Objectionable organisms in non-sterile medicinal products

Microbiological contamination of non-sterile medicinal products is an infrequent, but longstanding and recurring issue. But there is no ‘one size fits all’ approach towards objectionable organisms, says David Elder…

A RECENT survey of US product recalls indicated that objectionable organisms were implicated in nearly 75% of all cases of microbial contamination.1 However, the issue facing manufacturers is unique as there are no universally agreed definitions for objectionable organisms. Sutton defined them as: “Objectionable in view of the product’s intended use and for products not required to be sterile.”2 This caveat is important, as all viable microorganisms must, by definition, be excluded from sterile products.

The PDA3 defined objectionable organisms as, “microorganisms that, due to its numbers and pathogenicity can cause infection, allergic response or toxaemia in patients receiving the product”. It added an ancillary definition to reaffirm that this issue was constrained to non-sterile products, ie, “a microorganism that can adversely affect the appearance, physicochemical attributes or therapeutic effect of a non-sterile product”. However, there is an additional regulatory element to these definitions and the presence of some objectionable organisms, eg, Burkholderia cepacia and Bacillus cereus in non-sterile products or manufacturing plants, will certainly elicit close attention from certain regulatory agencies such as the FDA.2 So it is up to the manufacturer to show that any microorganisms present in their non-sterile medicinal products are safe.2

But producers are not manufacturing sterile products and therefore some level of microbial contamination should be ‘acceptable’. Good manufacturing practice (GMP) is designed to minimise microbial contamination and appropriate limits are enshrined in all of the major pharmacopoeias, ie, microbial limit tests (Ph Eur 5.14 or USP <1111>). Therefore, microbial product quality is governed using cGMP, the company’s pharmaceutical quality system (ICH Q10),4 and an underlying requirement to control less desirable organisms, ie, opportunistic pathogens. This particularly relates to Gram-negative Pseudomonas and Gram-positive spore formers such as Bacillus spp, which do not typically cause infections in healthy populations but may give cause for concern in sick, immunocompromised or vulnerable populations such as the elderly and children.1

The total exclusion of objectionable organisms from non-sterile oral products is extremely challenging, however. Objectionable organisms can be viewed as an ‘undefined critical quality attribute’, ie, there are no defined tests or specifications and as such there are limited control strategies available.3 A risk-based approach to this issue is therefore essential, as organisms cannot be considered ‘objectionable’ without an understanding of the numbers found, the organism’s potential pathogenicity, its ability to survive and/or grow in the medicinal product, the product’s attributes, its intended use, and the designated patient population. Unfortunately, the mere presence of some of these organisms within a manufacturing facility may prompt regulatory concern or action. One company was recently criticised for “accepting a level of spore formers as part of the standard environmental flora”.5,6 However, not all spore formers are bad! Bacillus subtilis is the main active component in a novel probiotic product and this was safe for human consumption at levels of 2×109 spores/day for 40 days.7


It is clear that there is no ‘one size fits all’ approach towards objectionable organisms. It is equally clear however, that an approach predicated on total avoidance will not work. The logical and scientific approach is based on risk assessment predicated on the identification of the organism, the numbers present, the proposed delivery route, and the patients to be treated. Even so, issues will still abound. For example, treating all members of a problematical class of bacteria, ie, Gram-positive spore formers, equally is also fl awed. While Bacillus cereus is undoubtedly an issue, Bacillus subtilis may even be good for us!


  1. Sutton S, Jiminez L. A review of reported recalls involving microbiological control 2004-2011 with emphasis on FDA considerations of “objectionable organisms”. Amer Pharm Rev. 01 January 2012.
  2. Sutton S. What is an objectionable organism? Amer Pharm Rev. 12 October 2012. Accessed 14 October 2017.
  3. PDA. Technical Report No. 67. 2014. Exclusion of objectionable organisms from non-sterile pharmaceuticals, medical devices and cosmetics.
  4. ICH Q10. Pharmaceutical quality systems. 2008. Current Step 4 version dated 4 June 2008.
  5. FDA. Zeppessis reprocessing, 8/9/13. 2013. Accessed on 16 October 2017.
  6. Sandle T 2014. The risk of Bacillus cereus to pharmaceutical manufacturing. Am. Pharm Rev 28 November 2014. Accessed 17 October 2017.
  7. Lefevre M, Racedo SM, Denayrolles M, Ripert G, Desfougères T, Lobach AR, Simon R, Pelérin F, Jüsten P, Urdaci MC. Safety assessment of Bacillus subtilis CU1 for use as a probiotic in humans. Reg Toxicol Pharmacol. 2017;83:54-65.


DAVE ELDER has nearly 40 years of service within the pharmaceutical industry at Sterling, Syntext and GlaxoSmithKline. He is now an independent GMC consultant. Dr Elder is a visiting professor at King’s College, London, and is a member of the British Pharmacopoeia. He is a member of the Joint Pharmaceutical Analysis Group (JPAG), and a member of the Analytical Division Council of the Royal Society of Chemistry.

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