How to avoid recall of injectable products because of particles

Medical device recall by FDA may occur due to the presence of particles. A new draft guidance document regarding the risk assessment of particles has been released.

Particulates present in injectable products may give rise to serious adverse events in the patient. Particles which remain at the site of injection can cause phlebitis, inflammatory reactions, and granulomas.  At the systemic level particles can induce infections, allergic reactions, and venous and arterial emboli; and in distal organs particles can cause microscopic emboli, abscesses, and granulomas. Particles may also lead to patient exposure to toxic chemicals and metals.

Due to the severity of the potential consequences to the patient, all products intended for parenteral administration must essentially be free of particulates as outlined in the U.S. Pharmacopeia General Chapter <790>; but producing injectable products free of particulate matter is challenging.

Multiple sources of particulates
Particles can be generated during the manufacturing process; they may come from components, containers, or packaging; or from handling, washing, and sterilization processes. Particles can also arise from the formulation or stability of the product, for example, protein therapeutics in contact with siliconized surfaces may generate protein-silicone complexes which may be immunogenic. Particles can also come from external contamination sources.

Unfortunately for manufacturers of medical devices, the presence of particles in their products may lead to a product recall by the U.S. Food and Drug Administration (FDA). In fact, particles have been a major reason for parenteral product recall by FDA in the past two decades. As high as 25% of FDA product recalls in 2014 were due to particulate matter.

FDA draft guidance on safe-by-design approach
To help companies prevent the risk of visible particle contamination, FDA has released a new guidance document draft which ‘addresses the development and implementation of a holistic, risk-based approach to visible particle control’ in injectable products.

The document specifies that the risk mitigation of particles should not be a downstream adjustment process, but rather, the risk assessment should be integrated into the design and development phases of the product. A safe-by-design approach which may require the manufacturer to predict the presence of particles; and therefore, require manufacturers to have a good understanding and knowledge of potential particle sources and appropriate analytical methods for particle characterisation. Manufacturers will benefit from working closely together with toxicologists early in the design phase.

Identify risks from the beginning
According to the draft guidance document Inspection of Injectable Products for Visible Particulates – Guidance for Industry, applicants must identify and characterise the visible particles (i.e., size, shape, chemical composition) and determine the risk based on factors such as route of administration, patient population and susceptibility. Other factors to consider include fate in body, dissolution, and chemical reactivity to certain cells or tissues, immunogenicity, infectivity, and carcinogenicity.

For more information on how to minimize the risk of particles, please contact toxicologist:

Astrid Skovmand
Tel +45 4516 9253