Confarma

Non-sterile products

Low microbial load or ‘bioburden’ in finished dosage forms is essential to comply with GMP regulations for the manufacture, storage and distribution of pharmaceutical preparations. This is due to the presence of some microorganisms in non-sterile preparations can reduce or even eliminate the product's therapeutic activity and constitute a potential danger to patient health.

The European Pharmacopoeia (Ph. Eur.), the United States Pharmacopeia (USP) and the Japanese Pharmacopeia (JP) defines requirements for the qualitative and quantitative composition of medicines, the tests to be carried out on medicines and on substances and materials used in their production. As such, there are two groups of non-sterile products that require microbiological analysis:

  • Pharmaceutical preparations and substances for non-sterile pharmaceutical use
  • Herbal medicines for oral use

We perform the following pharmaceutical analyses and validations in line with Pharmacopeial requirements:

Enumeration of microorganisms (Ph. Eur. 2.6.12, USP and JP 4.05)*

To check microbiological contamination, we count mesophilic bacteria, moulds and yeasts capable of growing aerobically in our dedicated Class II laboratories under laminar flow hoods class A (ISO 5).

Microbial detection (Ph. Eur. 2.6.13, USP and JP 4.05)*

We test for potential pathogens which include (but not limited to) the following:

  • Staphylococcus aureus
  • Escherichia coli
  • Pseudomonas aeruginosa
  • Candida albicans
  • Salmonella

Microbiological Quality of Non Sterile Pharmaceutical Products (Ph. Eur. 5.1.4, USP and JP 12)*

To validate microbiological quality of raw materials, formulations or finished products, pharmacopeia’s defined limits based on the application of the products:

Table 1. Acceptance Criteria for Microbiological Quality of Non-sterile Dosage Forms

Route of AdministrationAMC (cfu/g or cfu/mL)TYMC (cfu/g or cfu/mL)Specified Microorganism(s)
Substances for pharmaceutical use 103 102 /
Aqueous or Non-aqueous preparations for oral use 103 102 Absence of Escherichia coli (1 g or 1 mL)
Rectal use 103 102 /
Oro-mucosal use
Gingival use
Cutaneous use
Nasal use
Auricular use
102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Vaginal use 102 101 Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Candida albicans (1 g or 1mL)
Transdermal patches (limits for one patch including adhesive layer and backing) 102 101 Absence of Staphylococcus aureus (1 patch)
Absence of Pseudomonas aeruginosa (1 patch)
Inhalation use (special requirements apply to liquid preparations for nebulization) 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or1 mL)
Absence of bile-tolerant Gram-negative bacteria (1 g or 1 mL)
Special Ph. Eur. provision for oral dosage forms containing raw materials of natural (animal, vegetal or mineral) origin for which antimicrobial pretreatment is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 CFU/g or CFU/mL. 104 102 Not more than 102
CFU of bile-tolerant gram-negative bacteria (1 g or 1 mL)
Absence of Salmonella (10 g or 10 mL)
Absence of Escherichia coli (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)
Special Ph. Eur. provision for premixes for medicated feeding stuffs for veterinary use using excipients of plant origin for which antimicrobial treatment is not feasible. 105 104 Not more than 104 CFU of bile-tolerant gram-negative bacteria (1 g or 1 mL)
Absence of Escherichia coli (1 g or 1 mL)
Absence of Salmonella (25 g or 25 mL)

* These chapters are harmonized since 2005

Efficacy of antimicrobial preservation / antimicrobial effectiveness testing (Ph. Eur. 5.1.3 or USP)

Protecting products with minimal use of preservatives is a real challenge. The Ph. Eur./USP test provides a reproducible biological measurement of a product’s preservation system activity. This test is required for multi-dose presentations of pharmaceuticals as well as anhydrous ointments that contain a preservative system.

The measurement of microbial kill quantifies the number of surviving microorganisms after exposure to the antimicrobial agent over time. This represents neutralization in compendial microbiological tests and demonstrates method suitability. The compendial tests of the US and European Pharmacopeia have very similar methods, but they differ in sampling points and acceptance criteria. We can help you validate the formulation and audit continued preservation efficacy for all type of preparations according to Ph. Eur. or USP.

Water activity (Ph. Eur. 2.9.39. USP )

The measurement of the water activity influences the retention of a pharmaceutical product. It represents the free water available for the growth of micro-organisms – low water activity helps prevent microbial growth. The water activity is noted in ‘aw’ (activity of water) to describe water status of the analysed products. Unlike humidity measurements, the measurement of the aw value qualitatively illustrates the degree of availability and mobility of water in a product.