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Proposed guidance documents assist drug manufacturers in qualifying single-use systems for commercial drug production.
The increased market value and small batch sizes of biologics has led to a boom in the employment of single-use components for manufacturing therapeutics. The prevalence of these technologies within biopharmaceutical manufacturing has been widely disclosed (1).
Single-use components have gone from being niche devices used in upstream processing into widely deployed large-scale options for downstream and fill/finish operations. In the mature single-use market, there has been a shift from technological innovation to establishing the safety of the materials used in the components. An important aspect is how drug manufacturers qualify these components for use within their manufacturing processes.
The method by which single-use components are qualified and validated has been a source of contention between the end user and supplier groups. Recently, there has been increased collaboration between the industry groups such as the Bio-Process Systems Alliance (BPSA), BioPhorum Operations Group (BPOG), ASTM International, the International Society of Pharmaceutical Engineering (ISPE), and the American Society of Mechanical Engineers-Bioprocessing Equipment (ASME-BPE) in providing strategies on what determines whether a single-use component has been sufficiently and appropriately qualified by a vendor. Collaboration between these industry bodies has led to a number of benefits, as it allows the industry to effectively police itself by providing best practice approaches, which may then be incorporated into regulatory guidance. One example of this is that elements of the recent BPOG extractables standardization protocol are now being incorporated into a new United States Pharmacopeia (USP) chapter, USP <665> “Polymeric Components and Systems Used in in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products” (2).
While USP <665> is in the review stages, there are no regulatory guidance documents specific to single-use components. In the meantime, there are industry expectations based on documents used in the medical device industry and guidance on good manufacturing practice (GMP) for ensuring the safety, quality, and efficacy of the drug products in contact with plastic packaging materials and container closure systems.
Materials qualification should generate data on the safety of the plastics used in pharmaceutical manufacturing. USP <88> and USP <87> (3) detail a series of tests to demonstrate biocompatibility. USP <88>, “Biological Reactivity Tests, in vivo,” (3) describes tests designed to determine the biological response of animals to elastomers, plastics, and other polymeric material. Tests described in USP <87>, “Biological Reactivity Tests, in vitro,” (4) are used to determine biological response of plastics in contact with cell culture.
As detailed in USP <661.1> “Plastic Materials of Construction,” passing the biocompatibility tests is not sufficient for a complete risk assessment to be carried out. Understanding not just the material but the propensity for the material to leach unwanted and unknown chemicals into a drug product has been a requirement of the industry in recent times. This analysis has been principally achieved through extractables testing. Extractables are chemical compounds with the potential to migrate from product contact material under exaggerated conditions of time and temperature. Leachables are compounds that may migrate into the actual drug product under normal processing conditions and may be found in the final drug product. Leachables could be a subset of extractables, as long as the conditions used to generate the extractables are a reasonable worst case and adequately reflect the extremes of the process conditions, such as temperature, time, surface area to volume ratio, etc. Additional leachables may form on the reaction of an extractable and a drug product constituent.
Historically, assessment of extractables has been determined using tests listed in the USP <661>. The primary tests were non-volatile residue (NVR) and total organic carbon (TOC). NVR is the determination of weight of semi-volatile and non-volatile extractables after evaporation of the extraction fluid. TOC is a non-specific test that provides information about the amount of carbon in solution. NVR and TOC testing cannot determine the identity of any extractables. As analytical technologies have advanced, the techniques used to assess extractables and potential leachables has become highly developed. Newer analytical instruments are extremely sensitive and are able to detect the presence of compounds at levels in parts per million (ppm). These technologies are a far cry from the wet-chemistry tests reported in the previous compendia.
Providing the level of technical/validation data about the component material to the drug manufacturer early on facilitates the adoption of single-use technologies into drug processes faster. The new USP <665>-although in draft-serves as the first guidance in this area, allowing for the alignment of supplier and industry expectations.
In the draft USP <665>, one of the fluids recommended for extraction of plastic components used in the manufacture of drug products is a 50% ethanol/50% water solution. The use of 50% ethanol solution as an extraction fluid could be viewed as a worst-case model solvent in comparison to the extraction ability of a mostly aqueous drug product.
In light of upcoming guidance, single-use suppliers who understand the challenging market and regulatory environment for the drug manufacturers and provide the necessary technical data to prove that drug products are unaffected by the single-use components may be best placed to provide assistance for validation purposes.
Risk assessment is an important activity to ensure that there is sufficient information to qualify the single-use fluid pathway as being suitable for use. Although the onus of this activity as detailed in regulatory documents is the sole responsibility of the drug manufacturer, it could be shortened in part by having good technical data provided upfront by the single-use vendor. Additionally, a degree of knowledge is required to understand how the data could be used to illustrate that the component material will not adversely affect the drug product.
In terms of risk assessment of extractables data, there are no specific limits on extractables. However, drug manufacturers must demonstrate that any potential leachables found within a drug product is at a level low enough not to be of safety concern over the duration of treatment and at the dosage levels that the drug product will be administered.
The threshold of toxicological concern (TTC) is a risk assessment tool for evaluating substances with little or no toxicity data with a low level of exposure (5). The TTC was developed to provide an acceptable intake of any unstudied chemical that poses a negligible risk of carcinogenic effects or toxicity. For the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 µg per day has been set as an arbitrary limit. This corresponds to a 1 in 105 increased likelihood of cancer due to the presence of genotoxic impurity in a drug product. However, this level is associated with a lifetime dosing regimen of the drug product. The International Council for Harmonization has established limits based on less-than-lifetime dosages (6).
A small group of compounds, however, are known to be highly potent mutagens even at very small concentrations; it is not possible to risk assess these particular compounds. Compounds such as N-nitrosamines, aflatoxin-like compounds, azoxy-like compounds, dibenzodioxins, and dibenzofurans are excluded from the TTC approach. For these highly potent compounds, the best form of control is to ensure that they are not present in the materials used in single-use systems by knowledge and control of the materials supply chain.
As described above, risk assessment to determine the material safety can be complex when looking at single-use systems comprising of several different materials. Often, the supplier may be best placed to offer information on the component materials in order for the drug manufacturer to make an assessment that there are no compounds of a safety concern or that the extracted compounds are of a low enough concentration not to pose any risk.
For the validation and qualification of the disposable equipment, adequate risk assessment and risk mitigation approaches are the only way to ensure that global adoption of single-use systems and hybrid facilities continues at its accelerated pace. The overarching goal is that well-qualified manufacturing systems can only lead to benefits in the availability of safe medicines for patients.
1. R. A. Rader, Bioprocess Intl, 2007, 29.
2. USP Proposed General Chapter <665>, “Polymeric Components and Systems Used in in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products,”
3. USP, General Chapter <88> “Biological reactivity tests, in vivo,” USP 39-NF 34 (2016).
4. USP, General Chapter <87> “Biological reactivity tests, in vitro,” USP 39-NF 34 (2016).
5. R. Kroes et al., Food Technol Toxicol., 42 (1) 65 -83 (2004).
6. ICH M7, Harmonised Tripartite Guideline. Assessment and Control of DNA Reactive (Mutagenic. Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 4 version (2014).
Sade Mokuolu, PhD, is group product compliance manager, Watson-Marlow Fluid Technology Group.
Vol. 42, No. 2
When referring to this article, please cite it as S. Mokuolu, " New Standards Define Single-Use Materials Qualification," Pharmaceutical Technology 42 (1) 2018.