Key Takeaways from the FDA’s New Non-Sterile Guidance

Microrite founder and CEO Ziva Abraham walks us through new recommendations aimed at helping manufacturers assure control of microbiological quality of non-sterile drugs 

The FDA has released the new draft guidance “Microbiological Quality Considerations in Non-Sterile Drug Manufacturing ,” providing manufacturers with recommendations to help assess the risk of contamination with objectionable microorganisms. We recently provided an overview of the new guidelines on our Eureka blog , but today we would like to dive deep into this with Ziva Abraham. We followed up this topic with a webinar, presented by Ziva Abraham , the President and Founder of Microrite, Inc. in which she reviewed key elements of the document and discussed the need-to-know fundamentals of the draft guidance, assessing risk of non-sterile products and key points to consider when establishing objectionability of microorganisms in various non-sterile products.

Ziva has over 35 years of academic, research, clinical and industrial experience in microbiology and quality assurance. She received her master’s degree in microbiology with a focus on mycology and has conducted research on developing microbial insecticides using entomogenous bacteria and fungi towards her Ph.D. degree.

She has trained personnel from various industries in microbiology techniques and methods. She uses her extensive experience to teach why assessing risk of microbial contamination should be in the forefront of any company that has products for human/veterinary use. Her experience in clinical laboratories has provided her with the framework to understand the effects of microbial contamination in products from a patient safety perspective.

Chiara: From your perspective, what are the problems associated with the microbiological contamination of topical drug products, nasal solutions, and inhalation products? Are there any gaps in the Pharmacopeias?

Ziva: Great question! For a variety of reasons, we have seen several problems associated with the microbiological contamination of topical drug products, nasal solutions, and inhalation products. The USP Microbiological Attributes Chapter <1111> provides little specific guidance other than “The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user.” This is very vague, but it encompasses so much, and this is where most companies struggle. We need to understand how we decide what is objectionable in the non-sterile products we are making. The USP recommends certain categories to be routinely tested for total counts and specified indicator microbial contaminants. So, USP refers to specified microorganisms; these are not all encompassing. While the Tests for Specified Microorganisms indicate requirements to test for certain organisms depending on the product type, these lists are not exhaustive, and for certain sample preparations it may be necessary to test for other microorganisms. This is a gap, and I think that the new guidance really fills this gap.

Chiara: What are the products the draft guidance applies to? Are there recurrences of product recalls for non-sterile products due to microbial contamination?

Ziva: The new draft applies to solid non-sterile dosage forms, as well as semi-solid, and liquid non-sterile dosage forms (e.g., topically applied creams, lotions and swabs, and oral solutions and suspensions) and others. Non-Sterile Drugs (NSDs) can be prescription or nonprescription drugs, including those marketed under approved new drug applications (NDAs) or abbreviated new drug applications (ANDAs), and nonprescription drugs without approved new drug applications which are governed by the provisions of section 505G of the FD&C Act (often referred to as over the counter (OTC) monograph drugs).

With this draft, they have gone a step forward. They also specify that the term “objectionable microorganisms” as used here refers to organisms that are objectionable due to their detrimental effect on products or potential harm to patients or objectionable due to the total number of organisms. This is key, because for the first time somebody is looking at what is relevant to understand the infective dose. As a matter of fact, the guidance describes proper prevention of and testing for BCC ( Burkholderia cepacia complex) in aqueous dosage forms of NSD. BCC is very well documented, but there are other organisms that are objectionable, and we do not have any test for them in the compendial.

So, how do we go about them, knowing that these organisms are detrimental to the patient? Regarding the recalls, unfortunately, the reply to that question is yes. There are many recurrences of product recalls for non-sterile products due to microbial contamination. Actually, this is why the new guidance was drafted. Review of FAERs that occurred between 2014 and 2017 revealed FAERs associated with intrinsic microbiological or fungal contamination, and of those, reported serious adverse events. Because spontaneous reports in FAERs are voluntary, the Agency anticipates a degree of underreporting. The actual number of incidents associated with microbiological contamination is likely significantly higher than the number of events reported.

Chiara: Is there a list of objectionable microorganisms for all non-sterile products?

Ziva: Absolutely not. This is the work we must do, and it takes research. You must understand what is objectionable; if they are true or opportunistic pathogens, what is the infective dose and how do they proliferate in the body and harm the patient. There is no list. You cannot have a list because the recalls show us that there are always emerging and new infections coming up. Organisms are faster than us, they adapt fast, so please, keep them under control.

Chiara: Are organisms objectionable only if they exceed the microbial limits?

Ziva: No, it is important for you to understand that microbial limits have nothing to do with objectionable microorganisms. You must understand what your flora is when you are performing your microbial limit tests.

For more information on Microrite’s GMP consulting and training services, please visit their website.

Chiara Ocone is Strategic Marketing Specialists for Charles River's Microbial Solutions division.