Understanding Particulates in Single-Use Bags

The biopharmaceutical industry is facing many challenges. Global economic changes, increasing

healthcare costs, expiring patents, and increasingly personalized medicine all affect the way

manufacturers approach bioprocessing steps and the equipment and systems used to make biological

drug products (1). Demands for smaller batch sizes, greater process flexibility, reduced manufacturing

costs, and increased speed to clinic have driven the acceptance of single-use systems (SUSs) in this

industry (Figure 1). SUS suppliers have rapidly developed components such as fittings, tubing, pumps,

sensors, and flexible containers that are delivered to users presterilized and ready for use in single

campaigns or process steps.

Figure 1: 

Applications such as buffer preparation and media storage were the first to adopt single-use components

including filter capsules and plastic biocontainers. As single-use technology became accepted, it moved

into upstream processes with the implementation of disposable bioreactors and mixing systems. The

latest applications of SUSs are in downstream processes such as drug substance storage and final filling .

The benefits of single-use systems have been thoroughly investigated. Some key advantages over

traditional multiuse systems include reductions in capital expenditure; smaller, more flexible

manufacturing footprints; elimination of expensive clean-in-place (CIP) and steam-in-place (SIP)

processes; reduction in cross contamination; and facilitated process changeovers. Along with those

benefits, however, come new areas of concern associated with polymeric materials and disposable

systems.

One area of interest is the cleanliness of SUSs. Because they are intended to be used “as-is,” the

accountability for their cleanliness has shifted from end users to suppliers. Contaminants that are present

in a given system — such as leachable compounds or particulate matter — may be transferred to process

media. Contaminants in upstream SUS processes such as bioreactors and mixing systems pose less risk

because process fluids will be subjected to downstream filtration and purification steps, which could

remove such contaminants from the process stream. The closer SUSs are to final drug products, the

higher the need is to reduce their leachables and particles. Clearly, final process steps such as drug-

substance storage and final filling are high-risk activities that require the lowest levels of leachables and

particulates in SUSs.

Particle Sources

Particulates can come from many different sources. One source is the environment in which a drug

product is manufactured: e.g., heating, ventilation, and air conditioning (HVAC) systems; tools and

equipment used in the facility; and people supporting the manufacturing processes. Components and

used to contain, mix, purify, and transport media throughout such processes present another source of

particles. They include gaskets and seals, vials and syringes, and components making up SUSs such as

tubing, fittings, and bags.

The primary reason to better understand and control particles in SUSs is to reduce their clinical impacts

and ensure patient safety. If infused along with a biologic therapy, particulate matter can block blood

vessels, affecting functional body systems to cause tissue damage and even internal organ failures.

Particles also may be incompatible with a patient’s arterial system, essentially poisoning him or her. Other

potential effects include overtaxation of the immune system and reducing drug efficacy. Factors

determining whether particles in a drug product will affect patients include the size, shape, and quantity

of particles present; the composition of those particles; the dosage, frequency, and route of drug delivery;

and patient attributes such as age and health status (3).

Secondary to the possible clinical impacts are commercial ones. Particulates may contribute to lower

production yields and scrapped batches. The cost of goods sold (CoGS) is also negatively affected,

increasing as the need for more risk-mitigation measures and quality assurance (QA) inspections.

, companies may experience increased scrutiny from regulatory authorities. In one recent incident, 19 lots

of drug product were recalled because of glass particles found in vials (4). That occurred even after

several warning letters were issued by the US Food and Drug Administration (FDA) and expensive

upgrades were completed for multiple facilities (4).

In an ongoing effort to mitigate particles, several regulatory groups have developed standards that are

continually reviewed and updated by those same groups. Table 1 is a partial list of such standards. One

commonly referenced standard is USP Chapter <788>, which establishes methods to quantify particles

and provides acceptable limits for particulates in injections. Limits established in USP Chapter <788>

depend on the method used (light obscuration or microscopic particle count) and whether a sample

comes from a large-volume (>100 mL) or small-volume (≤ 100 mL) parenteral dose. Figure 2 lists those

limits