Review
Extractables and leachables considerations for prefilled syringes 1.
Introduction
2.
Chemical interactions between a prefilled syringe and its
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/02/14 For personal use only.
contents 3.
Conclusion
4.
Expert opinion
Dennis R Jenke Baxter Healthcare Corporation, Technology Resources Division, IL, USA
Introduction: Use of pre-filled syringes as both a packaging and delivery system for pharmaceutical drug products is accelerating. Pre-filled syringes must meet the quality and suitability for use requirements for both systems, including compatibility with the drug product. Relevant incompatibilities between pre-filled syringes and drug products include the safety of syringebased leachables that accumulate in drug products and the ability of leachables to interact with the drug product’s ingredients as such interactions can affect safety, efficacy, stability and physical viability. Areas covered: Relevant suitability considerations for pre-filled syringes are discussed herein and specific examples of suitability for use issues for pre-filled syringes are cited, focusing on extractables associated with prefilled syringes and leachables derived from such syringes. Aspects considered include the toxicological impact of leachables, their ability to alter the efficacy of drug products and to produce other undesirable outcomes such as aggregation and immunogenic responses. Expert Opinion: Materials used in pre-filled syringes and the conditions of use minimize the traditional safety risk associated with leachables. However, drug products that use pre-filled syringes are prone to non-traditional interactions such as disruption of protein conformation, leading to potential efficacy, safety and quality issues. In order to qualify pre-filled syringes for use, the traditional approach of measuring extractables and leachables and inferring their effect must be augmented by rigorous compatibility testing. Research into the fundamental relationship between leachables and drug substances will be necessary so the more time- and cost-efficient ‘measure and infer’ approach can be widely implemented. Keywords: aggregation, extractables, incompatibilities, leachables, pre-filled syringes, safety Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Prefilled syringes are important options in the packaging of pharmaceutical solution products, particularly biopharmaceuticals, as they provide several practical advantages including convenience due to simplified drug administration (facilitating home-based self-administration and use in emergency situations), reduction of errors such as misidentification, improper dosing and contamination, increased product lifespan, safer use and more accurate filling (i.e., reduction in overfilling), leading to reduced waste and tighter cost control [1,2]. These advantages, along with a critical mass of commercially available syringe systems, have fueled a rapid expansion of the market for prefilled syringes, with worldwide sales estimated to exceed 1 billion units and for annual sales to grow at a rate in excess of 10%. [3,4]. More recent estimates suggest that the global prefilled syringes market is likely to achieve sales of $6.9 billion by 2018, growing at a compounded annual growth
10.1517/17425247.2014.928281 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
1
D. R. Jenke
Article highlights. .
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.
.
.
.
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Prefilled syringes must be suited for use, specifically with respect to compatibility with the drug product they contain. Incompatibilities related to syringe leachables, which could be manifested as adverse safety effects, reduced efficacy and unacceptable quality, are particularly relevant to biopharmaceuticals as these drug products are susceptible to physical and chemical perturbations of their formulations. Given prefilled syringe’s materials of construction and their conditions of use, it is a lesser risk that they would be unsuited for use because they contained extractables that would accumulate in drug products to high enough levels as leachables to produce an adverse safety effect based solely on the leachable’s inherent toxicity. However, given the sensitivity of biopharmaceutical products to their chemical and physical environment, it is a greater risk that prefilled syringes could possess extractables that could accumulate in drug products to high enough levels as leachables to produce other potentially meaningful incompatibilities such as aggregation, loss of potency, decreased stability and secondary safety effects (e.g., immunogenicity). Although conventional screening of prefilled syringes for extractables and drug products in syringes for leachables is an effective means of establishing direct safety effects, such an approach is not useful for other incompatibilities as the relationship between leachables and these effects have not been clearly established. Direct testing of prefilled syringes and their contents for the manifestations of incompatibilities during product development and registration is the most effective means of surfacing and controlling such incompatibilities. Once an incompatibility has been uncovered, leachables screening may be appropriate to investigate and establish root cause.
This box summarizes key points contained in the article.
rate (CAGR) of 13.8% from 2012 to 2018. [5]. Currently, the prefilled syringe market is dominated by glass syringes. Although plastic syringes accounted for just 0.5% of the total prefilled syringes market in 2012, their share is expected to increase with the development of improved polymers that offer better leachables and extractables profile compared with glass syringes [5]; it is estimated that the market for plastic syringes will grow at a CAGR of 25% from 2013 to 2019 [6]. Conceptually, a prefilled syringe is a relatively simple device (Figure 1). The syringe barrel serves as the storage chamber for the drug product and is typically made from either Type 1 borosilicate glass or various plastic materials (e.g., polypropylene, cyclic olefin polymer, cyclic olefin copolymers). The plunger serves as both a closure (the equivalent of a vial’s cap) and as the means of providing the driving force for drug delivery. The tip cap serves the dual purpose of closure and protection. Both the plunger and tip cap are typically made from elastomeric materials, which may or may not be surface coated. Syringe barrels and plungers are typically coated with 2
an agent (e.g., silicone oil) to facilitate plunger movement. Plunger movement is accomplished by an attached piston rod (typically plastic). Other components of the syringe include the access component (needle or luer lock), and miscellaneous plastic components (tamper evidence component, grip extender, back stop). Although a prefilled syringe can function as both a packaging system and a delivery device, it meets the definition of a packaging system. For example, the FDA defines a container/ closure system as ‘the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components’ [7]. A similar definition is provided by the European Medicines Agency, although the concept of primary is replaced with the term immediate [8]. Thus, a prefilled syringe qualifies as a container/closure or packaging system and is subject to the associated guidelines and regulations. Because of its use and nature, prefilled syringes, as an injectable product, fall into the FDA’s highest risk category for the likelihood of a packaging component-dosage form interaction (Table 1 of reference [7]). Foremost among these regulations and guidelines are the expectations that revolve around suitability for intended use. As noted in the FDA Container/Closure Guidance: Every packaging system should be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for use with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly. Although the dimensions of protection and performance are key suitability for use issues, they fall outside the scope of this manuscript. Rather, this manuscript focuses on the chemical issues that can arise due to interactions between the prefilled syringe and its contents, as such interactions directly impact compatibility and safety.
Chemical interactions between a prefilled syringe and its contents
2.
Before the potential safety and compatibility issues associated with the chemical interaction of a packaging system (e.g., prefilled syringe) and its contents are discussed, it is appropriate to briefly consider the general topic of chemical interaction. There is a high intrinsic possibility that a packaging system and its contents will be incompatible to some extent as both the packaging system and its contents have independently been formulated and manufactured to serve different purposes. When the packaging system is filled with the drug product, and the drug product contacts its packaging for any reasonable length of time, it is likely that their inherent incompatibilities produce an interaction between the two. Although packaging and delivery systems are developed with the intent of minimizing the potential for interactions, no system is truly inert under
Expert Opin. Drug Deliv. (2014) 11(10)
Extractables & leachables considerations for pre-filled syringes
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Figure 1. Schematic diagram of a prefilled syringe. The components of a prefilled syringe include (1) the barrel, (2) the adaptor (fitting), (3) the finger grip, (4) the plunger rod, (5) the plunger stopper and (6) the tip cap. The drug product is contained within the barrel in the area defined by the plunger stopper and the adaptor fitting.
Table 1. Major organic extractables profile of the rubber material [16]. Identification
Octadecanoic (Stearic) acid* Hexadecanoic (Palmitic) acid* C-21 Oligomerz,{ Octadecanoic acid, methyl esterz Hexadecanoic acid, methyl esterz Dimethylterephthalate* Oleamide* Hexadecanoic acid, isopropyl ester* Octadecanez Octacosane* 1-(4-Morpholinyl)-octanoic acidz Morpholine* Tetracosane* 10-Oxo-octadecanoic acidz 4,4¢-Dioctyldiphenylamine* Hexadecanamide* Docosanez Nonadecanoic acid§
CAS RN
57-11-4 57-10-3 —# 112-39-0 112-61-8 120-61-6 301-02-0 142-91-6 593-45-3 630-02-4 5299-54-7 110-91-8 646-31-1 870-10-0 101-67-7 629-54-9 629-97-0 646-30-0
Chemical formula
C18H36O2 C16H32O2 C21H40 C19H38O2 C17H34O2 C10H10O4 C18H35NO C19H38O2 C18H38 C28H58 C22H43NO2 C4H9NO C24H50 C19H35O3 C28H43N C15H33NO C22H46 C19H38O2
Concentration in material, mg/g Aqueous solvent
Organic solvent
10 -- 100 10 -- 100 —# 1 -- 10 1 -- 10 —# —# —# —# —# —# —# —# —# —# —# —# 10 -- 100
> 1000 > 1000 100 -- 1000 —# —# 10 -- 100 100 -- 1000 10 -- 100 100 -- 1000 10 -- 100 10 -- 100 10 -- 100 10 -- 100 10 -- 100 10 -- 100 1 -- 10 1 -- 10 10 -- 100
*These identifications are classified as confirmed. z These identifications are classified as confident. § These identifications are classified as tentative. { 1-Isopropenyl-2,2,4,4-tetramethyl-6-(2,2,4-trimethyl-pentyl-1-)-cyclohexane. # — = Not present in this extract at detectable levels.
all possible conditions of contact with a drug product and thus interactions between the systems and the drug product are generally unavoidable. Considering the perspective of the drug product contents, there are three types of interactions. The first type of
interaction involves the permanent transfer or exchange of entities between the packaging and its contents. For example, entities initially present in the packaging could leach into the drug product contents, resulting in the introduction of new chemical entities into the contents and altering the nature of
Expert Opin. Drug Deliv. (2014) 11(10)
3
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D. R. Jenke
the contents. If the added substances are of toxicological concern, then their accumulation in the contents may adversely affect the content’s safety. If the added substances are reactive, then they may alter the chemical stability of the contents or may produce an undesirable transformation in the contents (e.g., formation of particulate matter or immunogenic agents). Lastly, the added substances may have some chemical property themselves (e.g., they are strong acids) that affects a quality attribute of the contents (e.g., its pH). The term leachables describes packaging-derived substances that accumulate into a drug product that is stored in the packaging. Thus, testing a packaged drug product for entities that have leached into the product is termed a leachables assessment. Another term that is encountered when exchange interactions are discussed is extractables. Although the concepts of extractables and leachable are related, they are not synonymous. Although leachables refer to entities that are present in the drug product, extractables refer to entities that reside in the packaging system. As the name suggests, extractables are substances that can be extracted from the packaging system, typically during laboratory investigations of the packaging or its materials and components of construction. It is reasonable that extractables and leachables could be related, specifically that extractables represent potential leachables. However, leachables may include entities other than extractables, and not all extractables become leachables in all situations. The second type of exchange interaction occurs when entities in the drug product are taken up by the packaging via absorption and adsorption. Here, the contents become deficient in its levels of one or more of its ingredients. If the exchanged substance is the active drug substance, then the exchange could produce a subpotent drug product. If the exchanged substance is a stabilizing or solubilizing agent, then the exchange could result in a shortened shelf-life or reduced solubility (typically manifested as particulate matter). The third type of interaction does not involve the permanent transfer of entities between the packaging and the contents. Rather, the mere presence of the packaging system may induce a chemical change in its contents (e.g., a chemical or conformational change to the protein due to its selective interaction with the packaging surface) or the transfer may be temporary (e.g., protein is bound on the surface, undergoes a conformational change and then the changed protein goes back into solution). Although such interactions are very rare with drug products based on small molecules, they are more prevalent in biopharmaceuticals. Although these interactions are potentially meaningful for all drug products packaged in a prefilled syringe, biopharmaceutical products containing proteins may be especially susceptible to the these interactions because of their structural complexity (and the close link between their structure and activity), their large surface area (allowing for many possible interaction sites), and their often relatively high dose volume 4
and high frequency of dosing (which increases the potential patient exposure to the interaction by-products) [9]. The general challenges of developing biopharmaceutical products packaged in prefilled syringes, including controlling undesirable interactions, have been considered by numerous authors [10-13]. Extractables and leachables Characterizing packaging systems such as prefilled syringes for extractables and/or packaged drug products for leachables has received much attention in the scientific and regulatory literature and, as a ‘hot topic in parenteral science and technology’ [14], developments in the design, implementation, interpretation and utilization of extractables and/or leachables assessments will continue to occur at a rapid pace. Leachables are a legitimate concern for prefilled syringe systems as there are numerous documented examples of both extractables in materials used in prefilled syringes and leachables that have produced suitability for use issues in prefilled syringe applications. It is beyond the scope of this manuscript to provide a detailed account of the means by which leachables information is obtained, interpreted and utilized. Rather, the reader is directed toward several useful overviews on this subject [15-18]. Nevertheless, it is appropriate to consider published information concerning extractables reported in either prefilled syringes or their materials of construction and leachables reported in drug substances packaged in prefilled syringes. Considering extractables, the general extractables properties of materials used in prefilled syringes, including glass, syringe barrel materials (glass, cyclic olefins and polypropylene) and potential plunger materials (elastomers) were examined by Jenke et al. [19]. In this study, test materials were extracted in aqueous solvents with a wide pH range (2 -- 12) and the extracts were analyzed for general properties (pH, UV absorbance and total organic carbon) and extracted metals. Considering the extract’s general chemical properties, which are generally indicative of organic leachables, these researchers noted that the syringe barrel materials had relatively low amount of extractable organics, with glass and the cyclic olefins having the smallest amounts. However, all the elastomers tested had much higher test results and thus the authors concluded that it would be the elastomeric components that would be the most significant sources of leachables. Additionally, a team from the Product Quality Research Institute (PQRI) established the extractables profile of an elastomer and a cyclic olefin copolymer, materials that are relevant to a prefilled syringe. The extractables reported for these materials are summarized in Table 1. As was the case with the general chemistry data reported by Jenke, the PQRI researchers found that the elastomeric material had a much more extensive extractables profile than did the cyclic olefin copolymer (Table 2) [20]. Several studies have been performed that establish the levels of elemental entities (metallic impurities) that can be extracted from syringes and their materials of construction. 2.1
Expert Opin. Drug Deliv. (2014) 11(10)
Extractables & leachables considerations for pre-filled syringes
Table 2. Major organic extractables profile of the cyclic olefin copolymer [16].
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Identification*
CAS RN
cis-Decahydronaphthalene trans-Decahydronaphthalene Di-(2-ethyhexyl) phthalate related{ Oleamide Dimethylterephthalate 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, methyl ester Hexadecanoic (palmitic) acid Irganox 1010
Chemical formula
Concentration in material (mg/g) Aqueous solvent
Organic solvent
493-01-6 493-02-7 117-81-7 301-02-0 120-61-6 20170-32-5
C10H18 C10H18 C24H38O4 C18H35NO C10H10O4 C17 H26 O3
—z —z —z —z —z —z
10 10 10 10 10 10
6386-38-5
C18 H28 O3
—z
10 -- 100
57-10-3 6683-19-8
C16H32O2 C73H108O12
—z —z
1 -- 10 P§
-------
100 100 100 100 100 100
*These identifications are classified as confirmed. z — = Not present in this extract at detectable levels. § Present in the extracts but not quantitated. { Total including both DEHP and MEHP. DEHP: Di-(2-ethylhexyl) phthalate; MEHP: Mono-(2-etylhexyl) phthalate.
Table 3. Extractable elemental entities from prefilled syringes. Concentration of the elemental impurity in the extracting solution§ Study 1*, units are mg/l Syringe 1 Aluminum Sodium Silicon Arsenic Tungsten
400 980 3290 0.5 250
Syringe 2 {
150 430 950 < 0.04 < 2.4
Study 2‡ Syringe 3
Units are mg/g
< 120 430 980 < 0.04 < 2.4
24 < 0.5
Extractables and leachables considerations for prefilled syringes 1.
Introduction
2.
Chemical interactions between a prefilled syringe and its
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/02/14 For personal use only.
contents 3.
Conclusion
4.
Expert opinion
Dennis R Jenke Baxter Healthcare Corporation, Technology Resources Division, IL, USA
Introduction: Use of pre-filled syringes as both a packaging and delivery system for pharmaceutical drug products is accelerating. Pre-filled syringes must meet the quality and suitability for use requirements for both systems, including compatibility with the drug product. Relevant incompatibilities between pre-filled syringes and drug products include the safety of syringebased leachables that accumulate in drug products and the ability of leachables to interact with the drug product’s ingredients as such interactions can affect safety, efficacy, stability and physical viability. Areas covered: Relevant suitability considerations for pre-filled syringes are discussed herein and specific examples of suitability for use issues for pre-filled syringes are cited, focusing on extractables associated with prefilled syringes and leachables derived from such syringes. Aspects considered include the toxicological impact of leachables, their ability to alter the efficacy of drug products and to produce other undesirable outcomes such as aggregation and immunogenic responses. Expert Opinion: Materials used in pre-filled syringes and the conditions of use minimize the traditional safety risk associated with leachables. However, drug products that use pre-filled syringes are prone to non-traditional interactions such as disruption of protein conformation, leading to potential efficacy, safety and quality issues. In order to qualify pre-filled syringes for use, the traditional approach of measuring extractables and leachables and inferring their effect must be augmented by rigorous compatibility testing. Research into the fundamental relationship between leachables and drug substances will be necessary so the more time- and cost-efficient ‘measure and infer’ approach can be widely implemented. Keywords: aggregation, extractables, incompatibilities, leachables, pre-filled syringes, safety Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Prefilled syringes are important options in the packaging of pharmaceutical solution products, particularly biopharmaceuticals, as they provide several practical advantages including convenience due to simplified drug administration (facilitating home-based self-administration and use in emergency situations), reduction of errors such as misidentification, improper dosing and contamination, increased product lifespan, safer use and more accurate filling (i.e., reduction in overfilling), leading to reduced waste and tighter cost control [1,2]. These advantages, along with a critical mass of commercially available syringe systems, have fueled a rapid expansion of the market for prefilled syringes, with worldwide sales estimated to exceed 1 billion units and for annual sales to grow at a rate in excess of 10%. [3,4]. More recent estimates suggest that the global prefilled syringes market is likely to achieve sales of $6.9 billion by 2018, growing at a compounded annual growth
10.1517/17425247.2014.928281 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
1
D. R. Jenke
Article highlights. .
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/02/14 For personal use only.
.
.
.
.
.
Prefilled syringes must be suited for use, specifically with respect to compatibility with the drug product they contain. Incompatibilities related to syringe leachables, which could be manifested as adverse safety effects, reduced efficacy and unacceptable quality, are particularly relevant to biopharmaceuticals as these drug products are susceptible to physical and chemical perturbations of their formulations. Given prefilled syringe’s materials of construction and their conditions of use, it is a lesser risk that they would be unsuited for use because they contained extractables that would accumulate in drug products to high enough levels as leachables to produce an adverse safety effect based solely on the leachable’s inherent toxicity. However, given the sensitivity of biopharmaceutical products to their chemical and physical environment, it is a greater risk that prefilled syringes could possess extractables that could accumulate in drug products to high enough levels as leachables to produce other potentially meaningful incompatibilities such as aggregation, loss of potency, decreased stability and secondary safety effects (e.g., immunogenicity). Although conventional screening of prefilled syringes for extractables and drug products in syringes for leachables is an effective means of establishing direct safety effects, such an approach is not useful for other incompatibilities as the relationship between leachables and these effects have not been clearly established. Direct testing of prefilled syringes and their contents for the manifestations of incompatibilities during product development and registration is the most effective means of surfacing and controlling such incompatibilities. Once an incompatibility has been uncovered, leachables screening may be appropriate to investigate and establish root cause.
This box summarizes key points contained in the article.
rate (CAGR) of 13.8% from 2012 to 2018. [5]. Currently, the prefilled syringe market is dominated by glass syringes. Although plastic syringes accounted for just 0.5% of the total prefilled syringes market in 2012, their share is expected to increase with the development of improved polymers that offer better leachables and extractables profile compared with glass syringes [5]; it is estimated that the market for plastic syringes will grow at a CAGR of 25% from 2013 to 2019 [6]. Conceptually, a prefilled syringe is a relatively simple device (Figure 1). The syringe barrel serves as the storage chamber for the drug product and is typically made from either Type 1 borosilicate glass or various plastic materials (e.g., polypropylene, cyclic olefin polymer, cyclic olefin copolymers). The plunger serves as both a closure (the equivalent of a vial’s cap) and as the means of providing the driving force for drug delivery. The tip cap serves the dual purpose of closure and protection. Both the plunger and tip cap are typically made from elastomeric materials, which may or may not be surface coated. Syringe barrels and plungers are typically coated with 2
an agent (e.g., silicone oil) to facilitate plunger movement. Plunger movement is accomplished by an attached piston rod (typically plastic). Other components of the syringe include the access component (needle or luer lock), and miscellaneous plastic components (tamper evidence component, grip extender, back stop). Although a prefilled syringe can function as both a packaging system and a delivery device, it meets the definition of a packaging system. For example, the FDA defines a container/ closure system as ‘the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components’ [7]. A similar definition is provided by the European Medicines Agency, although the concept of primary is replaced with the term immediate [8]. Thus, a prefilled syringe qualifies as a container/closure or packaging system and is subject to the associated guidelines and regulations. Because of its use and nature, prefilled syringes, as an injectable product, fall into the FDA’s highest risk category for the likelihood of a packaging component-dosage form interaction (Table 1 of reference [7]). Foremost among these regulations and guidelines are the expectations that revolve around suitability for intended use. As noted in the FDA Container/Closure Guidance: Every packaging system should be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for use with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly. Although the dimensions of protection and performance are key suitability for use issues, they fall outside the scope of this manuscript. Rather, this manuscript focuses on the chemical issues that can arise due to interactions between the prefilled syringe and its contents, as such interactions directly impact compatibility and safety.
Chemical interactions between a prefilled syringe and its contents
2.
Before the potential safety and compatibility issues associated with the chemical interaction of a packaging system (e.g., prefilled syringe) and its contents are discussed, it is appropriate to briefly consider the general topic of chemical interaction. There is a high intrinsic possibility that a packaging system and its contents will be incompatible to some extent as both the packaging system and its contents have independently been formulated and manufactured to serve different purposes. When the packaging system is filled with the drug product, and the drug product contacts its packaging for any reasonable length of time, it is likely that their inherent incompatibilities produce an interaction between the two. Although packaging and delivery systems are developed with the intent of minimizing the potential for interactions, no system is truly inert under
Expert Opin. Drug Deliv. (2014) 11(10)
Extractables & leachables considerations for pre-filled syringes
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Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/02/14 For personal use only.
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Figure 1. Schematic diagram of a prefilled syringe. The components of a prefilled syringe include (1) the barrel, (2) the adaptor (fitting), (3) the finger grip, (4) the plunger rod, (5) the plunger stopper and (6) the tip cap. The drug product is contained within the barrel in the area defined by the plunger stopper and the adaptor fitting.
Table 1. Major organic extractables profile of the rubber material [16]. Identification
Octadecanoic (Stearic) acid* Hexadecanoic (Palmitic) acid* C-21 Oligomerz,{ Octadecanoic acid, methyl esterz Hexadecanoic acid, methyl esterz Dimethylterephthalate* Oleamide* Hexadecanoic acid, isopropyl ester* Octadecanez Octacosane* 1-(4-Morpholinyl)-octanoic acidz Morpholine* Tetracosane* 10-Oxo-octadecanoic acidz 4,4¢-Dioctyldiphenylamine* Hexadecanamide* Docosanez Nonadecanoic acid§
CAS RN
57-11-4 57-10-3 —# 112-39-0 112-61-8 120-61-6 301-02-0 142-91-6 593-45-3 630-02-4 5299-54-7 110-91-8 646-31-1 870-10-0 101-67-7 629-54-9 629-97-0 646-30-0
Chemical formula
C18H36O2 C16H32O2 C21H40 C19H38O2 C17H34O2 C10H10O4 C18H35NO C19H38O2 C18H38 C28H58 C22H43NO2 C4H9NO C24H50 C19H35O3 C28H43N C15H33NO C22H46 C19H38O2
Concentration in material, mg/g Aqueous solvent
Organic solvent
10 -- 100 10 -- 100 —# 1 -- 10 1 -- 10 —# —# —# —# —# —# —# —# —# —# —# —# 10 -- 100
> 1000 > 1000 100 -- 1000 —# —# 10 -- 100 100 -- 1000 10 -- 100 100 -- 1000 10 -- 100 10 -- 100 10 -- 100 10 -- 100 10 -- 100 10 -- 100 1 -- 10 1 -- 10 10 -- 100
*These identifications are classified as confirmed. z These identifications are classified as confident. § These identifications are classified as tentative. { 1-Isopropenyl-2,2,4,4-tetramethyl-6-(2,2,4-trimethyl-pentyl-1-)-cyclohexane. # — = Not present in this extract at detectable levels.
all possible conditions of contact with a drug product and thus interactions between the systems and the drug product are generally unavoidable. Considering the perspective of the drug product contents, there are three types of interactions. The first type of
interaction involves the permanent transfer or exchange of entities between the packaging and its contents. For example, entities initially present in the packaging could leach into the drug product contents, resulting in the introduction of new chemical entities into the contents and altering the nature of
Expert Opin. Drug Deliv. (2014) 11(10)
3
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/02/14 For personal use only.
D. R. Jenke
the contents. If the added substances are of toxicological concern, then their accumulation in the contents may adversely affect the content’s safety. If the added substances are reactive, then they may alter the chemical stability of the contents or may produce an undesirable transformation in the contents (e.g., formation of particulate matter or immunogenic agents). Lastly, the added substances may have some chemical property themselves (e.g., they are strong acids) that affects a quality attribute of the contents (e.g., its pH). The term leachables describes packaging-derived substances that accumulate into a drug product that is stored in the packaging. Thus, testing a packaged drug product for entities that have leached into the product is termed a leachables assessment. Another term that is encountered when exchange interactions are discussed is extractables. Although the concepts of extractables and leachable are related, they are not synonymous. Although leachables refer to entities that are present in the drug product, extractables refer to entities that reside in the packaging system. As the name suggests, extractables are substances that can be extracted from the packaging system, typically during laboratory investigations of the packaging or its materials and components of construction. It is reasonable that extractables and leachables could be related, specifically that extractables represent potential leachables. However, leachables may include entities other than extractables, and not all extractables become leachables in all situations. The second type of exchange interaction occurs when entities in the drug product are taken up by the packaging via absorption and adsorption. Here, the contents become deficient in its levels of one or more of its ingredients. If the exchanged substance is the active drug substance, then the exchange could produce a subpotent drug product. If the exchanged substance is a stabilizing or solubilizing agent, then the exchange could result in a shortened shelf-life or reduced solubility (typically manifested as particulate matter). The third type of interaction does not involve the permanent transfer of entities between the packaging and the contents. Rather, the mere presence of the packaging system may induce a chemical change in its contents (e.g., a chemical or conformational change to the protein due to its selective interaction with the packaging surface) or the transfer may be temporary (e.g., protein is bound on the surface, undergoes a conformational change and then the changed protein goes back into solution). Although such interactions are very rare with drug products based on small molecules, they are more prevalent in biopharmaceuticals. Although these interactions are potentially meaningful for all drug products packaged in a prefilled syringe, biopharmaceutical products containing proteins may be especially susceptible to the these interactions because of their structural complexity (and the close link between their structure and activity), their large surface area (allowing for many possible interaction sites), and their often relatively high dose volume 4
and high frequency of dosing (which increases the potential patient exposure to the interaction by-products) [9]. The general challenges of developing biopharmaceutical products packaged in prefilled syringes, including controlling undesirable interactions, have been considered by numerous authors [10-13]. Extractables and leachables Characterizing packaging systems such as prefilled syringes for extractables and/or packaged drug products for leachables has received much attention in the scientific and regulatory literature and, as a ‘hot topic in parenteral science and technology’ [14], developments in the design, implementation, interpretation and utilization of extractables and/or leachables assessments will continue to occur at a rapid pace. Leachables are a legitimate concern for prefilled syringe systems as there are numerous documented examples of both extractables in materials used in prefilled syringes and leachables that have produced suitability for use issues in prefilled syringe applications. It is beyond the scope of this manuscript to provide a detailed account of the means by which leachables information is obtained, interpreted and utilized. Rather, the reader is directed toward several useful overviews on this subject [15-18]. Nevertheless, it is appropriate to consider published information concerning extractables reported in either prefilled syringes or their materials of construction and leachables reported in drug substances packaged in prefilled syringes. Considering extractables, the general extractables properties of materials used in prefilled syringes, including glass, syringe barrel materials (glass, cyclic olefins and polypropylene) and potential plunger materials (elastomers) were examined by Jenke et al. [19]. In this study, test materials were extracted in aqueous solvents with a wide pH range (2 -- 12) and the extracts were analyzed for general properties (pH, UV absorbance and total organic carbon) and extracted metals. Considering the extract’s general chemical properties, which are generally indicative of organic leachables, these researchers noted that the syringe barrel materials had relatively low amount of extractable organics, with glass and the cyclic olefins having the smallest amounts. However, all the elastomers tested had much higher test results and thus the authors concluded that it would be the elastomeric components that would be the most significant sources of leachables. Additionally, a team from the Product Quality Research Institute (PQRI) established the extractables profile of an elastomer and a cyclic olefin copolymer, materials that are relevant to a prefilled syringe. The extractables reported for these materials are summarized in Table 1. As was the case with the general chemistry data reported by Jenke, the PQRI researchers found that the elastomeric material had a much more extensive extractables profile than did the cyclic olefin copolymer (Table 2) [20]. Several studies have been performed that establish the levels of elemental entities (metallic impurities) that can be extracted from syringes and their materials of construction. 2.1
Expert Opin. Drug Deliv. (2014) 11(10)
Extractables & leachables considerations for pre-filled syringes
Table 2. Major organic extractables profile of the cyclic olefin copolymer [16].
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Identification*
CAS RN
cis-Decahydronaphthalene trans-Decahydronaphthalene Di-(2-ethyhexyl) phthalate related{ Oleamide Dimethylterephthalate 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid, methyl ester Hexadecanoic (palmitic) acid Irganox 1010
Chemical formula
Concentration in material (mg/g) Aqueous solvent
Organic solvent
493-01-6 493-02-7 117-81-7 301-02-0 120-61-6 20170-32-5
C10H18 C10H18 C24H38O4 C18H35NO C10H10O4 C17 H26 O3
—z —z —z —z —z —z
10 10 10 10 10 10
6386-38-5
C18 H28 O3
—z
10 -- 100
57-10-3 6683-19-8
C16H32O2 C73H108O12
—z —z
1 -- 10 P§
-------
100 100 100 100 100 100
*These identifications are classified as confirmed. z — = Not present in this extract at detectable levels. § Present in the extracts but not quantitated. { Total including both DEHP and MEHP. DEHP: Di-(2-ethylhexyl) phthalate; MEHP: Mono-(2-etylhexyl) phthalate.
Table 3. Extractable elemental entities from prefilled syringes. Concentration of the elemental impurity in the extracting solution§ Study 1*, units are mg/l Syringe 1 Aluminum Sodium Silicon Arsenic Tungsten
400 980 3290 0.5 250
Syringe 2 {
150 430 950 < 0.04 < 2.4
Study 2‡ Syringe 3
Units are mg/g
< 120 430 980 < 0.04 < 2.4
24 < 0.5
