Single-use systems (SUS) are changing the way end users think about validation. The complex supply chains of SUS are not always as robust as necessary. This presents both manufacturers and end users of SUS with validation challenges not present with a stainless steel equivalent. Given increased regulatory scrutiny on supply chain security and risk mitigation strategies throughout the development and manufacture of a therapeutic drug product, how can end users ensure the expected level of compliance in this new world of SUS? The secret: shared responsibility for validation with your supply chain.
WHY VALIDATION NEEDS TO BE A SHARED RESPONSIBILITY
Therapeutic drug manufacturers today face multiple challenges to produce safe and effective drugs. These include: downward cost pressures, in a highly regulated market, with a multi-tiered supply chain.
The trend away from stainless steel-based processes to single-use processes introduces a myriad of different suppliers and points of failure. Starting at the component level, suppliers use multiple raw materials in their supply chain. Some of the raw materials needed to manufacture the parts they supply to system integrators are themselves individual components with their own raw material supply chain. Many system integrators not only fabricate systems, but also manufacture some of the components used in a single-use assembly. Therefore, the system integrators also have their own raw material supply chain to manage and validate before they assemble and supply the finished system.
Validation of fixed pipe-based manufacturing systems used to be the primary responsibility of the drug manufacturer. However, that model is changing. It is not rigorous enough to ensure reliable and repeatable performance of all the products delivered from all suppliers of an SUS. In this new SUS world, validation needs to begin at the component raw material level and continue successively through all manufacturing, operational, and supply steps to the final assembly.
Many drug manufacturers understand how to validate in their own environment. But, what does a rigorous validation program look like for their component suppliers and systems integrators?
THE CHALLENGES OF COMPONENT VALIDATION
The basic building blocks of a single-use assembly are the components. Common components include connectors, filters, tubing, clamps, cable ties, ports, and bag chambers. This is where validation begins for the completed SUS. The drug manufacturer and system integrator need to ensure quality controls and robust systems are in place.
Yet, several challenges exist:
o lack of a reliable and repeatable production process
o inability to measure quality and performance accurately
o inefficiency caused by training required for different components
o inconsistencies across facilities
o restriction of implementation of flexibility due to limited interoperability
Several industry groups such as BPSA, BPE, and BPOG are proposing uniform procedures and methods, but major challenges still remain. For example, plastic films used in the manufacture of single-use bags are currently regulated under USP<661>, which is a standard written specifically for packaging. A proposed new standard (USP<665>) specifically for polymer components and systems used in manufacturing pharmaceutical and biopharmaceutical drug products is currently out for comment, but is not yet an industry standard. However, as specific standards for single use technologies evolve, the component suppliers will start to converge.
Despite these challenges, as the market matures, so do the players and their approaches to validation. The end users’ expectation is a robust, scientific approach that results in a stable and dimensionally centered process.
BEST PRACTICES FOR COMPONENT VALIDATION
What can component manufacturers do to produce and validate their products to help integrators and GMP manufacturers meet their regulatory needs? Component suppliers can do this primarily through validation of the product supply and design and validation of the manufacturing process.
Validation of the product supply and design
Validation of the manufacturing process
An evolving requirement is the expectation that the quality systems mirror that of a GMP operation. For component suppliers, minimum expectations include:
While these are not GMP-regulated, many component manufacturers describe their goal as being “GMP-compliant.”
Drug manufacturers are now auditing component suppliers to the same standards and with the same expectations as full system integrators. This approach serves to allow the drug manufacturers to both understand the whole supply chain for SUS, and also to drive the quality and validation requirements throughout the complete sourcing and manufacturing process.
THE CHALLENGES OF SYSTEMS INTEGRATOR VALIDATION
What does it take to supply a complete single-use sterile system to the biopharma market? It can be a complex process — even for a relatively simple product such as a storage bag comprised only of flexible film, face ports, tubing, clamps, connectors, and cable ties, double bagged and gamma irradiated.
Most integrators do not manufacture all of the products used in a single-use assembly. Some integrators don’t manufacture any of the components. This complex supply chain can include both external and internal suppliers, and in some cases, all suppliers will be external. The number of components, assembly steps and the actual suppliers may vary depending on the design and complexity of the final assembly.
BEST PRACTICES FOR SYSTEMS INTEGRATORS VALIDATION
Key requirements for achieving product quality at the systems integrator level include the following:
Manage the Supplier Base
Final product quality starts with selection, qualification, and validation of all raw material and component suppliers. This evaluation is the same as that undertaken by component suppliers but is critical to ensure that both parties are comfortable working together. One framework for supplier evaluation is called the 10-Cs of supplier evaluation.
Once a supplier has been selected, it must be qualified and validated. That includes validating manufacturing quality across all processes the supplier has in place: the quality program, product certification, returns process, paper and site audits, risk mitigation strategy, their supply chain security program, manufacturing controls, raw materials sourcing strategy, and corrective action process. From a risk management standpoint, do they dual source? Do they make or outsource? Do they have an active continuous improvement process and a new product development program that can support the integrator’s program?
Once a supplier is chosen, validation continues on the selected supplier’s ongoing processes. This includes but is not limited to quality, form, fit, and function of parts, service, delivery, and supplier score cards.
From a system manufacturing perspective, customization is one of the greatest advantages of single-use technology, but also a disadvantage. Customization presents challenges for supply chain management and product validation. Recognizing that different levels of validation are needed based on the level of customization, many manufacturers have adopted a multi-tier approach to system supply.
The focus on product quality continues through the validation of the manufacturing process, facility, equipment, and personnel who manufacture the assemblies.
o Operation and performance of the manufacturing environment to the required cleanliness
o Robust preventative maintenance schedule for all manufacturing and ancillary equipment
o Continual monitoring of critical process parameters such as particulates,
bioburden, temperature, pressure, and humidity
o Continual monitoring and validation of the set alarm levels that trigger alerts and actions.
o Is it integral, and fit for purpose?
o Does it conform to the design specifications for the customer?
o Is the packaging validated to protect the product during inventory, shipping, handling, and
storage prior to use?
o Is the irradiation process validated and certified?
o Is the assembled product full traceable through batch records to allow identification of
components/processes in the event of a failure?
o Does the product meet all appropriate industry standards?
o Is it certified to the level which the end user customer wants it to be?
5 CONSIDERATIONS FOR THE DRUG MANUFACTURER
Industry collaboration is still needed. As with the adoption of any new technology, there will be challenges with single-use technology until it matures. In the meantime, there are some critical areas where drug manufacturers and suppliers can work together to make the adoption of single-use technology simpler, more efficient, and less daunting for the benefit of the industry as a whole.
A TEAM APPROACH
Realizing the full benefits of single-use technologies requires an unprecedented level of communication and information exchange among the key players. More collaboration is needed by the drug manufacturers, integrators, component suppliers, and regulators than exists with traditional manufacturing systems. This increased collaboration must work through all aspects of the design, testing, manufacture, and validation of the single-use systems and the drug substances with which they are used for many years after approval. This creates a pathway for industry to share information and to partner at multiple levels.
Shared validation for single-use systems is only one step — but a very important step — in developing a greater understanding of the needs and constraints facing the industry and ensuring safe and effective drug products are supplied to patients in need.
CPC (Colder Products Company), the leader in single-use connection technology, offers a wide variety of bioprocessing connection solutions. Our innovative designs offer flexibility to easily combine multiple components and systems including process containers, tubing manifolds, transfer lines, bioreactors and other bioprocess equipment. Sterile fluid connections from CPC are available in a complete range of 1/8- up to 1-inch flow configurations. For more information, visit cpcworldwide.com/bio