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16.06.2017 - Pharmacy

Assessment of objectionable microorganisms in non-sterile pharmaceutical products - Part 1

Introduction

The testing of non-sterile products, such as tablets, capsules, powders, ointments, or inhalation products, is generally conducted according to chapters 2.6.12 and 2.6.13 of the European Pharmacopoeia (Ph. Eur.) and the acceptance criteria of chapter 5.1.4 are recommended. The methods and requirements described therein are considered harmonized with the United States (USP) and Japanese (JP) Pharmacopoeia (ICH Q4B 2007). They were officially introduced in 2006 and have been applicable in Europe since 2009. 

The old methods are no longer described in the pharmacopoeia since the implementation of Ph. Eur. Edition 6.3 and therefore are not considered validated. Care must be taken not to use the old methods unless a corresponding validation (e.g., according to Ph. Eur. chapter 5.1.6) or at least a risk assessment can be demonstrated. 

The requirements of Ph. Eur. chapter 5.1.4 are to be regarded as the absolute minimum. Meanwhile, many authorities expect that additional isolates found in the product should be assessed for their hazard potential. How such an assessment of so-called objectionable microorganisms can look is described in the present newsletter. 

The question arises whether this requirement also applies to herbal products. No such requirement is found in chapter 5.1.8 of the Ph. Eur. Nevertheless, consideration should be given to whether there are objectionable microorganisms for these products or patient groups. If this is the case, it must be considered how this can be monitored. This aspect is not further explored here.

Assessment of Objectionable Microorganisms 

Background

Assessment of Objectionable Microorganisms 
Two publications summarize the recalls of non-sterile products due to objectionable microorganisms (Jimenez 2007, Sutton & Jimenez 2012). For example, from 1998-2006, a total of 134 non-sterile products were recalled by the US agency (FDA) due to objectionable microorganisms (see also Fig. 1). 

Although this number seems small, Sutton & Jimenez's 2012 study shows a clear increase in the FDA's interest in this topic. Thus, every company should develop a corresponding strategy for evaluating what they consider critical for their products and document it in an SOP. 

Fig. 1: Percentage of recalls due to objectionable microorganisms in 134 non-sterile products from 1998-2006 (according to Jimenez 2007).

Third bar from the left: In these cases, no specific identifications were given.

Assessment Criteria 

What should one understand by objectionable microorganisms? There is no official definition of this. However, various publications contain information on this (e.g., CFR, FDA 1979, PDA 2014, Ph. Eur. 5.1.4, USP <1111> and <1115>). 

The primary concern is to microbiologically assess isolates found in the product. The following points should be considered: 

• What is the number of microorganisms found in the product? 
• How critical is the isolate found? 
• What are the properties of the product in which the isolate was found? 
• What is the potential effect on the patient group? 

Microbial Count: The number of microorganisms found primarily relates to the infectious dose. For certain microorganisms, just a few CFUs are enough to cause disease in the patient, whereas for others, it requires quantities far above the requirements of chapter 5.1.4 (Table 1). It should also be considered whether the existing amount of microorganisms could have a negative effect on the product (e.g., toxin formation or degradation of the product or parts of it). 

Table 1: Example of infectious doses (CFU) of various microorganisms (from various sources). No guarantee for accuracy!

Note: The ranges given result from different literature sources.

Found Isolate: Next, consideration must be given to the found isolate. Many microorganisms can be considered unproblematic (e.g., typical skin bacteria like Micrococcus luteus). Others, however, are repeatedly found in nosocomial infections, posing an increased patient risk. Currently, Burkholderia cepacia is considered number one (Fig. 1). This species is particularly critical for patients with cystic fibrosis or chronic granulomatous disease but can also cause wound infections, endocarditis, or pneumonia (see also Torbeck et al. 2011). 

Product Properties: Another important aspect is the product itself in which the isolate was found. Oral solid dosage forms are considered less critical than liquid inhalation products (PDA 2014). Another important point is the water activity of the product. For example, if it is below a value of 0.61, no microbial growth can occur (USP <1112>). 
But beware, this does not mean the microorganisms die! It only means they cannot reproduce. Ultimately, the historical data of the affected product should be considered. This assesses whether there have been previous contaminations and which microorganisms were found. 

Patient Group: Finally, the patient group must be considered. Here, infants, young children, elderly people, or (immuno-)compromised individuals are more critically affected than healthy individuals. 
With the compiled information, the microbiologist can then conduct an appropriate risk assessment. If a critical isolate is found, it may be worthwhile to obtain further evaluation from a medical microbiologist regarding patient risk.

Identification of Isolates 

Often, the question arises when and what should be identified during the testing of non-sterile products and at what microbial count a risk assessment must be conducted. Nowadays, it is generally expected to consider and, if necessary, identify and assess every single isolated microorganism found (e.g., from microbial count determination and/or testing for specified microorganisms). For chemically manufactured products, this is not a major effort since contamination is usually absent, but for other products (especially of natural origin), this is not always simple and sometimes not feasible. It is worthwhile, through risk assessment, to find a practicable way (see Fig. 2 as an example). 
The identification results allow early detection of weaknesses in the process and initiation of corrective actions.  

Fig. 2: Example of a possible decision tree for when an assessment (risk assessment) is necessary and which products can and cannot be released. IR = Investigation Report, ID = Identification, OOS = Out of Specification, OOE = Out of Expectation (Out of Trend).

Conclusion

How should one proceed? Since we work under GMP, a SOP is first required, describing the concept and approach. If necessary, a flowchart to reduce the workload for specific products can be included in the SOP (example see Fig. 2). It should be noted that if an isolate is to be assessed, the microbial identification must be very accurate, i.e., a method should be chosen that provides reliable results (e.g., DNA sequencing or MALDI-TOF). 
The assessment itself should be conducted by an expert (e.g., pharmaceutical microbiologist). More information on conducting such an assessment can be found in various sources (see Goverde 2012, Beckmann 2010, Roesti 2012, Sutton 2006, Sutton 2012, PDA 2014). 

Summary

In today's testing of non-sterile products, it is no longer sufficient to merely comply with the requirements of Ph. Eur. 5.1.4 (Table 1). Manufacturers must be able to demonstrate that they do not have objectionable microorganisms in their products. The simplest way is to identify all found grown colonies, which are then assessed according to a predetermined assessment scheme unless a corresponding risk assessment is available. 

In the following newsletter (Part 2), we will present concrete examples.