Application of the Risk Evaluation Matrix as per USP <665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing

The COVID-19 pandemic has given the bio/pharma industry lessons on being prepared to manufacture parenteral formulations for human use in emergency situations. Vaccines, remdesivir injection and amphotericin injection, are such recent examples. The challenge then becomes having enough flexibility in the manufacturing lines to facilitate manufacture of large volumes of unit doses of injectables as may be required with shorter changeover times, while assuring compliance and patient safety from the product contact parts used in the manufacturing line. Single-use manufacturing solutions provide the flexibility in terms of batch sizes, fill volumes, and ease of manufacturing, especially in terms of manufacturing different products in the same line with minimum line changeover requirements. This article reviews and elaborates the initial risk assessment process for extractable and leachables arising from single-use product contact manufacturing parts as per United States Pharmacopeia (USP) chapters <665> and <1665>, which go into effect May 1, 2026 (1,2). The determined risk can then be used to build the level of extractable profiling and process equipment-related leachables (PERLs) followed by assessing the patient safety for regulatory submissions.

Manufacturing systems used for biopharmaceutical drug substances or drug products can be partially or completely constructed from plastic materials. During the manufacturing process, the drug product and its components could directly come in contact with the plastics and potentially interact with one or more of the manufacturing system’s product contact components. The substances that leach from a product contact manufacturing component could become incorporated into the process stream. If these leached substances persist in the process stream and continue through the process operations, they could accumulate in the drug substance or drug product as PERLs (1,2). When present in the drug product, these PERLs can potentially alter the critical quality attributes of the drug product, such as its stability, efficacy, and safety. USP <665>, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, addresses these interactions by providing a risk-based means for chemically characterizing and qualifying plastic components used to manufacture biopharmaceutical drug substances and pharmaceutical and biopharmaceutical drug products. USP <1665>, Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, communicates the key concepts behind and provides additional information and guidance regarding the applicability and the application of USP <665>. The authors discuss a practical approach by which USP <1665> can be applied in a step-by-step manner for the risk assessment, using a case study involving the manufacturing process for remdesivir injection and single-use technologies (Merck).

The testing of a product contact component is driven by the risk that the component may be unsuited for its intended use based on chemical or biological effects attributed to PERLs (1). As such risks increase, the degree of required testing also increases. The risk assessment process is accomplished by a risk evaluation matrix that establishes the appropriate contributors to the dimension of risk, provides a quantifying means for the risk in each dimension, quantifies the total risk for each dimension, and links the quantified risk to an appropriate characterization strategy.

The risk evaluation matrix evaluates the dimensions that address the risk that a product contact part will be leached by a process stream to the extent that the extractables may be impactful on the final product. As shown in Table I, the dimensions include the duration of product contact, temperature during product contact, chemical composition of the product stream, and the nature of the material with which the product contact component is constructed. The risk evaluation matrix will then evaluate each dimension separately and assign a level of risk based on certain measures relevant to each dimension.

The risk evaluation of condition and duration of contact with the process stream addresses the driving force for the leaching. Depending on the duration of contact, the dimension has been divided into short term (<24 hours, Level 1), intermediate (1–7 days, Level 2) and long term (> 7 days, Level 3).

The risk evaluation of temperature of the process stream or the component during the contact duration drives the magnitude of leaching. Depending on the temperature during contact time, the dimension has been divided into low (refrigerated, Level 1), intermediate (ambient, Level 2) and high (elevated, Level 3).

The risk evaluation of the chemical nature of the contacting process stream addresses the process stream’s leaching power. The chemical composition of the process stream in terms of “aqueous”, “somewhat organic”, and “highly organic” are further discussed in Table II.

In case the process stream contains multiple solubilizers, such as a protein solution with a surfactant, the process stream is risk-assessed as a compounded risk associated with the individual agents.

The risk evaluation of the chemical and physical natures of the contacted component addresses the component’s propensity to be leached. The risk dimension for “the chemical composition of the component” can be identified as low, intermediate, or high based on the composition or physical properties of the component (2). By composition, the risk dimension can be identified based on the % level of additives in the plastic material. The component is considered to be low-risk if the plastic additives are ≤0.1% by weight, intermediate risk if the plastic additives are between >0.1% and ≤1% by weight, and high risk if the plastic additives are >1% by weight. By physical properties, the risk dimension is considered to be high risk if the component is sterilized by irradiation or at high temperature.

The component that is being assessed for risk is rated for risk dimensions as per Table I. The rating levels are assigned as 1, 2, or 3 in each of the risk dimensions. A numerical risk sequence is obtained as a result of the four assignments. If the level of risk is high for all four dimensions, then the numerical risk sequence will be 3333. The numerical order of the risk sequence values is largely inconsequential, and proper use of the numerical risk sequence requires that the sequence be given in order of decreasing digit values. Considering all the possible outcomes of the above application of the risk evaluation matrix, links between the numerical risk sequence and the characterization level have been proposed by USP <1665> (see Table III).

Once the characterization level is determined, the risk evaluation process should then consider the mitigation factors that can be used to adjust the characterization levels. After the component has been evaluated, the downstream process operations (such as the clearance step—for its ability to either eliminate, remove, or clear PERLs from the process stream or dilute them to an extent that the safety of the manufactured drug product is not affected since the extractables will not be present in the drug product as leachables post-this step) can be used to mitigate the risk by 1 level, and the level of characterization required. If the component is subject to flush or rinse as a part of the manufacturing process and the flush/rinse waste does not go into the main process stream, then this flushing or rinsing has an ability to reduce the number and amount of extractable in the final drug product. If the reduction or elimination of extractables has been established with the flushing or rinsing step, then the material reactivity risk level can be reduced by one level, for example a “high risk” component can become an “intermediate risk” component. Process dilution to a certain extent can be considered in terms of its ability to reduce or mitigate the effect of the extractables and can be used to mitigate the risk by 1 level. Clinical use can be considered as a mitigation factor for non-parenteral dosage forms clubbed with their daily dose volume and the duration of the clinical use. If the sum of mitigation factors that apply is 0, then there is no adjustment in the characterization level. If the sum of mitigation factors that apply is 1, then the characterization level established by other dimensions is reduced by one level of testing (example level B testing is reduced to level A testing). If the sum of mitigation factors that apply is 2, then characterization level A is applicable in all circumstances.

The next example looks at the risk evaluation process in a step-by-step manner for the risk assessment of the sterilizing grade filter used as a part of a single-use assembly (Mobius, Merck) in the manufacturing process of remdesivir injection.

Figure 1 shows a representative schematic of the single-use assembly used in the fill/finish of a biopharmaceutical drug product in this case study (3). In this example, the assembly has a polyvinylidene fluoride filter (Durapore, Merck) along with silicon tubing and connectors as the product contact parts. The assembly is sterilized by gamma irradiation.

Remdesivir for injection, 100 mg/vial, is a preservative-free, white to off-white or yellow lyophilized solid. The concentrate for solution for infusion contains 100 mg remdesivir that is to be reconstituted with 19 mL of sterile water for injection and diluted into intravenous (IV) infusion fluids prior to IV administration. Remdesivir injection is produced by aseptic filtration. The process steps include dissolution of betadex sulfobutyl ether sodium in water for injection, pH adjustment and dissolution of remdesivir, dilution with sufficient quantity of water for injection, pH adjustment (pH 3.0 to 4.0), bioburden reduction via filtration, sterile filtration, vial filling, stopper insertion, lyophilization, and capping. The product before lyophilization contains remdesivir 5 mg/mL, betadex sulfobutyl ether sodium 300 mg/mL, hydrochloric acid and/or sodium hydroxide in a quantity sufficient enough for pH adjustment, and water for injection. The liquid after sterilization by sterile filtration is filled into 20-mL vials under aseptic conditions before being subjected to lyophilization. Water for injection used as a base is removed during lyophilization (4,5). For this case study, it is assumed that the manufacturing batch size is 500 L and the maximum contact time of the final sterilizing grade filter is 12 hours at a temperature of 22.5±2.5 °C. It is also assumed that there is no flushing or rinsing during the manufacturing process.

Applying the risk evaluation matrix from Table I and Table II to this case study results in the risk level rating shown in Table IV.

The risk sequence will therefore be 3211. As per the manufacturing process provided, there are no steps that can be considered for risk mitigation, and hence the risk mitigation factor is 0. The risk level for level of characterization will be Level A or B. Applying the clauses as defined in Table III, it can be determined that a characterization of Level B will be required for this component.

Following the risk assessment, the next step will be to design and execute the extractable test corresponding to Level B, as per USP chapters <665> and <1665>, generating the extractables profile and PERLs. Extractables will be further evaluated for patient safety assessment. If the results are proven to be safe for the patient, then the documents will be ready for regulatory submission.

If a patient safety concern arises, then possible risk mitigation steps will have to be included in the manufacturing process, or the component may need to be replaced. If the patient safety concern still exists, then the characterization will need to be done by leachables testing followed by re-evaluation for patient safety. If the results are proven safe to the patient, then the documents would be ready for regulatory submission at that point. However, if after the re-evaluation the safety concern still cannot be resolved, then the component will need to be replaced to ensure patient safety.

References

1. USP. General Chapter <665>, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. USP–NF (Rockville, Md., 2022).
2. USP. General Chapter <1665>, Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. USP–NF (Rockville, Md., 2024).
3. Shea, J. The Role of BioPhorum Extractables Data in the Effective Adoption of Single-Use Systems. Whitepaper, March 2022.
4. EMA. EMA/178637/2020—Rev.2. Summary on Compassionate Use (April 3, 2020).
5. FDA. VEKLURY Label. FDA.gov, October 2020.

About the authors

Ramesh Raju Mavuleti*, rrajum@gmail.com, is head of operations, Validation Services India. Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC. Tathagata Ray is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd. K. Vasantakumar Pai, PhD, is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University. K. Sreedhara Ranganath Pai, PhD, is professor, Department of Pharmacology, Manipal Academy of Higher Education. Somasundaram Gopalakrishnan is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

*To whom all correspondence should be addressed.

Article details

BioPharm International®
Vol. 37, No. 6
June 2024
Pages: 27–31

Citation

When referring to this article, please cite it as Mavuleti, R. R.; Pai, K. V.; Pai, K. S. R.; et al. Application of the Risk Evaluation Matrix as per USP <665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing. BioPharm International 2024, 37 (6) 27–31.