About 80 percent of the $200 billion global biopharmaceuticals market covers the manufacture of early clinical trials materials in single-use systems (SUS).
The use of such systems for commercial-scale manufacture of biopharmaceutical systems is rapidly increasing, being estimated to have a value of about $1.2 billion in 2015 and growing at a compound annual growth rate (CAGR) of about 12 percent.
A survey of biopharmaceutical manufacturers carried out by BioPlan Associates last year showed that half of the respondents expected that by 2020 at least half of their clinical- and commercial-scale manufacturing operations would employ SUS, demonstrating that the technology is now an integral component of the biomanufacturing industry’s toolbox.
Controlling the Supply Chain
Users know that full supply chain control for SUS is difficult to achieve. They need to identify low-risk suppliers, or correct the actions of higher-risk ones to ensure that standards are maintained.
An important point to note is that safety qualification determines the suitability for use of a system in a biopharmaceutical manufacturing process, but does not in itself amount to validation of that process.
Factors that need to be considered in process safety evaluation include the physical and chemical compatibility of materials with the biomanufacturing process, as well as the toxicity profiles of SUS materials, including their general toxicity, cytotoxicity, systemic toxicity and genotoxicity.
Chemical impurities that migrate into solvents under exaggerated process conditions of pH, temperature and process time are termed “extractables,” whereas “leachables” are chemical impurities that migrate into the final drug product, mainly from pharmaceutical packaging (containers and closures).
There is the possibility that leachables may come from the process equipment in use, and such an occurrence may contaminate the final drug product. The advantages that SUS offer need to be assessed against the risks of change.
Impurities can be introduced at any point along the supply chain. The supplier of the raw polymer material master batch used in the fabrication of a SUS cannot support all the regulatory expectations of the end user for many reasons, not least that the SUS may be used across a number of industries, including the food and medical/pharmaceutical sectors.
For the SUS supplier, its role in the qualification for the end user has become critical to mitigate the risk of its products for the regulators who expect drug and medical device manufacturers to ensure supply chains are robust. The regulatory requirements of the end user are more or less satisfied by the quality standards of these suppliers.
The pharmaceutical end user needs a sustainable SUS product ready for use and expects suppliers to give the required supporting information when systems or operating procedures are changed.
Users also need valid data for pre-qualification of materials prior to their selection, and need to confirm the security of the supply chain, the compatibility of the SUS with the manufacturing process, and that impurities do not leach from the SUS into the finished drug product during the manufacturing process.
In addition, governments, health authorities and regulatory bodies expect products to meet regulatory requirements in order to protect patient safety. Regulatory bodies usually ask the end user to perform an extractable and leachables (E&L) risk assessment of the SUS in use, thereby giving the end user prime responsibility for patient safety.
Realizing the Reality
The quality of information given by SUS suppliers to end users often differs considerably from these ideals. SUS/consumable components have sometimes been changed without the user being given adequate information such as the chemical constituents of components, the relevant extractables information for materials, and information on the compatibility of materials with various solvents or with different operating conditions.
For example, sodium hydroxide is widely accepted for cleaning, sanitizing and storing chromatography media and systems for removing proteins. In biopharmaceutical processes, silicone tubing is used for passing the cleaning in place (CIP) solution through the system, and failure mode studies have shown that some silicones can be attacked by sodium hydroxide at high pH, leading to delamination and loss of polymeric mass.
The damage mechanism of polymeric materials is an important factor to understand in materials use compatibility, and failure mode studies should be conducted independently from E&L studies.
Other quality issues that can occur include inadequate quality procedures for incoming chemicals or raw materials; agreements in respect of changes to the quality control system are lacking; or measures for cleaning production equipment between production campaigns have been assessed as insufficient.
Any change in the chemical constituency of material could put the qualified status in question, so adequate impurity controls on raw materials must be established. In polymer processing, production equipment should be cleaned routinely to avoid carryover and the presence of environmental impurities, which could end up in the polymers, and therefore could also accumulate in the finished products.
SGS has carried out extensive testing of such materials in the last decade, and it has concluded that many substances of toxicological concern are sourced from uncontrolled side reactions from plastic processing. These impurities are already present in the raw materials, and so the onus is on suppliers to ensure that their quality systems are robust, and their supply chains are well controlled.
Product quality must be the responsibility of all parties involved in the clinical or commercial finished drug product supply chain, and the end user should ensure that there is a clear and proper legal framework in place that provides confidence that each supplier delivers equal quality regarding chemical profile from lot to lot.
In the U.S., the National Technology Transfer and Advancement Act (NTTAA) of 1995 requires federal government agencies to use standards developed by voluntary consensus whenever possible. The Act encourages agencies to work with other organizations on standards development, while OMB Circular No. A-119 actively discourages federal agencies from using standards that have been developed solely by government.
In Europe, the manufacture of human medicines is primarily covered by EU Directive 2001/83/EC and Regulation (EC) No 726/2004. The European Pharmacopoeia (Ph. Eur.) is legally binding in all the signatory states of the Convention of the Council of Europe, while in European Union (EU) countries, the legal basis for the European Pharmacopoeia is Directive 2003/63/EC.
The European Committee for Standardization does not have any specific standards for pharmaceutical manufacturing but there are some International Organization for Standardization (ISO) standards for container and closure systems.
Updating Standards to Ensure Patient Safety
Many organizations are actively engaged in developing standards for SUS in biomanufacturing, for example the American Society of Mechanical Engineers BioProcessing Equipment Extractables Task Group has updated its 2016 standard and non-mandatory Appendix, and others have proposed a new standard for determining and characterizing extractables from materials employed in single-use applications.
The U.S. Pharmacopeia (USP) has a range of standards for plastic materials, packaging systems and components used in the manufacture and distribution of pharmaceutical products.
The development of appropriate standards with respect to E&Ls in SUS biopharmaceutical manufacturing can be complex but this should not deter users of such systems from entering the debate on how SUS will be employed in the future and what standards will be required. SUS suppliers need input and feedback from biomanufacturers and the time is now suitable for that input.
An appropriate risk assessment employing these new standards needs to be performed to evaluate the suitability for use of single-use components in biomanufacturing processes.
Factors that need to be taken into account include potential E&Ls, the level of supplier support in the form of documentation, the operation of the supply chain and the supplier’s quality control of their products. Such a risk evaluation will ensure that only the most appropriate component, assembly and materials choices are made.
However, there may be a number of risks associated with employing only standard extraction protocols in SUS assessments, and misconceptions about their applicability may increase the risk of making inappropriate manufacturing decisions. For example, the standard extraction protocol procedures may be too harsh, causing a high level of polymeric breakdown products in the SUS and possibly also in the drug product through decomposition of the SUS polymer.
Thus the material qualification would no longer be valid and it could be the case that there may be no risk of material leaching into the drug product under real-use conditions. A simulated migration or a use study under real process conditions is particularly useful in identifying the actual risks associated with the manufacturing process.
Ensuring Best Practice
An appropriate, agreed definition of “medical-grade plastic” is needed. Users must ask suppliers for all the necessary information relevant to SUS materials, including physical and chemical resistance to other substances and to process conditions such as pH, temperature, etc.
It is vital to distinguish between chemical resistance testing and E&L testing: suppliers and polymer processors (converters) should restrict themselves to testing for unintentional added impurities in starter materials and avoid analyzing for process leachables.
Increased co-operation between polymer raw materials suppliers, SUS suppliers, contract biopharmaceutical manufacturers, biopharmaceutical companies and government/regulatory agencies will ensure the future safe manufacture of high-quality biopharmaceutical products.
(Dr. Andreas Nixdorf is the business development manager, extractables and leachables testing, at SGS Life Sciences. He is based in Germany.)
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