EUROPEAN PHARMACOPOEIA 11.0 5.1.4.

Microbiological quality of non-sterile products for pharmaceutical use

The above criteria express the recommended efficacy to be are given in Tables 5.1.4.-1 and 5.1.4.-2. Acceptance criteria
achieved. 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
01/2021:50104 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
5.1.4. MICROBIOLOGICAL QUALITY which acceptance criteria are set. The list is not necessarily
OF NON-STERILE PHARMACEUTICAL exhaustive and for a given preparation it may be necessary to
PREPARATIONS AND SUBSTANCES test for other micro-organisms depending on the nature of the
starting materials and the manufacturing process.
FOR PHARMACEUTICAL USE(1) If it has been shown that none of the prescribed tests will
allow valid enumeration of micro-organisms at the level
◊This chapter does not apply to products containing viable prescribed, a validated method with a limit of detection as
micro-organisms as active ingredients.◊ close as possible to the indicated acceptance criterion is used.
The presence of certain micro-organisms in non-sterile In addition to the micro-organisms listed in Table 5.1.4.-1, the
preparations may have the potential to reduce or even significance of other micro-organisms recovered is evaluated
inactivate the therapeutic activity of the product and has in terms of :
a potential to adversely affect the health of the patient. – use of the product : hazard varies according to the route of
Manufacturers therefore have to ensure a low bioburden of administration (eye, nose, respiratory tract) ;
finished dosage forms by implementing current guidelines – nature of the product : its ability to support growth, the
on Good Manufacturing Practice during the manufacture, presence of adequate antimicrobial preservation ;
storage and distribution of pharmaceutical preparations.
– method of application ;
Microbial examination of non-sterile products is performed
according to the methods given in general chapters 2.6.12 and – intended recipient : risk may differ for neonates, infants,
2.6.13. Acceptance criteria for non-sterile pharmaceutical the debilitated ;
products based upon the total aerobic microbial count – use of immunosuppressive agents, corticosteroids ;
(TAMC) and the total combined yeasts/moulds count (TYMC) – presence of disease, wounds, organ damage.

Table 5.1.4.-1. – Acceptance criteria for microbiological quality of non-sterile dosage forms
TAMC TYMC
Route of administration (CFU/g or (CFU/g or Specified micro-organisms
CFU/mL) CFU/mL)
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
Absence of Staphylococcus aureus (1 g or 1 mL)
Cutaneous use 102 101
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Nasal use
Auricular use
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Vaginal use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Candida albicans (1 g or 1 mL)
Transdermal patches (limits for 1 patch Absence of Staphylococcus aureus (1 patch)
102 101
including adhesive layer and backing) Absence of Pseudomonas aeruginosa (1 patch)
Absence of Escherichia coli (1 film)
◊Orodispersible films (limits for 1 film) 102 101 Absence of Staphylococcus aureus (1 film)
Absence of Pseudomonas aeruginosa (1 film)◊
Absence of Staphylococcus aureus (1 g or 1 mL)
Inhalation use (special requirements apply to Absence of Pseudomonas aeruginosa (1 g or 1 mL)
102 101
liquid preparations for nebulisation) Absence of bile-tolerant gram-negative
bacteria (1 g or 1 mL)
♦Special Ph. Eur. provision for oral dosage Not more than 102 CFU of bile-tolerant gram-negative
forms containing raw materials of natural bacteria (1 g or 1 mL)
(animal, vegetal or mineral) origin for which
antimicrobial pretreatment is not feasible and 104 102 Absence of Salmonella (10 g or 10 mL)
for which the competent authority accepts Absence of Escherichia coli (1 g or 1 mL)
TAMC of the raw material exceeding 103 CFU/g Absence of Staphylococcus aureus (1 g or 1 mL)♦
or CFU/mL.
♦Special Ph. Eur. provision for premixes for Not more than 104 CFU of bile-tolerant gram-negative
medicated feeding stuffs for veterinary use bacteria (1 g or 1 mL)
105 104
using excipients of plant origin for which Absence of Escherichia coli (1 g or 1 mL)
antimicrobial treatment is not feasible. Absence of Salmonella (25 g or 25 mL)♦

(1) This chapter has undergone pharmacopoeial harmonisation. See chapter 5.8. Pharmacopoeial harmonisation.

General Notices (1) apply to all monographs and other texts 657
5.1.5. Application of the F concepts to heat sterilisation EUROPEAN PHARMACOPOEIA 11.0

Where warranted, a risk-based assessment of the relevant (

FH = D160 log10N0 - log10N )
factors is conducted by personnel with specialised training in
microbiology and the interpretation of microbiological data. D121 = D-value of the reference spores (5.1.2) at 121 °C ;
For raw materials, the assessment takes account of processing
to which the product is subjected, the current technology of D160 = D-value of the reference spores (5.1.2) at 160 °C ;
testing and the availability of materials of the desired quality. N0 = initial number of viable micro-organisms ;
Table 5.1.4.-2. – Acceptance criteria for microbiological quality N = final number of viable micro-organisms.
of non-sterile substances for pharmaceutical use
TAMC TYMC Table 5.1.5.-1 – Parameters for moist heat and dry heat
(CFU/g or CFU/mL) (CFU/g or CFU/mL)
sterilisation
Theoretical Reference Minimum
Substances for 103 102 Sterilisation F z-value temperature temperature
pharmaceutical use (°C) (°C) (°C)
♦Recommended acceptance criteria for microbiological quality Moist heat F0 10 121 110
of herbal medicinal products for oral use and extracts used in
their preparation are given in general chapter 5.1.8.♦ Dry heat FH 20 160 140

For both dry and moist heat sterilisation cycles, the relevant
01/2021:50105 F-value is used to demonstrate that the required sterility
assurance level of equal to or less than 10-6 is consistently
achieved.

07/2017:50106
5.1.5. APPLICATION OF THE F corrected 11.0
CONCEPTS TO HEAT STERILISATION
PROCESSES
The following chapter is published for information.
INTRODUCTION 5.1.6. ALTERNATIVE METHODS FOR
Heat sterilisation can be differentiated into 2 types : moist CONTROL OF MICROBIOLOGICAL
heat sterilisation using saturated steam or water heated to the
sterilisation temperature ; and dry heat sterilisation using hot QUALITY
air with a moisture content so low as to have an insignificant The following chapter is published for information.
biological activity.
1. GENERAL INTRODUCTION
DEFINITIONS
The objective of this chapter is to facilitate the implementation
The D-value (or decimal reduction value) is the time in and use of alternative microbiological methods where this
minutes required at a defined temperature to reduce the can lead to efficient microbiological control and improved
number of viable test micro-organisms by 90 per cent. It is assurance for the quality of pharmaceutical products.
only of significance under precisely defined experimental
conditions. The microbiological methods described in the European
Pharmacopoeia have been used for over a century and
The z-value is the change in temperature in degrees Celsius these methods for detecting, enumerating and identifying
required to alter the D-value by a factor of 10 (the z-value micro-organisms still serve microbiologists well. Over the
relates the resistance of a micro-organism to changes in years, these methods have been invaluable for the production
temperature). The z-value is calculated using the following of microbiologically safe pharmaceutical products. However,
equation : these microbiological methods are slow, and in the case of
T2 - T1 sterility tests, results are not available before an incubation
z= period of 14 days. Consequently, the results from these
log10 D1 - log10 D 2
methods seldom enable proactive corrective action to be taken.
D1 = D-value of the micro-organism at temperature T1 ; Alternative methods for the control of microbiological quality
have shown potential for real-time or near real-time results
D2 = D-value of the micro-organism at temperature T2 ; with the possibility of earlier corrective action. These new
T = temperature. methods, if validated and adapted for routine use, can also
offer significant improvements in the quality of testing.
The F-value of a heat sterilisation process (F0 for moist Alternative methods may be used for in-process samples of
heat sterilisation or FH for dry heat sterilisation) is the pharmaceutical products, particularly for the application of
lethality expressed in terms of the equivalent time in minutes Process Analytical Technology (PAT), for environmental
at the reference temperature delivered by the process to monitoring and for industrial utilities (e.g. production and
the sterilisation load, with reference to micro-organisms distribution of water, steam etc.), thereby contributing to the
possessing the relevant theoretical z-value in Table 5.1.5-1. quality control of these products.
The total F of a process takes into account the heating and In this chapter, alternative microbiological methods
cooling phases of a cycle and can be calculated by integration for pharmaceutical application are described. For each
of lethal rates with respect to time at discrete temperature method, the basic principle is stated and the advantages and
intervals above the minimum temperature specified in disadvantages of the method are discussed along with any
Table 5.1.5-1. critical aspects to be considered. Potential uses that may be
The following mathematical relationships apply : envisaged based on the principles of the method concerned are
given, but it is not intended to suggest that such applications
(
F0 = D121 log10N0 - log10N ) have been realised or that the list provided is exhaustive.

658 See the information section on general monographs (cover pages)