The
European Commission has made an important announcement about endotoxin limits
in relation to substances for pharmaceutical use. For new substances,
pharmacopeia monographs will no longer specify endotoxin limits. It will be
left to the user to determine if a substance requires testing and what the
appropriate limit should be.
The
issued text reads:
Bacterial
endotoxins Ph. Eur. policy for substances for pharmaceutical use (Approved by
the Ph. Eur. Commission at its 149th Session, June 2014)
1.Reasons for requirements for testing for bacterial
endotoxins
Bacterial
endotoxins are contaminants from gram-negative bacteria and are the most common
cause of pyrogenicity in pharmaceutical products. Any preparation administered
parenterally should be sterile and comply with the test for bacterial
endotoxins (BET) as described in the Ph. Eur.
Substances
to be used in parenteral preparations must comply with the BET, whatever their
origin, since:
- Contamination by bacterial endotoxins can take place prior to or during the manufacturing process;
- Bacterial endotoxins cannot easily be removed by the manufacturing process;
- Bacterial endotoxins should be detected as early as possible in the manufacturing process.
- It is to be noted that the ICH Guideline Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products provides the following recommendation under section 4.1 Drug Substance Specification: “Pharmacopoeial tests (e.g., endotoxin detection) should be performed on the drug substance, where appropriate.”
2. Requirements for bacterial endotoxins in the Ph. Eur.
The
Ph. Eur. provides requirements for testing for bacterial endotoxins as follows.
The
general monograph Substances for pharmaceutical use (2034) and individual
monographs on substances for pharmaceutical use require compliance with the BET
when substances are used in the manufacture of parenteral preparations. The
monographs refer to general chapters 2.6.14. Bacterial endotoxins and 5.1.10.
Guidelines for using the test for bacterial endotoxins.
According
to the general monograph Parenteral preparations (0520), pharmaceutical
preparations to be used parenterally have to comply with the test for bacterial
endotoxins or, where justified and authorised, the test for pyrogens.
3. Problem statement
During
the elaboration of a monograph, it is not always known at the level of the
manufacturing of the substance whether the substance is to be used for the
production of a parenteral preparation and therefore it is not known whether
compliance with the BET is needed or not.
With
regard to the limits to be applied for the test, individual monographs provide
limits whereas general chapter 5.1.10 provides a way to calculate the endotoxin
limit:
Values
of K to be used for the calculation of the endotoxin depend on the route of
administration and are given in the general chapter (Table 5.1.10.-1). There
are other ways to establish limits, for example based on process capability,
patient population or specific requirements of the competent authority. These
are not clearly stated in the Ph. Eur. This might result in apparent
contradictions between the different BET requirements.
4. New policy on the way to prescribe the BET
in the Ph. Eur.
With
consideration to the above, the Ph. Eur. Commission recommends the following approach
to bacterial endotoxins.
Elaboration
of new individual monographs
A
test for bacterial endotoxins is not included in new monographs for substances
for pharmaceutical use. The requirements of the general monograph Substances
for pharmaceutical use (2034) apply.
- A test is included only where a specific method has to be described, for example if a specific sample preparation has to be used or if a specific method has to be applied.
- If a test is included in the monograph, no limit is given for the test.
Existing
monographs
BET
specifications are kept in individual monographs for substances for
pharmaceutical use. Existing limits remain in individual monographs to maintain
the use of well-established limits.
In
order for the policy to be applied, the following changes are proposed to
existing Ph. Eur. texts.
- General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.
- General monograph Substances for pharmaceutical use (2034) is slightly reworded in order to take the above policy into consideration.
5. Consequences of the new BET policy for Ph.
Eur. users
It
is up to the user of the Ph. Eur. to determine whether compliance to BET is
needed or not for a given substance. Where a test is included in the monograph
with no specific limit, it is up to the user to set the limit for the
substance, based on the following considerations: use of the substance (route
of administration, patient population); calculation according to the formula
given in general chapter 5.1.10; process capability; or any other
considerations raised by the competent authority.
Posted by Tim Sandle
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