Is Monitoring Objectionable Organisms in Pharmaceutical Waters for Non-Sterile Drug Manufacturing an FDA Requirement?  

There are no testing requirements mandated for objectionable organisms found in either the USP Purified Water or the WFI monographs.  The USP General Information Chapter <1111> Microbiological Examination of Non-sterile Products outlines acceptance criteria for specific organisms depending on the route of administration of the product manufactured, but does not suggest any specific tests or limits for objectionable organisms in pharmaceutical waters.  Although USP Chapter <1111> is not mandated, 21 CFR 211.113 is an enforceable requirement that states the following:

Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.

A manufacturing process designed to prevent objectionable organisms should have a testing plan in place to assure this requirement is met.  By extension, whether an ingredient or used as part of a non-sterile manufacturing process, pharmaceutical water would also need to be monitored for these critical quality attributes as well.  Due to its very nature, the risk of water as a source of contamination by objectionable organisms is significant.  Consider the following statement from USP General Information Chapter <1115> Bioburden Control Of Nonsterile Drug Substances and Products:

“Water used in active ingredient manufacturing, formulation, cleaning, and housekeeping is the single most important risk element contributing to the contamination of nonsterile products.”

As end-product testing alone is not sufficient for any critical quality attribute, monitoring pharmaceutical waters for objectionable organisms is patently required.  Appropriately, FDA observations to non-sterile drug manufacturers requesting that alert and action levels be established for objectionable organisms in pharmaceutical waters are now commonplace.  Consider the following excepts from recent FDA Warning Letters:

to a hand sanitizer and antimicrobial soap manufacturer:

“Provide…. the current action/alert limits for total counts and objectionable organisms used for your (b)(4) Water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.”

to an OTC drug manufacturer:

“Provide….the current action (and alert, if any) limits for total counts and objectionable organisms used for your purified water system. Ensure that the total count limits for your purified water are appropriately stringent in view of the intended use of each of the products produced by your firm.”

to a hand sanitizer manufacturer:

“Provide the following….the current action/alert limits for total counts and objectionable organisms used for your (b)(4) Water system.”

It is clear that FDA expects that a routine monitoring plan be established for the presence of objectionable organisms in pharmaceutical waters regardless of the nature of the final product, and even if the product and process is considered non-sterile.  

What Organisms are Considered Objectionable in Water?

Although development of controls for objectionable organisms should be considered for every non-sterile product, it is not practical to establish alert and action levels in pharmaceutical waters for every organism that may be considered objectionable.  There is no definitive list for which organisms may be considered objectionable as it is dependent on many factors including the nature of the product, the dosage form, the route of administration, the ability of the specific organism to grow in the product, etc.  Loosely defined, an organism may be considered objectionable if it has the ability to cause harm to the patient or affect the efficacy or stability of the product.  Test procedures for several organisms, commonly considered objectionable, are outlined in USP Chapter <60> for Burkholderia Cepacia Complex (BCC), and USP Chapter <62> for P. aeruginosa, E. coli, S aureus, Salmonella, C. albicans, and Clostridia.  As well, USP General Information Chapter <1111> mentions several microorganisms of concern but notes that: 

“The list is not necessarily exhaustive, and for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process.“

A risk assessment should be developed to identify potential objectionable organisms for a specific manufacturing process with the testing extended from final product to any pharmaceutical waters used in processing steps.  The extent of testing will certainly vary and even the most robust sampling plans cannot ensure the absence of all objectionable organisms found in pharmaceutical waters.  Most importantly, manufacturers should have a documented plan in place for verifying the integrity of pharmaceutical waters which includes a reasoned approach to monitoring of objectionable organisms.