October 2023
La Vague n°79
Special A3P Congress 2023 : Annex 1, Environmental and process monitoring.
Table of Contents
- EU GMP Annex 1 (2022): Aseptic Process Simulation (APS). New challenges for the pharmaceutical industry?
- How to evaluate pyrogenic risk in an injectable pharmaceutical process? Decision-making tool
- Introduction to the dual chamber systems (DCS) filling process
- Implementation of decontamination processes in the pharmaceutical industryentation of decontamination processes in the pharmaceutical industry
- Container Closure Requirements in the New EU GMP Annex 1 - Enabling Compliance with a Holistic Science-Based Approach
- Improving the efficiency & reliability of AVI qualification: Determining the optimal number of runs with the KNAPP method
- Case Study: Effective Sterile Powder Transfer for Parenteral Drug Products
How to evaluate pyrogenic risk in an injectable pharmaceutical process? Decision-making tool
In 2016, Chapter 5.1.10 of the European Pharmacopoeia “Guidelines for using the test for bacterial endotoxins” changed, with notably the addition of the requirement to carefully evaluate the risk of the presence of non-endotoxin pyrogens (NEPs) in the substance or the product to be tested in order to be able to use the bacterial endotoxin test as the sole test for pyrogens.
During the A3P 2017 conference with the ocean as a backdrop, this chapter was the topic of discussion in our group of microbiologist friends from different companies. During the course of the discussion, numerous questions emerged, such as: “What are the different pyrogenic substances? How can they be detected? What are the advantages and disadvantages of the different detection methods? How to evaluate the risk of the presence of pyrogens for a new product?
This article presents an example of an approach that can be used in the case of injectable products and made available to manufacturers, while complying with regulatory recommendations.
1. The large family of pyrogenic substances
An exhaustive bibliographic search allowed us to draw up a list of the following substances mentioned in the literature as liable to have a pyrogenic action (See Table 1).
It is notable that very many substances, of varying natures although mainly derived from living beings, are recognized as having a pyrogenic effect. Within these substances, endotoxins derived from Gram-negative bacteria are known and recognized as those with the highest pyrogenic activity. This probably explains why pyrogens and bacterial endotoxins are sometimes confused.
2. Detection of pyrogens: the advantages and disadvantages of different methods
Different methods are described in the European Pharmacopeia for the detection of pyrogens. Table 2 presents the advantages and disadvantages of these techniques. In recent years regulations have encouraged the gradual elimination of pyrogen tests on rabbits, in order to dispense with animal testing.
Moreover the use of recombinant reagents is also introduced as an alternative to reagents of animal origin.
3. Method for evaluating the risk of the presence of pyrogens for a new product
Our reflection and our lively and constructive exchanges during the face-to-face working sessions, at a time when this was the norm (2018), led us to define the questions to ask and the information to compile, to standardize and justify the choice of the type of test to be applied. The fruit of our work is summarized in the decision tree (illustration 1).
With the aim of having an approach at once structured and reproducible we redefined the response criteria to each of the essential questions. Quantitative criteria are not indicated in this article, as it is each manufacturer’s responsibility to define them on the basis of the risks inherent in the process evaluated.
With the aim of having an approach at once structured and reproducible we have redefined the response criteria to each of the essential questions. Quantitative criteria are not indicated in this article, as it is each manufacturer’s responsibility to define them on the basis of the risks inherent in the process evaluated.
Question 1. Is the risk of the introduction of NEPs by raw materials acceptable ?
As one of the major sources of the introduction of NEPs in materials is linked to the presence of microorganisms other than Gram-negative bacilli, particular attention is paid to controlling the bioburden of materials used in the manufacturing process.
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| Illustr. 2: Is the risk of the introduction of NEPs by raw materials acceptable? |
Table 2: list of substances mentioned in the literature as liable to have a pyrogenic action
Question 2. Is the risk of the introduction of NEPs by primary packaging items acceptable ?
This question may take into account the existence or absence of a validated process for reducing the pyrogen burden at the supplier’s premises during the manufacturing process (10:37). Note that washing is a bioburden reduction process that can also reduce the pyrogen burden (specific validation to be conducted).
Question 3. Is the risk of the introduction of NEPs by production equipment acceptable ?
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Illustr. 3: Is the risk of the introduction of NEPs by production equipment acceptable?
Question 4. Is the risk of the introduction of NEPs by the production environment acceptable ?
Illustr. 4: Is the risk of the introduction of NEPs by the production environment acceptable?
Question 5. Detection of pyrogens by the MAT test on 3 validation batches ?
In the event of a negative response to questions Q1 to Q4, the MAT test may be performed on 3 validation batches. If pyrogens are detected, an investigation must be conducted to define the origin of the presence of the pyrogen(s). Depending on the results of the investigation, the routine implementation of a mat test may be envisaged.
4. Conclusion
The tool presented is an example of an approach that can be used to respond to the problem of the possible presence of pyrogens in injectable products. This reflection should be included when developing a new product. The recent appearance of Annex 1 has only accentuated the need to conduct risk analyses at all levels in order to reduce the risks of microbiological, particulate and a pyrogenic contamination. This will be also reinforced with the upcoming appearance of a new chapter of the European Pharmacopoeia, Chapter 5.1.13 Pyrogenicity, currently under review for comments.
This working group, set up spontaneously, is further proof of the extent to which all manufacturers are confronted by similar problems, and that working together enriches us all.
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