Aiding Material Qualification and Risk Assessment for Single-Use Biomanufacturing

Single-use technologies provide many benefits; however, they require additional preparative work before being implemented. This includes regulatory approval and assurances that extractables and leachables (resulting from the use of disposable equipment) remain at or below acceptable levels. Vendors can facilitate extractable and leachable studies by providing robust, reliable, and accessible information, thus reducing the time and resources needed to prepare documents for drug approval submissions.

Increasing Adoption of Single-Use Technology

Access to the right information is crucial across the pharmaceutical industry. When stainless-steel equipment was predominant, the focus was on obtaining information about the raw materials used to produce drug products. The increasing adoption of single-use (SU) technologies (SUT) has created the need for additional information about the components of disposable systems.

Drug manufacturers require both access and clarity to information, which is driving greater collaboration and more innovative means of sharing. MilliporeSigma has one of the broadest product portfolios in the pharma sector, covering basic chemicals, complex SU devices, and the biocontainers, pumps, tubing, filters, and components comprising them. 

To improve the ease of use of SU systems for our customers, we have committed to understanding what information they need. We are providing the documentation
required in an easy-to-access solution that comes with additional support services and the ability to customize data for tailored analyses and assessments.

The Emprove^® Program 

The Emprove^® Program began with the provision of chemical data for pharma raw and starting materials. This data is easily accessible and designed to facilitate regulatory compliance. Our original focus was on offering higher-quality products with full supply chain transparency and the information necessary for performing quality assessments.

The program expanded into filters and single-use products approximately five years ago and more recently into cell culture media and chromatography products. SU technology offers many benefits, including faster setup and the reduction or elimination of cleaning and cleaning validation. It creates reliance on SU vendors for manufacturing equipment at a level on par with raw materials. In addition to assurance of supply, extractables and leachables (E&L) must be addressed. 

The Emprove^® Program for SUT provides comprehensive data sets for customers and gives them a higher level of support around regulatory acceptance and approval as they work through their validation processes. It entails organized, detailed product information and assistance to help customers with material qualification and risk assessment of biomanufacturing devices, as well as process optimization. By avoiding the need to develop test methods, search quality-related documents, or evaluate scientific data, customers can reduce the effort required to prepare documents for drug approval submissions.

At the base level, MilliporeSigma has developed specific information for the materials for our SU products. Customers may need this information to support audits or other quality-based functions. Material Qualification Dossiers (MQDs) report on a material’s fundamental properties and also feature manufacturing flowcharts, product characterization, regulatory statements, and more.

Quality Management Dossiers (QMDs) include a self-assessment of quality while documenting detailed supply information for the material, including its complete chain of custody from manufacture to final release. These dossiers present additional useful information, such as shelf-life data, sterilization, validation, and packaging requirements. 

The most comprehensive and valuable piece of the Emprove^® Dossier offering for our SU products is the Operational Excellence Dossier (OED). The OED includes product-specific data required to support the use of disposable systems in drug manufacturing. They include product quality reports with elemental impurities information and extractable profiles and specify the analytical procedures used to obtain this data. The goal is to provide high-quality test data to support our customers.

MQDs are accessible directly on the MilliporeSigma website. Access to the higher-level QMDs and OEDs are offered via a subscription service. While these aspects of the Emprove^® Program can theoretically be purchased individually, we encourage customers to become members of the Emprove^® Suite so that they can source all of the documentation reports for our SU products, as well as filter devices, chemicals, cell culture media, and chromatography resins. 

While there are still some chemicals available that are not included in the program, we have found that customers really appreciate the advanced documentation offered by the Emprove^® Program, because it can be used for their approval processes. The program has added significant value to our product lines and exemplifies our commitment and willingness to support and collaborate with customers. 

Since bringing the filter and SU products into the program, we have received valuable feedback from customers as they have worked through their final drug product approval processes. The OEDs, in particular, provide comprehensive data sets that aid their ability to conduct risk evaluations. Our Emprove^® Suite subscribers appreciate how all of the information is provided in a consistent format that they can readily use for their own assessments. 

Balance Between Functionality and Ease-of-Use

The flexibility and mobility of SU systems in combination with the elimination of cleaning processes provide a tremendous advantage over stainless-steel systems. Cost, time, and the risk of cross-contamination are all reduced. These benefits and functionality are achieved because of the use of plastics, which can contain certain additives to ensure stability and function. There is a reasonable expectation that the levels of these additives in a drug product will be low. 

SU technologies are designed with this consideration in mind. They are extensively tested to ensure that E&L profiles are minimal. If drug manufacturers use SU systems as recommended, such as flushing filters before use, the E&L risk to patients is significantly reduced. The key is making sure the right functionality is achieved with the right materials during process optimization and drug product formulation combined with risk mitigation.

Focus on Extractables & Leachables

When the plastics used to make disposable manufacturing equipment are exposed to media, cells, buffer, drug products, and other materials used throughout biologics production processes, there is a potential for chemicals in the plastic SU components to be extracted into the bioprocess fluid. 

Extractables represent the comprehensive range of chemicals that could potentially be extracted into a drug product formulation. They are identified by exposing the plastic materials under a range of highly aggressive conditions intended to represent worst-case scenarios in the manufacturing environment. Model solvent streams are used, such as 50% ethanol, as well as highly acidic and highly basic solutions. Leachables are the process-specific compounds with the potential to be extracted into the drug product formulation under actual processing conditions. 

The ultimate goal of E&L testing is to ensure patient safety. As such, once potential E&L compounds are identified, the next step is to determine whether they will pose a risk to the patient if present in the final drug product. Relevant risks could include anything from a rash to cancer, as well as any potential reactions between E&L compounds and other ingredients in the drug product formulation that cause a problem, either acute or long term.

In general, drug manufacturers must evaluate the SU components that are in contact with the product under the given process conditions, such as duration, temperature, solvents, or material characteristics. Any risk-mitigating steps occurring later in the process can be taken into consideration. At this stage, an extractables profile, if available, would facilitate product, process, and dosage-specific assessments. If thus far, the patient safety evaluation indicates no risk, the findings may simply be reported and monitored for future changes. 

On the other hand, if there is a risk to the patient, a leachables study may be conducted under normal product application or storage conditions. Risk may also be mitigated through a process-step modification, such as including an additional flush. A final option could be to change the material of the component.

Multiple Analytical Methods

Determining risk and interpreting extractables data to construct a reasonable validation strategy is a complex process. If only one chemical could potentially be extracted from SU systems, E&L strategies would be fairly simple. However, there are often multiple chemicals that must be detected and quantified, and there is no single method that can be used. Multiple analytical methods must be employed to gain a broad understanding of the different potential compounds. The challenge is to design an effective E&L strategy that provides consistent and meaningful data. 

Whether a pharma manufacturer conducts E&L testing in-house or relies on a contract testing lab, the process is expensive and time consuming. The Emprove^® Program helps alleviate this burden. With the Emprove^® Dossier, results of multiple analytical methods are used to evaluate a wide range of compounds, including volatile, semivolatile, and nonvolatile organic compounds. These methods include gas chromatography mass spectrometry, both headspace and direct injection, and liquid chromatography mass spectrometry with multiple detection modes, along with other methods. In addition, inductively coupled plasma mass spectrometry is used for evaluation of elemental impurities. Subscribers to the Emprove^® suite have immediate access to this large data set, eliminating months if not years of work. 

Regulatory Clarity

There are no specific regulatory guidelines pertaining to E&L used in the manufacturing of drug products, other than that pharmaceutical manufacturers must demonstrate that the materials used are not reactive, additive, or absorptive. There is also a regulatory expectation that researchers will test for E&L. Agencies such as the U.S. FDA’s Center for Biologics Evaluation and Research (CBER) recommend a risk-based approach to evaluation.¹ In such an approach, indication, safety, product characteristics, dosage, formulation, and stability are all factors. If there appears to be a lower risk with the materials in question, the sponsor can submit supplier data, a detailed justification for applying this data, and an explanation of why no more testing is required.

If there is relevant risk, the sponsor may have to determine toxicity based on maximum dosage of potential leachables derived from extractables data. If the risk of maximum dosage of potential leachables remains, leachables evaluation and testing may be necessary. Furthermore, if product quality could be affected by potential leachables, studies may need to assess the effect on product quality, including efficacy. These evaluations are possible when the supplier provides extractables data, which can supplement final product quality assessments.

Beyond the regulatory sphere, a range of industry organizations have created best-practice strategies for implementing extractables studies. The Parenteral Drug Association’s PDA Tech Report 66 is a good consensus document within the industry, not just on E&L, but regarding single-use technologies in general.² It has been quite useful for customers that are just beginning to adopt disposable manufacturing solutions. 

The BioPhorum Group, a global consortium of large biopharmaceutical manufacturers, has also been active in the E&L space. In the absence of official E&L-specific guidance, many manufacturers are fulfilling regulatory expectations by following the BioPhorum³ and/or U.S. Pharmacopeia (USP) <665>⁴ draft recommendations. 

While these protocols are not identical, the general approach is similar, and at least one or the other can apply to most drug products and substances. Testing is performed at various time points and temperatures. Resulting extraction solutions are subjected to robust and extensive analyses to determine what levels of volatile, semivolatile, and nonvolatile organic compounds and metals have been extracted. Either approach will produce an array of data that must then be evaluated in the context of the proposed process.

USP is expected to finalize USP <665>⁴ and <1665>⁵ in the near future. These documents are a starting point for global guidance. However, they still lack information on how to conduct extractables studies. Which model solvent stream should be used is indicated, but not what testing should be conducted. More comprehensive guidance is still needed.

There is currently a workstream through the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) to standardize the risk assessment approach for E&L. The final concept paper “ICH Q3E: Guideline for Extractables and Leachables (E&L)” was published on June 30, 2020, outlining the issues to be addressed in the proposed guideline that the working group will develop.⁵

The Benefits of Emprove^® Dossiers

It can be complicated to understand how the extractables that might come out of a filter or other SU system relate to the product in a vial, but that is ultimately what a pharma manufacturer must determine. MilliporeSigma’s Emprove^® OED provides the comprehensive data set needed to start making that determination. Having access to that consistent data set for all of our products can really streamline the process because we have standardized our data based on the BioPhorum and USP recommendations.

Using the broad data set on extractables, customers can identify the potential leachables for each specific product/process. Since the data we provide is generated under worst-case conditions, it may be beneficial for the customer to conduct leachables testing if their actual process conditions are much milder. MilliporeSigma can support these efforts as well, not as part of the Emprove^® Program, but through other services offered by the company.

Validation Services

The Emprove^® program for many customers is in fact a starting point. While many big pharma customers have in-house toxicologists and E&L assessment capabilities, many small and medium-sized firms do not have these resources. MilliporeSigma’s BioReliance^® Validation Services can provide the support they need to conduct full risk assessments, starting with choosing the model solvent streams and conditions based on the process information provided, all the way through to performing the safety evaluation.

If the worst-case scenario data suggests the need for further leachables testing under actual process conditions, the validation services group can also conduct that additional product-specific testing. For instance, leachables testing is often required for large-volume parenteral drug products that are administered frequently and in large doses to patients, such as fluids given to dialysis patients multiple times per week. 

Information Expansion

As single-use technologies evolve and new classes of drug candidates enter the pharma pipeline, data needs continually change. In addition, as regulators become more comfortable with SU technologies, their information requirements are evolving too. As a result, the content of the MQDs, QMDs, and OEDs within the Emprove^® Program will always be in flux.

The expansion of information included in our Emprove^® Dossiers is the result of collaborations between MilliporeSigma and our customers, who bring us requests for new types of information on a regular basis. Most recently, discussions centered on packaging validation and additional supplier information could be added to support customers in this area. These are just two possible examples; we fully expect the Emprove^® Program to constantly evolve with the industry.

Despite these constant improvements, MilliporeSigma is committed to maintaining the integrity of the data we provide through the Emprove^® Program; we recognize the value of the peace of mind afforded by robust and reliable data. As importantly, through strategic development in conjunction with our customers, we continue to strive to simplify and streamline the data acquisition process. 

Relying on Expert Guidance

SU technologies provide numerous benefits for pharmaceutical manufacturers. However, there is additional preparative work required, much of which relies on access to reliable and robust data. Despite the current absence of guidance, regulatory expectation does require evaluation of patient safety with supporting data for manufacturing components that directly come into contact with drug manufacturing process streams. Readily available extractables data can help manufacturers using SU technology to accelerate product qualifications, risk assessments, and process optimization. 

E&L risk analysis is a complex process, and expert guidance is critical to ensure compliance and drug safety. While the task of analytical E&L test data interpretation and submission can be daunting, the right SU system supplier can save time by providing SU system E&L data in well-organized, easy-to-use formats. The right information must be available for conducting risk assessments depending on the specific processes and products involved.

Having confidence that vendors of disposable systems are using safe and appropriate materials and providing correct information is essential to facilitating the use of SU technologies and enabling manufacturers to fully realize the advantages they provide. Relationships grounded in trust are a must for success. That is why MilliporeSigma has taken the steps to establish the Emprove^® Program, not only for pharma raw materials and intermediates, but for filters and other SU technologies. We pride ourselves on providing this high-quality service built through close collaborations with our customers and continue to work hard to earn and deserve their business.

References

1. Pharmaceutical cGMPs for the 21^st Century – A Risk-Based Approach. Rep. U.S. Food and Drug Administration. Sep. 2004. Web. 

2. Technical Report No. 66 Application of Single-Use Systems in “The BioPhorum extractables protocol and portal, and leachables best practices guide.” BioPhorum Operations Group. N.d. Web. 

3. USP <665> “Polymeric Components and Systems Used in the Manufacturing of Drug Products.” Pharmacopeial Forum. 1 May 2017. Web. 

4. USP <1665> “Characterization of Polymeric Components and Systems Used to Manufacture Pharmaceutical and Biopharmaceutical Drug Products.” Pharmacopeial Forum May 2017. Web.

5. “ICH Q3E: Guideline for Extractables and Leachables (E&L).” International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 30 Jun. 2020. Web.