Successfully Navigate the Regulatory Landscape for Chemicals and Single-Use Consumables

Successfully navigating the landscape of regulatory guidance during the drug development process can be daunting, especially for companies advancing their first clinical candidate. Understanding quality standards, guidelines and expectations is essential to avoid unnecessary delays and assure success in the regulated pharmaceutical and biopharmaceutical industry.

The Emprove^® program, supports our filtration, single-use, chromatography, cell culture media and chemicals portfolios and is designed to accelerate risk assessments and maintain compliance with current Good Manufacturing Practices (GMPs). Now in its 20th year, this program provides easy access to a vast amount of product and quality information and provides confidence that the raw materials and components you purchase meet the qualitative, regulatory, technical and supply needs for their designated application, use and function.

This page provides an overview of terminology and describes key considerations related to regulatory expectations for chemical raw materials and qualification of components and single-use assemblies including extractable and leachable testing.

Section Overview

• Chemical Raw Materials
  • Understanding Foundational Regulatory Terminology
  • GMP Requirements During Clinical Development
  • Strategies for Mitigating Nitrosamine Risk
• Single-Use Systems
  • Considerations for Single-Use Systems
  • Shared Responsibilities for Qualifying Single-Use Assemblies
  • Timely Access to Comprehensive Product Documentation via the Emprove^® Program

Chemical Raw Materials

Understanding Foundational Regulatory Terminology

Good Laboratory Practice (GLP)

GLP is a quality system focused on the organizational process and conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived, and reported. GLP principles apply to nonclinical studies on pharmaceuticals; results may be submitted for registering or licensing the tested substance or any product derived from it.

Good Manufacturing Practice (GMP)

GMP is a set of processes, procedures, and documentation requirements that ensures biopharmaceuticals are consistently produced and controlled according to globally accepted quality standards. While process chemicals are sometimes available in GMP and non GMP forms, it is expected that GMP forms are used if they are entered into regulated areas, such as Active Pharmaceutical Ingredients (API) according ICH Q7a or GMP grade excipients.

Traceable and comprehensive documentation, as well as change control procedures, is standard for GMP materials while documentation for non-GMP material can be quite limited. If a change in the manufacturing process of a critical non-GMP material occurs, the impact should be evaluated. In general, the use of non-GMP materials in pharmaceutical manufacturing requires additional controls in the manufacturing process and justification in drug registration. If non-GMP materials are used, there is always a risk. For example, lack of information about changes in the entire production chain can negatively affect the pharmaceutical production process.

GMP Requirements During Clinical Development

Different GMP standards and requirements are applied for different phases of clinical development. Chapter 19 of the ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients (APIs) provides detailed information about GMP requirements for APIs for use in clinical trials.

During early development, when a single batch of API is produced or where process changes make batch replication difficult, process validation is not normally applicable. Instead, a combination of controls, calibration and equipment qualification assure API quality during this phase. Controls should be consistent with the stage of development and appropriate GMP concepts should be applied, while process validation should be conducted in accordance with ICH Q7.

When batches are produced for Phase 3 or commercial use, even if at pilot or small scale, drug manufacturing must follow GMP requirements. Even though it is expected that changes will occur as the manufacturing process develops, every change in production, specifications, or test procedures should be recorded and approved as required by the relevant authority.

Documentation of API manufacturing and access to raw material information, such as that provided in the Emprove^® program, can help manufacturers optimize development and support risk assessments. Documentation from the supplier can empower the biomanufacturer’s decision making by providing information on:

• The quality system of the supplied materials
• Release testing methods
• The validation approach of the manufacturing
• Change notification commitments
• Information about the applied testing methods and the release control and shelf-life information

Strategies for Mitigating Nitrosamine Risk

Nitrosamines are chemical compounds identified as probable human carcinogens and in 2018, emerged as a public health concern when unacceptable levels of N-nitrosodimethylamine (NDMA) were found in pharmaceutical products containing Valsartan. In response, regulatory authorities published guidance on how to avoid the presence of nitrosamines in medicinal products and how to test for the presence of nitrosamines. In addition, they require drug manufacturers to develop control strategies to limit the presence of these impurities and, where necessary, improve their manufacturing processes.¹

Information related to the presence of nitrite is provided in the Emprove^® dossiers that accompany more than 350 of our products. Download free Emprove^® chemicals demo dossiers.

Single-Use Systems

Considerations for Single-Use Systems

Single-use systems (SUS) offer significant improvements in efficiency and productivity when incorporated into the biomanufacturing workflow. They reduce capital investments, eliminate cleaning validations, decrease facility set-up time, and reduce the risk of cross-contamination.

However, when adopting single-use technologies, the potential impact of extractables and leachables must be considered as they could impact the efficacy and quality of the drug product, and ultimately patient safety. Extractables are compounds that can be extracted from the elastomeric or plastic components of single-use assemblies when exposed to certain solvents under extended time periods and exaggerated temperatures. Leachables are compounds that leach from the elastomeric or plastic components of the SUS into the process fluid under normal use conditions.

Drug manufacturers are responsible for understanding the interactions between the process fluid and single use components, and typically this begins with a risk assessment. The risk assessment identifies all materials or components in contact with the process fluid and determines risk in the context of the process stream composition, materials of construction, temperature, and contact duration. This risk assessment is often performed by the biomanufacturer in close collaboration with a trusted supplier who can leverage product specific compatibility data to assess risk related to product and process conditions. Dependent on results of the analysis, product, and process specific extractables data may be needed to determine if there is risk to patient safety. If a safety risk is identified, a leachable study should be conducted and the risk to patient safety re-assessed in the context of mitigation steps.

United States Pharmacopeia (USP) Guidelines for Extractables and Leachables Testing

USP <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, establishes a baseline for the qualification of single-use systems used in the manufacturing of pharmaceutical and biopharmaceutical drugs.
USP <1665>Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, is a companion document to USP <665> which offers guidance for assessing risk of plastic materials and additional information on the extraction methods and analyses.

United States Pharmacopeia (USP) Guidelines for Biological Reactivity

The biological reactivity testing used to assess the responses of mammalian cell cultures and animals to elastomerics, plastics, and other polymeric materials in single-use systems were originally applied to medical devices such implants or storage containers. The lack of industry standards for qualification of plastics used in bioprocessing led the industry to adopt medical device standard (Class VI) as a default. This resulted in excessive animal testing and a reconsideration of the suitability of USP <88>. USP has provided options to minimize redundant testing of existing plastic and elastomeric materials and eliminate unnecessary animal testing for new materials. The industry is transitioning to USP <87> and the equivalent international standard ISO 10993-5, Biological Evaluation of Medical Devices for testing plastic components for manufacturing pharmaceutical drugs.

USP <87> Biological Reactivity Test, In Vitro. “Determines the biological reactivity of mammalian cell cultures following contact with the elastomeric plastics and other polymeric materials with direct or indirect patient contact or of specific extracts prepared from the materials under test”.

USP < 88> Biological Reactivity Tests, In Vivo. “Determines the biological response of animals to elastomerics, plastics, and other polymeric material with direct or indirect patient contact, or by the injection of specific extracts prepared from the material under test”.

Shared Responsibilities for Qualifying Single-Use Assemblies

When single-use technologies are implemented into the workflow both the supplier and the end user share responsibilities for different aspects of the implementation.

The supplier is responsible for qualification of component raw materials to assembly and transportation of the bag and system. The supplier is also expected to apply best practices for assembly qualification in terms of particulates, endotoxin, bioburden, extractables and leachables, sterilization, shelf life, packaging and transport, and integrity testing.

The end-user is responsible for correctly receiving and storage of materials and inspection through assembly use and disposal. The end user must also conduct audits of their single-use suppliers that include the bag manufacturing process, the type of equipment used, in-process testing, and leak and/or integrity release testing.

If you are interested in Extractables data or other premium content, download free Emprove® custom assemblies demo dossiers.

Timely Access to Comprehensive Product Documentation via the Emprove^® Program

The ICH Q9 guideline incorporates the principles of quality risk management into pharmaceutical production. Quality risk management relies on risk assessments which lead to identification of the measures needed to manage risk and maintain control. Risk assessment includes evaluations of the raw and starting materials used in manufacturing. Having access to traceable information is essential during the assessment process and availability of information in the early stages of development may significantly reduce risks for late-stage clinical development.

Collection and compilation of the vast amount of product and testing information from suppliers to ensure that raw materials and components meet the technical, regulatory, and quality needs for designated use and function, is time- and labor-intensive. The Emprove^® Program improves control and compliance of the manufacturing workflow by providing this detailed information in an easily accessible, online format. The program includes more than 500 raw materials, 1,100 filtration products and 450 single-use components, all supported with up-to-date, comprehensive information. Emprove^® dossiers support the different steps in the raw material and component risk assessment continuum – streamlining supplier selection, material qualification, process optimization, patient safety evaluation and more.

Explore our portfolio of Emprove^® products and dossiers:

Emprove^® Chemicals

• Simplify raw material selection while meeting regulatory requirements with our Emprove^® chemicals portfolio. Explore more than 500 pharmaceutical raw materials categorized for different stages of biopharmaceutical development.
• View a webinar and read a whitepaper describing current regulations related to materials risk assessment and understand risk criteria and raw material scope per BioPhorum guidelines.

Emprove^® Filters and Single-Use Components

• Accelerate material qualification, risk assessment and process optimization with the Emprove^® filters and single-use components. Emprove^® Operational Excellence Dossiers provide component extractables data based on industry standards and guidelines recommended by BioPhorum and USP <665>. These data facilitate safety risk assessments, accelerate identification of potential leachables and risk to patients based on process conditions.
• Single-Use Assemblies require extensive qualification of all components. The new Emprove^® Advanced Qualification Dossier combines all component information into one comprehensive dossier including the Extractables data to further expedite assessment of risk.

Emprove^® Chromatography

• The Emprove^® chromatography portfolio streamlines resin selection and qualification for biopharmaceutical manufacturers.

Emprove^® Cell Culture Media

• Cell culture media are essential to support upstream productivity and ensure the final drug product has the required critical quality attributes. With an intense regulatory focus on raw materials, it is recommended to include media in drug product risk assessments. The Emprove^® Program for cell culture media provides information for our CellVento^® CHO media product line.

If you are interested in Emprove^® premium content, Demo dossiers are available to download including data for custom assemblies, chemicals and consumables.