Bio Hazard: Developments in safety, toxicity and E&L standards

Dr. Andreas Nixdorf, business development manager, extractables and leachables testing at SGS - Life Sciences, examines new developments in safety, toxicity and E&L standards for single use manufacturing.

The single use system (SUS) market will grow rapidly as the technology is adopted for commercial manufacturing of pipeline products, having been estimated in 2015 to be about $1.2 billion, with an upstream market of more than $750 million growing at a CAGR of 14% and a downstream market of more than $270 growing at a CAGR of 8%.

According to BioPlan Associates Inc.’s 2015 Annual Report, 49.1% of biopharmaceutical manufacturers surveyed, said at least 50% of their commercial/clinical operations will be single-use by 2020.

Supply chain control

With the industry shift to SUS, it is important to recognise that safety qualification determines suitability for use and initial selection of materials in a biopharmaceutical manufacturing process, but does not constitute process validation itself. The most significant factors to be assessed for safety validation include physico-chemical material compatibility with the biopharmaceutical manufacturing process and the toxicity profiles of these materials to ensure there are no possible adverse effects on patients’ health. General toxicity, biological reactivity/cytotoxicity, systemic toxicity (sensitivity) and genotoxicity of SUS materials all need to be assessed.

Single-use systems offer numerous advantages, but also introduce a new set of materials into the production process and consequently expose biomanufacturers to a new set of risks related to those materials. There are several publications reporting that polymer films have negatively impacted culture growth by the introduction of leaching substances into biopharmaceutical processes.^1-3 The compound bis(2,4-di-tert-butylphenyl)phosphate, which leaches at trace levels from bag films, was shown to be highly detrimental to cell growth. The toxic compound is derived from the breakdown of tris(2,4-di-tertbutylphenyl) phosphite, a common antioxidant additive present in many polyolefin formulations. Cell growth experiments with multiple recombinant protein-expressing CHO cell lines show a 50% reduction in culture growth.

Furthermore, an unexpected impurity can be introduced at any point along the supply chain. The supplier of the raw polymer material master batch used in construction of a SUS cannot support all the regulatory expectations of the end user for different reasons. The SUS supplier wants to deliver high-quality materials to meet the expectations of different clients, ranging from companies operating in the food industry to medical/pharmaceutical sectors. Consequently, the SUS becomes a critical part of the qualification system at the end-user side. The role of the supplier is therefore now more critical, and regulators expect drug and medical device manufacturers to mitigate any risk with close partnerships and thorough knowledge of their suppliers’ quality systems and supply chains.

The regulatory requirements of the end user are more or less satisfied by the quality standards of these suppliers.

The pharmaceutical end user demands a sustainable SUS product, fit and ready for its intended use, and expects the support of suppliers when changing systems or operating procedures. The end user also expects to receive all valid and sustainable data from suppliers for pre-qualification of materials prior to selection. It is also necessary for the end user to confirm the security of the supply chain, the compatibility of the SUS with the pharmaceutical manufacturing process, and that no leachables accumulate in the finished drug product. Qualification is, in fact, the critical criteria that must be achieved at the end users side.

Finally, official bodies expect drug products to meet, and over and above, all their regulatory requirements. Regulatory bodies normally request that the end user carries out an extractable and leachables (E&L) risk assessment also for the SUS being employed in the manufacture of the drug product.

Reality check

Based on pharmaceutical companies’ feedback, the reality is often very different from these ideals. SUS components have sometimes been changed without adequate information being given to the end user. It is often the case that important data are missing. Chemical and physical resistance is important information to assure that materials can resist process conditions, such as high and low temperatures or corrosive chemicals. For example, sodium hydroxide is widely accepted for cleaning, sanitising and storing chromatography media and systems for removing proteins. As with any sanitising agent, certain precautions should be taken and compatibility with both chromatography media and systems determined. In bio-pharmaceutical processes, silicone tubing is used for passing the cleaning in place (CIP) solution through the system. In a failure mode study it has been observed that some silicones can be easily attacked by sodium hydroxide at high pH, and delamination and loss of polymeric mass occurred. The damage mechanism of polymeric materials is an important factor to understand in materials use compatibility, and failure mode studies should be conducted separately 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. As a company, we have analysed hundreds of disposable materials over the past decade. Any change on materials chemical constituents could put the qualified status in question. From our point of view it is a serious disadvantage that there are often no sufficient impurities controls for incoming starter materials established. In polymer processing, production equipment should be cleaned to avoid carryover. Even if the extent of carryover is not controlled by appropriate cleaning validation, environmental impurities could end up in the polymers, and therefore could also be accumulate in the finished products. Our conclusion is that many substances of toxicological concerns are sourced from uncontrolled side reaction from plastic processing. These impurities are already present in the raw materials, and so all suppliers must ensure that their quality systems are robust, and their supply chains are well controlled. Product quality must be the responsibility of all parties involved that make up the clinical or commercial finished drug product supply chain. The end user should ensure that there is a clear and proper legal framework in place that provides confidence that supplier delivers equal quality regarding chemical profile from lot to lot.

Work in progress

There are numerous organisations⁴ engaged in most of the relevant activity areas. The American Society of Mechanical Engineers BioProcessing Equipment Extractables Task Group, having made several updates to its 2016 standard. The U.S. Pharmacopeial Convention (USP), has developed a range of standards for plastic materials, packaging systems and components used in the manufacture and distribution of pharmaceutical products.

The next decade will see the field of extractables within the growing area of SUS evolve and it is crucial all stakeholders within the supply chain work together to ensure the guidelines and standards being developed can be applied through an appropriate risk assessment, to evaluate the suitability of single-use components in production processes. Assessments need to consider the overall risk of the components and their use, including their suitability for the process and any potential E&Ls. It is vital that support is given from suppliers in providing documentation and evidence of supply chain security.

It is also crucial that the risks associated with employing only standard extraction protocols in assessing SUS are addressed. There are misconceptions about the applicability of these methods, which may increase the risk of the end user making inappropriate manufacturing decisions. In some cases, standard extraction protocol procedures may be too harsh, causing decomposition of the SUS polymer network. The overall effect of this is that material qualification would no longer be valid, and it could be the case that under real-use conditions there may be no risk of material leaching into the drug product. Therefore, the best practice to assess risk from SUS such as bags, tubes, connectors and filters would be to perform a simulated migration or customised use study under real process conditions.

Recommended practice

A legal, established definition of what ‘medical-grade plastic’ exactly means is needed. End users must ask suppliers to give them all the information that is relevant to SUS materials, including resistance to chemicals, pH, temperature, radiation, moisture etc., and the exact significance of test results assessed. Such approaches will result in design of the most appropriate E&L strategies for customised manufacturing processes.

Moreover, it is essential to distinguish between chemical resistance testing and E&L testing: suppliers should test for unintentional added impurities in critical raw materials. Increased co-operation between polymer raw materials companies, SUS suppliers, biopharmaceutical manufacturers and regulatory agencies is the key to ensuring the safety and quality of the biopharmaceutical products of the future.