FDA Inspection Readiness – is your company ready?
Considering the on-going issues with drug shortages, which could potentially be exacerbated by Brexit, we were reminded recently by the editor of the PDA newsletter of an excellent Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products. This perspective was published by Bukofser et al. and is attached in the link below.
PDA J Pharm Sci and Tech 2015, 69, 123-139
The expectation for safe and effective injectable drug products requires that these products are manufactured “essentially free” of extraneous matter. As we know, this is a very challenging activity and the authors highlight that between 2008-2012, particle related issues led to 22% of product recalls for injectable products. The guidance on the expectations for inspection methods and acceptance criteria for particles are described in the various Pharmacopeias: USP, EP and JP. All Pharmacopeias require that each container, where possible, is inspected and those containing particles are rejected. The inspection process must be designed and qualified to ensure each lot is “essentially free” of visible particles. The relevant chapters of the USP identify inspection conditions and quantitative limits based on acceptance sampling from each lot of injectable product. The EP and Annex 1 further define: illumination intensity, background, pace and conditions for inspection, and vision tests and break periods for inspectors. It is recognized in the Pharmacopeias that the inspection process is based on the probability of detection and it is not absolute.
The medical data to support the safety risk of particles in humans is relatively scarce and a knowledge gap exists between the inherent presence of particles in injectable products and documented adverse events resulting from inadvertent administration of particles to patients. It is suggested by the author that the lack of medical literature on the harm caused by particles in pharmaceutical products may reflect the high standards of existing sterile manufacturing processes.
It is generally acknowledged that injectable drug product availability has presented a risk to patient safety and this can in part be attributed to inconsistent product release decisions and recall decisions related to particles. In the context where there is limited availability of essential sterile injectable products, it is incumbent on patients, care providers, manufacturers and regulators to consider the risk-benefit of potentially administering injectable products containing particles to patients. This is further supported when we recognise the probabilistic nature of particle detection and limited data on adverse events resulting from the presence of particles in injectable products.
The medical risk assessment required for such a risk-benefit consideration follows ICH Quality Guideline Q9: Quality Risk Management principles. The overall risk could be considered as the [likelihood of hazard] x [severity of harm]. This could be further refined to the [likelihood of particle presence] x [(likelihood of harm) x (severity of harm)]. The likelihood of particle presence must be understood from the manufacturing process and where particles can be generated, detected and removed from the product over its life-cycle. Statistical data from inspections, manufacturing trend history, supplier incoming data and complaint data can all be used for evaluating the likelihood of particle presence. The assessment of likelihood and severity of harm must be an extensive investigation into the five P’s: the particle, the product, the path, the patient and the prevention (see table 1 below).
Table 1. The five P’s of assessing the likelihood and severity of patient harm from particles
| Particle | – Size, type (intrinsic/extrinsic/inherent),
– characteristics (shape, composition, reactivity), – Source – Quantity |
| Product | – Route of Administration (Subcutaneous, Intramuscular, Intravenous, Infusion, Intrathecal etc.),
– Volume of Administration (particles per volume unit) |
| Path | – Likely fate of the particle in the patient (remains at site of administration, central or peripheral venous administration etc.) |
| Patient | – Age
– Gender – Weight – Illness – Immune status |
| Prevention | – Particle reduction mitigation, point of filtration in manufacturing or administration |
By combining the understanding of the likelihood of the particle hazard and the severity of the harm associated with particle presence, an overall medical risk can be established. On this basis, which is a more holistic approach to patient risk, informed decisions can be made when deciding to recall a product from the market that is potentially short in supply with little or no alternative. It is most likely that the requirement for automatic recall due to a single particle in a single unit should only occur in specific and special circumstances.
Patient harm associated with injections is extremely limited at the current levels of particle matter contained in injectable drug products. Small quantities of inert particles are unlikely to cause clinically meaningful harm to patients, in particular for intramuscular or subcutaneous routes of administration. 100% “particle free” injectable drug products should be the goal for manufacturers but not the requirement. While manufacturers strive to ensure injectable products are particle free, Bukofser et al. have succinctly outlined considerations important in assessing the risk-benefit ratio of administering products potentially containing particles to patients.
If you would like further information or wish to discuss how PharmaLex can support you with queries on Risk Analysis in Drug Product manufacture, please connect with us at +353 1 846 4742 or contactirl@pharmalex.com.
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