Microbiological Quality of Non-sterile Pharmaceutical Preparations and Substances for Pharmaceutical Use (1) (Ph. Eur. 5.1.4.) ​

​​(1)This chapter has undergone pharmacopoeial harmonization. See chapter 5.​8. Pharmacopoeial harmonization.

The presence of certain micro-organisms in non-sterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient. Manufacturers therefore have to ensure a low bioburden of finished dosage forms by implementing current guidelines on Good Manufacturing Practice during the manufacture, storage and distribution of pharmaceutical preparations.

Microbial examination of non-sterile products is performed according to the methods given in general chapters 2.6.12 and 2.6.13. Acceptance criteria for non-sterile pharmaceutical products based upon the total aerobic microbial count (TAMC) and the total combined yeasts/moulds count (TYMC) are given in Tables 5.1.4.-1 and 5.1.4.-2. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts are performed (e.g. direct plating methods).

When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows:

  • 101 CFU: maximum acceptable count = 20;
  • 102 CFU: maximum acceptable count = 200;
  • 103 CFU: maximum acceptable count = 2000, and so forth.

Table 5.1.4.-1 includes a list of specified micro-organisms for which acceptance criteria are set. The list is not necessarily exhaustive and for a given preparation it may be necessary to test for other micro-organisms depending on the nature of the starting materials and the manufacturing process.

Table 5.1.4.-1. – Acceptance criteria for microbiological quality of non-sterile dosage forms

Route of administration
TAMC
(CFU/g or CFU/mL)
TYMC
(CFU/g o​​r CFU/mL)
Specified microorganisms
Non-aqueous preparations for oral use
103
102
Absence of Escherichia coli
(1 g or 1 mL)
Aqueous preparations for oral use
102
101
Absence of Escherichia coli
(1 g or 1 mL)
Rectal use
103
102
 
Oromucosal 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 1 ml)
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 nebulisation)
102
101
Absence of Staphylococcus aureus
(1 g or 1 mL)
Absence of Pseudomonas aeruginosa
(1 g or 1 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/gram 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.105104​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)

If it has been shown that none of the prescribed tests will allow valid enumeration of micro-organisms at the level prescribed, a validated method with a limit of detection as close as possible to the intended acceptance criterion is used.

In addition to the microorganisms listed in Table 5.1.4.-1, the significance of other micro-organisms recovered is evaluated in terms of:

  • use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract);
  • nature of the product: its ability to support growth, the presence of adequate antimicrobial preservation;
  • method of application;
  • intended recipient: risk may differ for neonates, infants, the debilitated;
  • use of immunosuppressive agents, corticosteroids;
  • presence of disease, wounds, organ damage.

Where warranted, a risk-based assessment of the relevant factors is conducted by personnel with specialised training in microbiology and the interpretation of microbiological data. For raw materials, the assessment takes account of processing to which the product is subjected, the current technology of testing and the availability of materials of the desired quality.

Table 5.1.4.-2. – Acceptance criteria for microbiological quality of non-sterile substances for pharmaceutical use

 
​TAMC
(CFU/g or CFU/m​L)
TYMC
(CFU/g or CFU/mL)
Substan​​ces for pharmaceutical use
103 102

Recommended acceptance criteria for microbiological quality of herbal medicinal products for oral use and extracts used in their preparation are given in general chapter 5.1.8.

Publisert: 03.04.2017