Regulatory Update: How FDA Assesses Microorganisms in Drug Products

What FDA Considers When Assessing Microorganisms in Non-Sterile Drug Products

BY Lynne Ensor, Vice President, Technical, Parexel - 10.2.19 -

The presence of microorganisms in sterile drug products is of paramount concern to patient safety.  However, it may be less obvious why concern for the presence of microorganisms in non-sterile drug products (NSDPs) exists.  

The routes of administration for NSDPs typically have less access to areas of the body, which could result in extreme immune system responses or patient fatality.  The presence of microorganisms in NSDP is obviously considered lower risk when compared to sterile drug products.  NSDPs may also be entering the patient’s system through a part of the body that may already be populated with microorganisms as part of the body’s normal flora.

However, the presence of microorganisms in NSDPs still poses a risk to pharmaceutical manufacturing and patient safety and, therefore, must be controlled.  Recent NSDP incidents with contaminants, such as Burkholderia cepacia complex in non-sterile aqueous products, resulting in serious product adverse events, deaths, and recalls have highlighted FDA focus on the microbial quality of NSDPs.

FDA requires data to support the control of microorganisms during the manufacturing of drug products as well as in the finished dosage form.  The amount and type of data required to support a drug product application differs depending upon the risk to the patient.  Considerations to the drug product’s risk include the route of administration (e.g., injectable, topical administered to intact skin, topical administered to non-intact skin, oral, mucosal, etc.), the product’s physical characteristics (e.g., aqueous, solid, preserved, etc.), and its intended use (e.g., patient population, multidose, etc.).

Microorganisms can be present in the drug product’s raw materials, in the manufacturing environment (including any operators), and proliferate during the production of the product.  Thus, microbial contamination associated with the manufacturing process as well as the finished dosage form must be controlled.   

It is recommended that NSDP manufacturers perform a risk-based impact assessment that considers the product specific characteristics (e.g., dosage form, water activity, intended use, packaging, and components and composition) and the manufacturing process to demonstrate to regulatory authorities the control over  the finished drug product, the component ingredients of the drug product (raw materials, APIs, excipients), and the manufacturing process.

Microorganisms present in raw materials should be controlled by the drug substance/excipient or component manufacturer or supplier.  Many compendial excipients have microbial limits.  Informational chapter USP <1111>, MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use, recommends microbial limits for non-sterile drug substances intended for pharmaceutical use.  This focuses on limiting the total levels of the microorganisms, including bacteria, yeast and mold, and the absence of potentially pathogenic bacteria (e.g., Escherichia coli) depending upon the intended route of administration.

Control of microorganisms in the manufacturing environment should also be demonstrated.  ISO 7/8 lays out the expectations for their control during the manufacture of a NSDP.  Facilities should also be compliant with all current good manufacturing practices and this compliance will typically be scrutinized during facility inspection. 

Developers should also scrutinize the ability for microorganisms to proliferate during the manufacturing process.  For microorganisms to grow and proliferate, they need nutrients (which may be present in the product formulation), water (which some product manufacturing processes require), and time (since their growth is logarithmic).  Other factors affecting microbial growth are the temperature and pH during the different phases of manufacture.  Some of these variables can be controlled and should be, while others may not (i.e., nutrients in the product formulation and water). 

It is important to control those variables which can be and be aware of those that cannot be controlled.  Typically, the time, especially any holding periods during the manufacturing process, is best to be controlled and kept minimal, when possible.  It is also possible to include antimicrobial manufacturing steps, such as high heat or pressure, to minimize microbial contamination.

Microbial release testing for NSDPs currently consists of two parts, USP <61> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: Microbial Enumeration Tests and USP <62> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: Tests for Specified Microorganisms.  USP <61> demonstrates the total number of microorganisms in the product and USP <62> ensures that harmful or pathogenic microorganisms are not present (e.g., E. coli or Staphylococcus aureus).  Some products must also be antimicrobial.  Recommendations for microbial acceptance criteria may be found in USP <1111>, with limits provided in USP <61> and specified organisms in USP <62>.

On December 1, 2019, USP <60> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS - Tests for Burkholderia Cepacia Complex (BCC), will become official.  Testing for BCC was developed due to numerous adverse events reported, especially in aqueous product where BCC may be associated with manufacturing water systems. USP <60> may be utilized to determine the microbial quality of NSDS, such as those intended for inhalation use or aqueous products for oral, oromucosal, cutaneous or nasal use, to demonstrate the absence of BCC. 

FDA has a risk-based assessment of non-sterile drug products, which includes that all NSDPs must have a microbial control strategy.  The release and stability testing requirements are scaled to patient risk and control of upstream manufacturing.  Reduced testing may be applicable to products based on their characteristics and manufacturing process.  Solid oral dosage forms may be good candidates for reduced testing.  Information should be provided in the product’s application and available for assessment during inspection of the manufacturing facility, as this information is requested for all NSDPs.

As mentioned above, it is possible to demonstrate the microbiological aspects of a NSDP by end-product testing.  However, inherent flaws in testing methods may exist when dealing with living microorganisms which may be present at low levels or undetectable levels depending upon test sampling size and techniques. 

Therefore, microbial control throughout the manufacturing process, from raw materials to finished drug product throughout the product’s lifecycle, is best engineered and controlled by using quality by design when developing the manufacturing process and controlling variables. This control is vital to manufacturing safe and quality NSDPs.  

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