The leachable challenge in polymers used for pharmaceutical applications.

The use of elastomers in the medical industry is as old as the rubber industry itself. Soon after the discovery of the vulcanization process, Charles Goodyear wrote about the use of vulcanized natural rubber in medical instruments, tubing, surgical bottles, urine bags, varicose stockings and hot water bottles (ref. 1). Some of the first rubber IV (intravenous) tubing that was used in World War I was made by Faultless Rubber from natural rubber (ref. 2). With respect to cleanliness, even during World War II, dried blood, plasma and penicillin injections were occasionally reconstituted under battle conditions with available water, frequently from stagnant puddles. It was essential to get these materials into a traumatized patient who would otherwise have lost his life (ref. 3). We have come a long way from those days with respect to material development of drug packages and their concomitant regulatory requirements.

Types of polymers

There are three common types of polymeric materials used in drug packages: Thermosets, thermoplastics and thermoplastic elastomers. The thermosets are defined as those polymers that have been chemically crosslinked using some type of crosslinking agent. Common examples of these types of polymers are the synthetic rubber polymers, polyisoprene and polyisobutylene. These polymers do not melt and cannot be easily reformed due to the intractable nature of the crosslinks.

The thermoplastics are generally referred to as plastics. Commonly used medical plastics are polyethylene, polypropylene, polystyrene and polyvinylchloride (ref. 4). These polymers can be melted and reformed into a different shape. These are the recyclable polymers. The third type is the thermoplastic elastomers (TPE). These polymers are more similar to the thermoplastic materials since they can be melted and reformed into a different shape if desired, but are elastomeric in nature. Common examples of these are the block copolymers of styrene, isoprene and butadiene. These have found limited use in pharmaceutical products due to their incompatibility related to steam sterilization processes.

The thermosets (elastomeric compounds) are the most challenging in obtaining FDA approval in drug packages due to their propensity to contain extractable moieties. Concomitantly, the formulation development effort requires a thorough understanding of the interactions of the ingredients with each other, the vulcanization/curing chemistry, and the subtle interactions with the active pharmaceutical molecule and excipients in the formulation.

Pharmaceutical applications

Many of these polymers are used in pharmaceutical applications, both in drug packages and in medical devices. 'Pharmaceutical' is defined as having some direct contact with drugs, i.e., drug vial closure, IV set injection site, etc. Of course, there are many polymeric materials used in "medical" applications which encompass a much broader scope of applications, but have no direct contact with drugs.

Drug products and packaging

Drug products have a wide range of dosage forms and routes of entry into the patient. These include oral tablets, creams, inhalation and liquid injectables. Injectable drugs can be packaged in drug vials for parenteral and lyophilized (freeze-dried), pre-filled syringes, IV bags and drug delivery pump cartridges.

For parenteral drugs, the drug packages are more complicated and require an array of polymeric materials. In the case of syringes, there are two general classifications, unfilled and pre-filled. The unfilled syringes are normally made from polyolefins for the barrel and plunger rod, and an elastomer for the plunger tip, and are considered a medical device by the FDA. The pre-filled syringes are also made from the same polymers, but need to have extremely low extractables, since the drug is in contact with the barrel and the plunger of the syringe for several months during storage. The packages are considered combination packages and normally require both drug (Center for Drug Evaluation Research--CDER) and device (Center for Device and Radiological Health--CDRH) approval from the FDA. In either case, most syringes have plungers that are elastomeric in nature, and also need to be very clean and contain low extractables.

Many technical papers and technical method bulletins have been published related to the cleanliness of elastomeric closures, which include extractables in closures (refs. 5 and 6), sorption of preservatives and leachables (refs. 7-10), effects of coatings on closures (refs. 11-13), toxicity of extractables (ref. 14) and particulates (ref. 15). Guidelines for container closures were published in 1999 that provided some initial direction regarding extractables for elastomeric components (ref. 16).

Generally, polyisoprene, halobutyl and butyl are the polymers used in drug vial closures and syringe plungers. Drug vials require an elastomeric closure, since these drugs are accessed using a syringe to either inject directly into a patient or into an IV bag or IV set connected to a patient. Again, these closures need to be very clean and exhibit very low extractables. The elastomeric closures are divided into two classes of drugs, i.e., liquid and lyophilized. The liquid drugs need to be sterile and stable for several months, and these parameters are regulated by the FDA. The lyophilized drugs are drugs in which the liquid portion has been evaporated off under freeze drying conditions and the solid "cake" of the drug is located in a drug vial with an elastomeric closure. When the medical professional is ready to administer the drug, the cake is reconstituted (solubilized) in the appropriate vehicle and then injected. Under these conditions, the requirements for the packaging are reduced, since the reconstituted drug is only in contact with the package for minutes after dissolution and before use. The polymers of choice for the drug vials are generally halobutyls, but there are cases where nitrile, EPDM, silicone, isoprene or SBR are used.

These elastomeric formulations can contain a variety of ingredients to achieve the functional and safety requirements of the drug package. These formulations typically contain about 40-50% polymer and about the same amount of inorganic fillers, i.e., clays, talcs and silica. Together, these constitute about 90% of the compound. Although these ingredients contribute to the extractables, the largest contributors are the minor ingredients such as accelerators, activators, antidegradants and lubricants. These are usually only present in concentrations less than 1%.

The IV (intravenous) bag is another drug package that is generally made from flexible extruded or blow molded polyvinylchloride (PVC), but has elastomeric components like the downport IV spike entry dust cover (which can be a TPE) and the injection site rubber septum (drug additive port). Of course, flexible PVC is not a thermoset, but is a plasticized rigid plastic, which contains a high percentage of plasticizers such as phthalates and epoxidized plant oils (soybean and linseed). The current trend is to make IV bags using polyolefins due to safety concerns with the phthalates.

IV sets are the connecting conduit between a gravity feed IV bag or IV set pump. These tubing sets are currently made from PVC, but polyolefins and polybutadienes have been used. These sets also contain a variety of components made from PVC and thermoplastics, i.e., drip chamber, y-connectors and shutoff devices.

Regulatory requirements for drug closures and syringe plungers

The requirements for packaging materials for both drugs and medical devices are generally defined in the U.S. Pharmacopeia and by ISO 10993-1 guidelines. The USP guidelines are divided into elastomeric closures for injection and plastic containers.

The elastomeric closures requirements are defined in USP <381> which outlines three biological tests, USP <87> (invitro) and <88> (in-vivo) and five chemical tests (table 1). There are similar requirements for Europe (EP) and Japan (JP) listed in their pharmacopeias, respectively.

Currently, the USP requirements for <381> are being aligned with the EP guidelines, since the current tests do not have any limits, whereas the EP does. These requirements are scheduled to go into effect in August 2008. In addition to the biological and chemical tests, the USP will also include the three functional tests, including fragmentation, self-sealing and penetrability.

Extractable profiles

In addition to these initial screening tests, the FDA has recently been requesting that a new drug submission/application (NDA), in addition to meeting the drug related requirements, i.e., stability, sterility, etc., also must address the extractable/ leachable issues for the polymeric components (vial, closure or plunger) in a range of solvents that simulate the drug vehicle. These requirements have caused some confusion related to the scope of these profile studies.

For example, if an elastomeric butyl closure is extracted with very aggressive solvents and compared to extracting in buffered water (a typical drug vehicle), the HPLC fingerprint will be dramatically different. Figure 1 is a chromatogram of a 70-day extract from an inverted vial at 70[degrees]C filled with a pH 3 buffer solution. Only a few trace components are observed using a reverse phase gradient (acetonitrile in water) and UV detection at 210 nm. Figures 2 and 3 show the dramatic changes when the experiment is conducted for 42 days in aqueous solution containing propylene glycol and for 56 days in 100% acetonitrile. The number of extractable peaks increases, and for each extractant, unique peaks are observed.

[FIGURE 1 OMITTED]

Extractables/leaehables

A working group organized by the Parenteral Drug Association (PDA) and the Pharmaceutical Quality Research Institute (PQRI) was formed to look at this issue and make recommendations. An initial study was conducted from 2003-2006 for inhalable drugs, since these products are considered to have the highest safety concerns for extractables. This working group completed its report (272 pages; Sept. 8, 2006), which contained several recommendations to the FDA (ref. 17). The FDA is currently reviewing the recommendations. In summary, regarding elastomeric components, the working group recommended that the definition of extractables and leachables from an inhalation device (OINDP) be clearly defined. The report states that:

"Extractables are compounds that can be extracted from OINDP device components or surfaces of the OINDP container/closure system in the presence of an appropriate solvent(s) and/or condition(s). Thus, extractables are individual chemical entities that can be extracted from individual component types, e.g., rubber seals, plastic valve parts, of an OINDP container/closure system under relatively vigorous laboratory conditions using appropriate solvents or solvent systems. Extractables can, therefore, be considered as potential leachables in OINDP.

Leachables are compounds which are present in the drug product due to leaching from container/closure system components. Leaching can be promoted by the formulation, or components of the formulation, e.g., CFC or HFA propellants in MDIs. Leachables are often a subset of or are derived directly or indirectly from, extractables. Due to the time-dependent nature of the leaching process, leachables appear in an OINDP formulation over the shelf-life of the product as determined during appropriate stability and accelerated stability studies. As some extractables and leachables may affect product quality, safety and efficacy, regulatory guidances have provided recommendations regarding their analysis and toxicological safety assessment, i.e., qualification."

The report also gives a list of key extractables and leachables (not exhaustive) that are commonly found in these polymer-based products.

* Elastomeric container/closure system components, e.g., gaskets, seals, etc.;

* monomers and oligomers from the elastomer

* secondary reaction products from the curing process;

* chemical additives, including antioxidants, stabilizers, plasticizers, etc.;

* trace level contaminants and reaction products contained within chemical additives;

* processing aids, e.g., chemicals applied to surfaces of processing/fabrication machinery, or directly to components:

* mold release agents--lubricants; and

* pigments

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

The working group also developed this two-part hypothesis for scientific evaluation:

* Scientifically justifiable thresholds based on the best available data and industry practices can be developed for:

--the reporting and safety qualification of leachables in orally inhaled and nasal drug products, and

--the reporting of extractables from the critical components used in corresponding container/closure systems. Reporting thresholds for leachables and extractables should include associated identification and quantitation thresholds.

* Safety qualification of extractables would be scientifically justified on a case-by-case basis.

The conclusion to the report states that:

"Through investigation of the hypothesis, the working group formulated several conclusions and proposals addressing safety thresholds, safety qualification, and best practices for extractables and leachables testing. The Recommendations are divided into two main parts, which cover these topics: (i) the derivation and justification of safety thresholds, and (ii) best practices for extractables and leachables studies in pharmaceutical development programs for OINDP. The key conclusions and recommendations are listed below.

Thresholds

* Scientifically justifiable safety evaluation and qualification thresholds for leachables in OINDP can be established. The working group proposes a Safety Concern Threshold (SCT) of 0.15 [micro]g per day, and a Qualification Threshold (QT) of 5 lag per day for an individual leachable in an OINDP.

* The SCT is defined as the threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects.

The QT is defined as the threshold below which a given leachable is not considered for safety qualification (toxicological assessments) unless the leachable presents structure-activity relationship (SAR) concerns.

These safety thresholds are represented as absolute exposures, expressed in total daily intake (total exposure per day). They must be converted into relative amounts, expressed in terms such as amount of an individual leachable in a particular drug product, e.g., [micro]g per canister in an MDI, to be useful to analytical chemists conducting leachables and extractables studies. This conversion is performed by using information on the drug product configuration such as the number of actuations per canister, number of doses per day, number of actuations per dose, number of actuations per day, etc. The convened SCT, which should be used by the analytical chemists, is called the Analytical Evaluation Threshold (AET). Scientifically justifiable analytical thresholds for extractables and leachables in OINDP can be established. These analytical thresholds, however, should not be considered "reporting" or "identification" thresholds as traditionally used in other applications, such as in the ICH process for limits on drug substance-related impurities and degradants. To avoid confusion with the ICH terms, the working group proposes the AET. The AET is developed during extractables studies and is applied to both extractables and leachables. The AET is defined as the threshold at or above which a chemist should begin to identify a particular leachable and or extractable and report it for potential toxicological assessment. The AET will vary depending on (i) the particular drug product configuration and (ii) the method(s) used to detect and quantify the extractables and leachables. The methods used will affect the AET value because of the analytical uncertainty inherent in the response factors of individual leachables (or extractables) analyzed by any given analytical technique/method."

A new working group was established in 2008 to make similar recommendations for parenteral drugs and related closures, plungers and containers. The group is made up of technical experts from the pharmaceutical industry (ref. 18).

Drug master file 

Many pharmaceutical elastomeric compounds have a drug master file (DMF) that resides at the FDA. This DMF is a submission to the Food and Drug Administration that may be used to provide confidential information about facilities, processes and articles used in the manufacturing, processing, packaging, and storing of a human drug (ref. 19). Such a submission is not required by law or FDA regulation; the DMF is submitted solely at the discretion of the manufacturer. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, or an export application. These files are not approved or disapproved. They are confidential and require a letter of authorization from the holder of the file to gain access to the information in the file.

There are five types of DMFs covering manufacturing sites, drug substances, packaging materials and excipients in the drug formulation. Elastomeric closures or other polymer materials used in the drug package would be listed by compound, with the concomitant USP and physical property data, as well as the formulation information.

Medical devices

Medical devices span a large range of medical products. Polymers used in these devices normally are tested using the USP requirements discuss previously. In addition to those tests, the regulatory requirements are also based on ISO 10997 (ref. 20). These requirements are based on the type of contact with the patient, the duration of contact and the biological impact. Table 2 gives the four main categories for a medical device (ref. 21).

Each one of these categories can then have a series of biological tests (table 3) that are required to prove that the device is safe to use. This matrix of tests must be used, and the data are submitted to the FDA as a part of the approval process.

These tests cover the range of potential biological issues related to human exposure, i.e., toxicity, genotoxicity, cell toxicity, blood compatibility, carcinogenity, mutagenicity and biodegradation.

Conclusion

Elastomer materials used in drug packages need to contain low levels of extractables, and any ingredients that can potentially extract must be non-toxic. Therefore, elastomeric compounds used in these pharmaceutical applications require careful formulation, product design and manufacturing processes that insure that these materials are safe and clean. The FDA requirements to achieve this goal encompass a wide range of tests that need to be conducted. They include the USP chemical, biological and soon to be added functional testing. In the near future, more specific extractable/leachable profiles will most likely be a new requirement from the FDA.

References

(1.) "The Goodyear story, "R. Korman, Encounter Books, 2002, pp. 7, 115, 118, 146.

(2.) "Living the American Dream: The Myers and Miller families of Ashland, Ohio," Howard Covington, Jr. 1996, p. 52.

(3.) "Parenteral technology manual, "Michael J. Groves, Interpharm Press, 1985, p. 5.

(4.) "High performance biomaterials, a comprehensive guide to medical and pharmaceutical applications," edited by Michael Szycher, 1991.

(5.) "Extractables from elastomeric closures: Analytical procedures for functional group characterization/identification," Parenteral Drug Association, Technical Methods Bulletin No. 1 (1980).

(6.) "Elastomeric closures: Evaluation of Significant performance and identity characteristics," Parenteral Drug Association, Technical Methods Bulletin No. 2 (1981).

(7.) "Identification and risk-assessment of extractables and leachables," J. Kauffman, Feb. Pharmaceutical Technology (2006); http://pharmtech.findpharma.com/pharmtech/Validationandcompliance/article /detail/309314.

(8.) "Determination of extractables, leachables, residual solvents and unknowns by mass spectroscopy," J. Kauffman, Pharmaceutical Technology (2003); www.lancasterlabs.com/ News/PT6268e.pdf

(9.) "Chemical leaching of rubber stoppers into parenteral solutions," J. Danielson, G. Oxborrow and A. Placencia, Journal of Parenteral Science and Technology, 37, pp. 89-92 (1983).

(10.) "Quantitative determination of chemicals leached from rubber stoppers into parenteral solutions," J. Danielson, G. Oxborrow and A. Placencia, Journal of Parenteral Science and Technology, 38, pp. 90-93 (1984).

(11.) "Lined and unlined rubber stoppers for multiple dose vial solutions I. Sorption of preservatives and leaching of extractives," L. Lachman, P. Sheth and T. Urbanyi, Journal of Pharmaceutical Sciences, 53, pp. 211-218 (1964).

(12.) "Lined and unlined rubber stoppers for multiple dose vial solutions II. Effect of Teflon lining on preservative sorption and leaching of extractives," L. Lachman, W. Pauli, P. Sheth and M. Pagliery, Journal of Pharmaceutical Sciences, 55, pp. 962-966 (1966).

(13.) "Oxygen permeation and microbial ingress through a film-coated and uncoated elastomeric closure in a glass vial: A comparative study," M. Andress, H. Dull, T. Gurley, E. Remo, J. Grillo, F. Navasca and T. Berger, Journal of Parenteral Science and Technology, 58, pp. 32-44 (2004).

(14.) "Toxicity potential of compounds found in parenteral solutions with rubber stoppers," J. Danielson, Journal of Parenteral Science and Technology, 46, pp. 43-47 (1992).

(15.) "A wide pH range stopper for improved particulate quality in parenteral solutions," J. Knapp, H. Dull, P. Bjorndal, S. Brakl and P. Yuen, Journal of Parenteral Science and Technology, 38, pp. 129-138 (1984).

(16.) U.S. Food and Drug Administration, "Guidance for industry container closure systems for packaging human drugs and biologics, "pp. 1-56 (May 1999); www.fda.gov/cder/guidance/ 1714fnl.htm.

(17.) L/E Recommendations to the FDA (PDF 2 MB), www. pqri.org.

(18.) PQRI structure//working groups//reporting and qualification thresholds for leachables in parental and ophthalmic drug products working group; www.pqri.org.

(19.) Guidelines for drug master files, www.fda.gov/cder/guidance/dmf.htm.

(20.) ISO 10993 guidelines, www.devicelink.com/mddi/archive/98/01/023.html.

(21.) Four phase flowchart for medical device safety evaluation; www.namsa.com.

by Thomas Gurley, consultant, Manning Wood LLC, www.manningwood.com

Table 1--comparison of international pharmacopeia requirements

Test                                 Current USP           Proposed USP

Biological tests--in vitro
Cytotoxicity                           Pass/fail              Pass/fail
Pyrogen
Hemolysis
Biological tests--in vivo
Acute systemic injection               Pass/fail              Pass/fail
Intracutaneous reactivity              Pass/fail              Pass/fail
Extraction tests
Turbidity                               No limit              Pass/fail
Reducing agents                         No limit               < 3.0 ml
Heavy metals                            No limit        < 2 ppm as lead
A pH                                    No limit   [+ or -] 1.0 pH unit
Total extractables                      No limit         < 4.0 mg/100ml
UV absorbance                                                   < 0.2 A
Foam test

Ammonium ions                                                   < 2 ppm
Volatile sulfides                                             Pass/fail
Soluble zinc                                                  < 0.5 ppm

Ash tests--lead
Ash tests--cadmium
Functional tests
Penetrability                                              < 10 Newtons
Fragmentation                                                < 5 cores/
                                                            12 stoppers
Self-sealing                                                   Dye test

Test                                    European               Japanese

Biological tests--in vitro
Cytotoxicity
Pyrogen                                                       Pass/fail
Hemolysis                                                     Pass/fail
Biological tests--in vivo
Acute systemic injection                                      Pass/fail
Intracutaneous reactivity
Extraction tests
Turbidity                              Pass/fail
Reducing agents                       < 3.0 ml <    2.0 ml kMn[O.sub.4]
Heavy metals                     < 2 ppm as lead
A pH                        [+ or -] 1.0 pH unit   [+ or -] 1.0 pH unit
Total extractables              < 4.0 mg/100ml <        < 2.0 mg/100 ml
UV absorbance                            < 0.2 A                < 0.2 A
Foam test                                                 No foam after
                                                              3 minutes
Ammonium ions                            < 2 ppm
Volatile sulfides                      Pass/fail
Soluble zinc                           < 0.5 ppm             < 1 ppm in
                                                               solution
Ash tests--lead                                                 < 5 ppm
Ash tests--cadmium                                              < 5 ppm
Functional tests
Penetrability                       < 10 Newtons
Fragmentation                         < 5 cores/
                                     12 stoppers
Self-sealing                            Dye test

Table 2--medical device category and definition

Device category                        Usage definition
Body contact               <24 hrs./1-30 days/permanent
Surface devices                   Skin/mucosal membrane
                                     /breached surfaces
Externally communicating     Blood path-indirect/tissue
  devices                            /circulating blood
Implant device                             Tissue/blood

Table 3--biological impacts

Biological effect
Cytotoxicity
Sensitization
Irritation/intracutaneous
Acute systemic toxicity
Subchronic toxicity
Genotoxicity
Implantation
Hemocompatibility
Chronic toxicity
Carcinogenicity
Reproductive/development
Biodegration