Risky business: The importance of risk assessment in the single-use market
Dr Sade Mokuolu, group compliance manager, Watson-Marlow Fluid Technology Group, examines the importance of risk assessment in qualifying SU components to ensure global adoption continues at an accelerated pace.
The increased market value and small batch sizes of biologics has led to a boom in the employment of single use (SU) components for manufacturing therapeutics. The prevalence of these technologies within biopharmaceutical manufacturing has been widely disclosed.1
SU 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 SU 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 SU components are qualified and validated has been a source of contention between the end user and supplier groups. More recently, there has been increased collaboration between the industry groups such as Bio Process Systems Alliance (BPSA), Biophorum Operations Group (BPOG), American Society for Testing and Materials International (ASTM), International Society of Pharmaceutical Engineering (ISPE), American Society of Mechanical Engineers-Bioprocessing Equipment (ASME-BPE) in providing strategies on what determines whether a SU 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 eventually into regulatory guidance. One example of this is the recent BPOG extractables standardisation protocol and elements of this approach which is now finding its way into the new chapter, United States Pharmcopeia (USP) 665.2
Qualification/Validation of SU components
As yet there is no regulatory guidance specific to SU components. However, the USP are publishing a new guidance, USP 665, Plastic components and systems used in pharmaceutical manufacturing systems (draft). In the meantime, there are industry expectations based on documents used in the medical devices 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. A series of tests used to demonstrate biocompatibility or biological safety are those detailed in USP 88 and 87.3 USP 88 describes the set of biological reactivity tests, in vivo. These tests are designed to determine the biological response of animals to elastomers, plastics and other polymeric material. Additional tests are described in USP 87. These tests are used to determine biological response of plastics in contact with cell culture.
As detailed in USP 661.1, passing the biocompatibility tests is not sufficient for a complete risk assessment to be performed. 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 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 and so on. However, additional leachables may be formed 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 main 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. Using NVR and TOC, it is not possible to determine the identity of any extractables.
As the analytical technologies have advanced, the techniques used to assess extractables and potential leachables has become highly developed. The analytical instruments are extremely sensitive and are able to detect the presence of compounds at levels in parts per billion (ppb). These technologies are a far cry from the wet chemistry tests reported in the previous compendia.
By providing the level of technical/validation data about the component material to the drug manufacturer early on facilitates the adoption of SU 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, it is the SU suppliers — who understand the challenging market and regulatory environment for the drug manufacturers and are able to provide them with necessary technical data to prove that their drug products are unaffected by the SU components — who may be best placed to provide assistance for validation purposes.
Risk assessment tools — the TTC approach
Risk assessment is an important activity to ensure that there is sufficient information to qualify the SU 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 SU 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, it is required to 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) approach is a risk assessment tool for evaluating substances with little or no toxicity data with a low level of exposure.4 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 micrograms per day has been set as an arbitrary limit. This corresponds to a 1 in 100,000 increased probability of cancer due to the presence of genotoxic impurity in a drug product. However, this level is associated with a lifetime dosing regime of the drug product. ICH has established limits based on less than lifetime (LFL) dosages.
However, there is a small group of compounds which are known to be highly potent mutagens even at very small concentrations and 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 SU systems. This is demonstrated by good control and knowledge of the materials supply chain.
Supplier validation packages
As described above, risk assessment to determine the material safety can be complex when looking at SU systems comprising of several different materials. Often the supplier may be best placed to offer information on the component materials 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.
Conclusion
Adequate risk assessment and risk mitigation approaches when it comes to validation and qualification of the disposable equipment is the only way to ensure that global adoption of SU 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.
References:
- Rader, R.A., BioProcess Int., 2007, 29.
- USP 661.3 (665) – Plastic components and systems used in pharmaceutical manufacturing systems, 2016 (draft).
- United States Pharmacopeial Convention, chapter <88>/<87>, Biological reactivity tests, In vivo,/in vitro 2008.
- Kroes, R., et al., Food Technol. Toxicol. Lett., 2004;42:65–83.