17.03.2016 |

LOGFILE No. 21/2016 – Qualification of Single-Use Component: The Need for Standardization

Qualification of Single-Use Component: The Need for Standardization

by Christopher Smalley

Dr. Sabrina Restrepo and Chris Smalley presented a poster on behalf of Merck, Sharp & Dohme at the Parenteral Drug Association (PDA) Annual Meeting held in San Antonio, Texas on 14-16 March.
The poster was entitled,” Qualification of Single-Use Component: The Need for Standardization ,” which made the argument that there is a need for standardization of several attributes of single use components to enable their rapid adoption and use in advancing pharmaceutical and biopharmaceutical manufacturing.

Problem Statement

The proliferation of custom designs, many very similar to each other, create a greater number of SKUs (stock keeping units) to manage. This proliferation translates into supply chain complexity, a greater number of supplier change notifications, more resources required to successfully manage these notifications, risk to component reliability as well as inventory management challenges.

Proposed Solutions

Clear expectations on the part of the users are necessary, and as an example described the expectations that Merck, Sharp & Dohme (MSD) communicates to its suppliers. These expectations can consist of several of the following:

  • Attribute 1: Biocompatibility testing
  • Attribute 2: Mechanical properties
  • Attribute 3: Gas transmission properties
  • Attribute 4: United States Pharmacopeia (USP) <661> test for plastics
  • Attribute 5: European Pharmacopeia (E.P.) 5.2.8. on TSE-BSE
  • Attribute 6: Total Organic Carbon (TOC) analysis
  • Attribute 7: pH/Conductivity
  • Attribute 8: Extractable/Leachable testing
  • Attribute 9: Chemical compatibility testing
  • Attribute 10: Protein adsorption studies
  • Attribute 11: Endotoxin testing
  • Attribute 12: Sterilization validation (e.g., gamma irradiation)
  • Attribute 13: Container closure integrity
  • Attribute 14: Particulates
  • Attribute 15: Calibration of embedded instrumentation
  • Attribute 16: Free from Special Case Compounds

Not all attributes become expectations:

Attribute 15, calibration of embedded instrumentation, instead of applying universally, would apply to bioreactors, but not tubing, connectors or filters. Attributes that are consistently applied are attribute 1, biocompatibility testing (USP <87 and <88>, ISO 10993), attribute 2, mechanical properties (gas and vapor transmissions, for example), attribute 4, USP <661> when the component is a plastic, attribute 5, demonstrating safety by not transmitting BSE/TSE, attribute 8, extractables and, where appropriate, leachables testing, and attribute 16, freedom from special case compounds. Note that the attributes which are consistently applied are bolded in the listing of attributes.

This last attribute, freedom from special case compounds, has posed a quandary for Merck, Sharp & Dohme. PQRI (Produce Quality Research Institute) issued guidance for extractables in OINDP (Oral Inhalation and Nasal Drug Products) that says that no special case compounds should appear in process contact components used for OINDP manufacturing or packaging. The special case compounds are PAH (Poly aromatic hydrocarbons), PNA (Poly nuclear aromatics) and 2-MBT (Mercaptobenzothiazole), which occur with high frequency in carbon black, which is used as a filler in black EPDM (ethylene propylene diene monomer). In the absence of guidance for extractables in parenteral components, MSD has been using OINDP, however every manufacturer of black EPDM MSD has tested includes these special case compounds. Because the guidance says ‘must contain no …’ MSD feels they are not even able to use a risk assessment to justify any present. However, for many high pressure/high temperature applications such as clean steam and steam sterilizers, there aren’t many good alternatives.

This is but one of many reasons to attempt to standardize several of the attributes of single use components. What does that standardization look like for the attribute extractables and leachables?

  • Single Use System (SUS) Suppliers leverage BioPhorum Operations Group (BPOG) Standardized Extractable Protocol (by Weibing Ding, Gary Masen, Ekta Mahajan, Seamus O’Connor and Ken Wong, Pharmaceutical Engineering, November/December 2014, Vol. 334, No. 6). This standardized protocol describes the analytical methods to be used, including which solvents, and the time points at which to remove samples for testing, for consistency in developing extractables data.
  • SUS suppliers provide to end-users well documented, reproducible and readily interpretable testing study data that end-users leverage for a scientific and risk-based implementation that ensures no impact to product quality, safety or efficacy.
  • Robust and standard technical/data packages which facilitate effective submissions to regulatory agencies
  • SUS suppliers work with end-users to improve process robustness of the standardized extractable protocol based on testing data results
  • Risk score methodologies and Design Space are developed to reduce the need for leachable studies when risk is low

» Potential risk score variables: Proximity to final product, Extraction capability of solvent, Contact time, Contact Surface Area, Temperature

Hoping to intrigue members of the pharmaceutical and biopharmaceutical industry with the concept of a Design Space for quickly and efficiently performing risk assessment, Drs. Restrepo and Smalley proposed a Design Space capable of embracing most single use components as having the following process parameters:

  • Temperature: ≤ 60 degrees C
  • Time: ≤ 72 hours (could be expanded based on BPOG Standardized Protocol)
  • pH: 3—11
  • Water based-solvents

Overall, MSD’s strategy to achieve standardization is to work on several fronts, including:

  • Implementation of Single-Use Network (SUN) internal to MSD, working across the network
  • Single-use Catalogue for key single use components with supportive knowledge management tool
  • Supplier data leveraged
  • Single-Use Standard development
  • Design Space Implementation
  • Standard risk assessment with clear expectations for additional in-house qualification as needed based on risk scope

Message to the Readers

As an industry, we need to work together to contribute to the effort to achieve standardization by:

  • Participate in Industry efforts to standardize
  • Participate as author and reviewer of the ISPE Single-Use Guide
  • Participate in the BPOG / Bio-Process Systems Alliance (BPSA) joint efforts:
    o Supplier Change Notifications (changenotification@biophorum.com)
    o User Requirements Specifications (userrequirements@biophorum.com)
  • Work to implement the BPOG Standardized Extractable Protocol
  • Employ a Design Space with the most commonly used process conditions, and for those SUS that fit within that Design Space, simplify the risk assessment and qualification necessary for implementation.


MSD hopes that sharing its approach to Single Use will engender conversations with peers and with Health Authorities to provide better definition for what is expected of single use components, and facilitate the provision of part of those requirements from suppliers as well as making the achievement of those expectations easier, quicker and simpler. Standardization will facilitate rapid adoption and use of single use components.


Christopher Smalley
Merck & Co., Inc. (known as Merck Sharp & Dohme outside of North America), West Point, PA 19486, USA

Qualification of Single-Use Component: The Need for Standardization.pdf