. Pharma IQ maintain that end users can benefit from complete control over their entire process, as SUT provides flexible equipment which can be easily customised to meet the requirements of the end user compared to a “one size fits all” approach of fixed stainless steel equipment [2].

2.1.1 History

A brief account of the history behind flexible polyvinyl chloride (PVC) bags and their use in biomedical applications is given in an article by (Kapp et al., 2010). Their evolution began as storage bags for blood and its components, largely replacing the traditional glass bottle due to its greater sterility, reduced risk of contamination, and lower associated costs. Following this, the transition of PVC bags into parallel markets was a natural progression to SUT as we now know it. One of the first examples of Disposable bag systems is presented in (Shukla and Gottschalk, 2013) where the author describes its first application in cell culture. This is significant in that it marks the first areas of bioprocessing to benefit from this t echnology. Single-use technology originates back to its initial use in laboratories several years ago, where its use as disposable tissue culture flasks was commonplace.

However, for biopharmaceuticals large scale manufacture was limited to the early stages of cell culture which involved the use of shake flasks or T-flasks. According to (Shukla and Gottschalk, 2013) it was the launch of the WAVE bioreactor in the year 1996, which marked the introduction of the original single-use equipment which was then implemented for large scale production. Following this, a range of other disposable bioreactors such as the Orbitally shaken bioreactor, Pneumatically mixed bioreactor, and Stirred tank bioreactor were developed in succession. Since then, the number and sophistication of single-use assemblies has steadily grown (Whitford, 2010).

Abbildung in dieser Leseprobe nicht enthalten

Figure 1: Schematic of the WAVE bioreactor (Source: 26)

2.2 Single-Use Technology (SUT)

What exactly constitutes a Disposable or Single-use system? The following definition describes a commonly used industry definition for single-use systems, as defined by Bio- process Systems Alliance (BPSA). “Single-use systems consist of fluid path components to replace reusable stainless steel components”. Although this definition is quite simplistic, nevertheless it remains a straightforward description of what SUS represent. A comprehensive range of polymeric single-use products currently exist, including disposable bags and containers, tubing and connectors, filters and chromatography columns which encompass a wide range of capacities.

A polymer is described as a large macromolecule composed of many smaller repeating units containing Carbon, Hydrogen, Oxygen, Nitrogen, Silicon, Chlorine, Fluorine, Bromine, Phosphorus or Sulfur. Polymers typically exhibit a linear or branched framework where the molecular mass can vary from a few thousand to several million grams per mole (g/mol). The main groups are classified as Elastomers, Thermoplast, and Thermo sets. The mechanical strength of a polymer is affected by the Melting point (Tm), Glass transition temperature (Tg), Degree of crystallinity, and amount of cross-linking in its structure [10].

One way in which plastic manufactures achieve certain polymer properties are through the fabrication of polymer blends, where two or more different types of polymers are blended together. The use of additives provides stability and improves the materials performance when incorporated into the polymer resin. While the use of additives imparts beneficial characteristics to the resulting polymer, they may also undergo conversion or degrade during use. Any reaction by-products must also be regarded as potential leachable contaminants, together with the intact additive ingredients [10].

Abbildung in dieser Leseprobe nicht enthalten

Note: 1= Polyethylene Terephthalate (PET), 2=Polyamide (PA), 3= Tie Layer, 4= Ethyline Vinyl Alcohol (EVOH)’ 5= Ultra Low Density Polyethylene (ULDPE)

Figure 2: Composition of Sartorius Stedim Biotech Flexel 3D disposable bioprocessing container (Source: 27)

Disposable bag systems are typically constructed from several layers of polymeric material. Some commonly used polymers include Ethylene-vinyl-acetate (EVA), ethylene-vinyl- alcohol (EVOH), and polyethylene (PE) among others. EVA is known to impart flexibility and permit the flow of gas and moisture, while PE is associated with lower levels of degradation products, and for this reason is often the polymer of choice for coating the inner walls of the system which has the greatest contact with the process fluid. The combination of polymeric layers each impart their unique characteristics on the final single-use component to give strength, flexibility, resistance, and ensure low product absorbance (Eibl and Eibl, 2009).

2.2.1 Advantages of SUT

(Shukla and Gottschalk, 2013) argue that one of the core aspects of a GMP manufacturing facility are adequate and consistent cleaning procedures such as Cleaning-in-place (CIP) and Sterilisation-in-place (SIP), which are performed between production batches. A great deal of work must be dedicated to ensure cleaning procedures are fully validated and documented to effectively demonstrate the elimination of bioburden and thus, mitigate the risk of cross- contamination between production batches in a traditional steel facility. The design elements dedicated to CIP and SIP can now be completely eliminated as each SUS is discarded after its single use, the risk of batch cross contamination is virtually eliminated. This contributes to a significant reduction in costs and safety concerns (Eibl and Eibl, 2009).

This argument is analogous with statistical figures revealed in a recent survey conducted by Pharma IQ, which indicated that 63% of companies were eager to establish a completely flexible manufacturing process, and were willing to invest between £100,000 and £500,000 over the next year in customised disposable assemblies [1]. The results also showed that 64% of biopharmaceutical manufacturers stated that the main driver towards an investment in disposables was reduced cross-contamination issues [1]. (Eibl and Eibl, 2009) consider this technology to be particularly advantageous to contract manufacturing organisations (CMOs) as it enables the production of several drug products simultaneously, and there is no risk of cross-contamination due to the closed system design.

Abbildung in dieser Leseprobe nicht enthalten

Figure 3: Pharma IQ survey 2014 - The main drivers for implementing SUT (Source: 11)

Due to an increased surge in biosimilar medicine the commercial setting is facing increased pressure to lower the cost of their drug products, and as a result (Shukla and Gottschalk, 2013) believe that there is a need for companies to realign their business strategy to support this future trend. It is estimated that a fully equipped disposable production facility can potentially reduce operational costs by up to 40% compared to a traditional hard-piped facility.

While financial savings was cited as one of the main reasons for the adoption of disposable systems, the point was also made that single-use systems are ideal for new product development as they can be quickly assembled and are flexible to allow for manufacturing changes as required. With an estimated 60% of Phase II clinical studies unsuccessful, this emphasises the need for faster solutions to currently incurable diseases globally [3]. While there is no doubt that single-use technology has created a new dynamic within the industry, (Kapp et al., 2010) believe that the use of stainless steel tanks will not become completely replaced by single-use systems, but highlight the fact that this technology possesses the unique key capabilities to drive this paradigm shift.

2.2.2 Concerns with SUT

Single-Use technology is not without its problems as (Eibl and Eibl, 2009) explain that while single-use systems possess many benefits, they are limited in scalability when compared to stainless steel vessels which can accommodate volumes of up to several thousand litres. Another drawback with the use of plastic processing materials is the issues in relation to both temperature and pressure sensitivity, and also the fact that plastic components are liable to puncture due to the nature of the materials of construction. However, the one common theme that continues to dominate much of the published literature on single-use technology is the issue of Extractables and Leachables. This concern continues to be a topic which is high on the agenda among industry professionals.

The following definitions outlined for extractables and leachables are accepted by both regulatory authorities and industry professionals. Extractables are defined as “chemical compounds that migrate from any product contact material when exposed to an appropriate solvent under exaggerated conditions of time and temperature”. Leachables, however, are “chemical compounds typically a subset of extractables that migrate into the drug formulation from any product contact material as a result of direct contact with the drug f ormulation under normal process conditions, or accelerated storage conditions and are f ound in the final drug product” (Subramanian, 2012).

Abbildung in dieser Leseprobe nicht enthalten

Figure 4: Venn diagram illustrating the relationship between Extractables and Leachables (Source: 10)

Extractables and Leachables are degradation products which derive from any material that is in direct contact with a drug solution and can have deleterious effects on the critical quality attributes (CQAs) of the final drug product [6]. These harmful compounds can alter the drug formulation, affect stability and impurity profiles, and alter the smell, taste, and colour of the drug substance. Some common sources of extractables include residuals, reaction by- products, pre-sterilisation, the use of processing aids, and additives such as stabilisers, lubricants, antioxidants, heat stabilisers, and plasticisers (Appendix – A). The use of additives serve to impart certain desired properties on the final polymeric material (Eibl and Eibl, 2009). (Yu et al., 2008) argue that the concept of Extractables and Leachables is of great pharmaceutical importance because they have the potential to adversely affect patient safety, which ultimately is of primary concern.

A survey conducted by (Ding and Martin, 2010) challenges this argument, claiming that in fact only 13% of end-users considered the evaluation of EL to be a barrier in the integration of single-use systems in their process. They explain that this statistic is reflective of an apparent change of mind-set towards disposables due to an increased amount of publications on the topic which include case studies, peer reviews, and industry guides. However, it could be argued that while the availability of literature on this topic has been somewhat beneficial to both suppliers and end users, there is yet to be a standardised set of EL testing requirements officially accepted by the regulators.

2.3 Regulatory Outlook

(Shukla and Gottschalk, 2013) claim that one of the key obstacles facing both developers and end users of SUT is the clear absence of standardisation and regulatory guidance in relation to extractables and leachables testing requirements. The author considers the absence of standards to be one of the main barriers against the implementation of single-use technologies. In agreement, (Kapp et al., 2010) highlight the strong need for greater transparency within supply chains to ensure adequate Good manufacturing practices (GMP) and controls are observed which could lessen the concerns about EL in relation to the materials of construction used to fabricate disposable components [3].

Much of the guidance documents published has been ambiguous simply outlining that the manufacturing equipment should not present any hazards to the drug product, and also that it is the ultimate responsibility of the product sponsor to determine the risk of EL on product safety and efficacy. While the submission of vendor-supplied data has been acceptable in some cases, there is a general lack of uniformity between vendor extractables data which makes assessing the suitability and comparison of single-use components for the end user an extremely difficult task. As a result, there is a strong need for harmonised supplier data to an accepted industry standard to be made available [2].

In the absence of standardisation several risk-based approaches and scientific principals have been used to evaluate ELs which have subsequently been accepted by regulatory authorities. For disposable systems, this has involved assessing the compatibility of the processing material with the process formulation, or performing a simulated EL study. (Bestwick and Colton, 2009) claim that in situations where the vendor has provided high quality extractables data, this may be sufficient to support the subsequent analysis of leachables in the final drug product by the end user. However, it is acknowledged that the extent and quality of vendor-supplied data has been known to greatly vary, and so the data should be assessed by the end user in collaboration with the supplier on a case-by-case basis for the intended product situation.

2.4 Primary Data

During the course of this research, primary data was gathered from a number of interviews and questionnaires carried out with industry professionals with expertise in the field of SUT (A ppendix – E). Below are a list of questions which were asked and a brief summary of the responses are given.

Q1. What do you consider to be the greatest concern for end users when considering the adoption of Single-Use manufacturing technology.

The main areas of concern were in relation to product quality and supplier quality. The unknown level of risk associated with SUS in terms of what compounds could potentially migrate from the material, and also what could be absorbed onto the material were regarded as cause for concern. The migration of leachable species was recognised as a major threat to the drug product and ultimately, the patient receiving the medicine.

Q2. With regards to the evaluation of Extractable and Leachable contaminants, what do you believe to be the greatest difficulties currently facing end users.

The lack of standardisation in relation to EL testing requirements was viewed as the biggest obstacle among all respondents. In general, vendor-supplied data was regarded as inadequate in relation to demonstrating the chemical compatibility of their polymeric materials under various testing conditions. In some instances, the extractables reports supplied by the vendor were considered incomplete and lacked evidence of quality control checks of incoming raw materials used to manufacture the disposable components. Other issues included the correct interpretation of data to ensure end patient safety, and the need to generate data in a manner that directly satisfies regulators. As one contributor interestingly pointed out “It would be very easy for one supplier to conduct an extractables study using a solvent at fairly benign conditions, while another supplier performs the same test using identical materials under harsher testing conditions with a more aggressive solvent. Both suppliers would produce a very different extractables profile potentially making one product appear less suitable than another supplier’s product, when in fact it could potentially be far superior”.

Q3. What is your view on the current regulatory framework for EL testing. Are there sufficient guidance documents available to implement a robust risk assessment strategy for the assessment of EL to satisfy subsequent regulatory expectations.

It was expressed that there is insufficient guidance from the regulators, only a very high level of information has been provided which is considered to be open to interpretation. There were mixed views in relation to guidance documents provided by industry groups such as Product Quality Research Institute (PQRI) and Bio -Process Systems Alliance (BPSA). Some respondents considered them valuable resources, while others disagreed, stating that the testing conditions employed were often too harsh and sometimes not chemically compatible to the polymeric materials. A quality by design (QbD) approach to risk assessment was recognised as the best approach for end users and SUS suppliers to achieve regulatory compliance.

Q4. What do you regard to be the current best practices with regards to testing for EL in situations where data from single-use suppliers is inadequate.

The general consensus from survey participants was to implement a risk assessment strategy as early as possible in the development process. An in-depth understanding of the process, product interaction, and nature of extractables were considered of paramount importance. While the purpose of generating extractables data was recognised as a risk mitigation strategy, the threat of leachables to the drug product was ultimately seen as the main driver for end users. It was also noted that care should be taken to ensure that extraction conditions are harsh enough to include all potential leachables, but not too aggressive so as to lead to complete deformulation of the material.

Q5. What improvements would you like to see implemented in this technology for the future.

The majority of respondents said they would like to see improvements in SUT particularly with regards to robustness of processing materials, and the ability to examine them over a wider operating range using harsher conditions. Other improvements included the implementation of simplified testing to a standardised protocol, greater comprehension of the risks associated with various classes of compounds, such as small molecules compared to biologics, where testing requirements could be quite different for both.

Q6. What trends do you think will emerge over the coming years for the future of Disposables and Single-Use systems.

For the future of Disposables and Single-Use Systems, many respondents anticipate SUS will evolve to handle larger production scales. The availability of a standardised set of testing requirements was predicted however, product sponsors would still be obliged to ensure that their drug product is safe by performing leachables studies. Others believe that the future of SUT shall see the partnership of single-use component suppliers with drug product manufacturers, which would facilitate the generation of reliable uniform test data relevant to the specific drug product/component interaction.


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Disposable Technology and Single-Use Systems. Regulatory Perspective, Best Practices and Future Trends of Extractables and Leachables
MSc. Industrial Pharmaceutical Science
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ISBN (eBook)
ISBN (Book)
disposable, extractables, trends, future, practices, best, perspective, regulatory, systems, single-use, technology, leachables
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Suzanne Culleton (Author), 2015, Disposable Technology and Single-Use Systems. Regulatory Perspective, Best Practices and Future Trends of Extractables and Leachables, Munich, GRIN Verlag, https://www.grin.com/document/507038


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