Nitrosamines are a multifaceted topic that will continue to accompany all marketing authorisation holders not only today but also in the future.
Nitrosamine impurities in medicinal products can have various causes. Most frequently, nitrosamines are introduced via the synthesis of active ingredients. Possible other causes are, for example, recovered solvents, degradation products or packaging materials containing nitrocellulose.
The guidelines of the Committee for Medicinal Products for Human Use (CHMP) provide for a three-step assessment procedure for all (human) finished medicinal products. In the first step, a risk assessment is carried out. If a risk of nitrosamine formation has been identified in step 1, confirmatory testing must be carried out in the second step using validated and sufficiently sensitive methods. In step 3 of the procedure, a variation is filed.
Marketing authorisation holders will find good guidance on how to implement the requirements in some guidelines, as well as questionnaires for suppliers, e.g. EMA Q&A paper, EFPIA risk assessment guide, APIC and IPEC questionnaires.
The key is analytical methods that must be sufficiently sensitive to detect and quantify traces of nitrosamine impurities.
The EDQM has developed and published various analytical methods. However, these are predominantly coupled chromatographic techniques, such as GC-MS and HPLC-MS, which are often not available in routine QC laboratories.
Forced degradation studies can be used to investigate the stability of the drug molecule and identify degradation products. Challenging for the structure determination of impurities is to isolate a sufficient amount of the impurity. An elegant analytical method couples HPLC (UV/MS) with automated solid phase extraction, which allows accumulative trapping of the impurities, and NMR (NMR-SPE-LC).
High quality supplier qualification, including on-site audits, is important to minimise the risk of nitrosamine impurities. This also helps to improve manufacturing processes for active ingredients.
(Sabine Paris, PhD)
Cleaning is an important part of the overall quality concept in the production environment. In this context, cleaning is caught between the conflicting priorities of effectiveness, economy and the ability to be validated. The cleaning technology has a decisive influence on the effectiveness of the cleaning process. Knowledge of the process types and modes of operation is necessary in order to select effective and targeted processes and to optimise them under practical conditions. With the aim of using resources such as water, energy and time sparingly, the processes can be optimised and made efficient by exploiting the technical and organisational possibilities. Ultimately, the cleaning process must lead to defined and reproducible results so that it can be validated.
A distinction is made between automatic CIP or WIP processes and manual COP processes. Which process is the most effective under the given conditions can only be determined after analysis of the data. Fully automatic CIP is usually only considered for special applications. Manual cleaning, although fast and inexpensive, is difficult to standardise and may include safety hazards. WIP systems are often a suitable compromise. Compared to manual cleaning, the efficient use of the potential of chemicals and temperature in the WIP process is a major advantage. In addition, the binding of personnel capacities is lower.
For the realisation of a GMP-compliant CIP plant, knowledge of the different process types and modes of operation is necessary. As part of the design steps, the process, chemicals and rinsing steps are selected, as are the instrumentation and control systems. In CIP systems, a distinction is made between solution-recovery cleaning (batch cleaning with reuse of the cleaning solution) and single-pass or single-use cleaning (one-time use of the cleaning solution).
The same requirements apply to the design of CIP systems as to production facilities: low dead space design of components, smooth surfaces and turbulent flow in piping. The selection of spray heads in terms of type, shape, power, placement and number determines the success of cleaning.
As an advantage over manual cleaning, cleaning-relevant parameters such as flow rate, pressure, temperature and conductivity can be measured and used for qualification and validation.
Validation requirements and further standardisation require a detailed under-standing of the cleaning process and more automation in the future. The targeted interaction of the different fields of pharmaceutical production supports the planning and efficient design of cleaning systems.
Binding requirements for computerised systems and their validation can be found in various national and international regulations.
The EU GMP Guide contains far-reaching and detailed specifications. This applies in particular to Annex 11 Computerised systems.
In the United States, the regulations relevant to GMP also set out numerous requirements for computerised systems, their validation and the handling of electronic data. Here, 21 CFR Part 11 plays a special role.
In practice, requirements for the systems themselves and for system validation are often “lumped together”.
However, with regard to the required qualification of computer hardware and the associated IT infrastructure on the one hand and the validation of computer-based systems in processes on the other, a clear demarcation between these requirements is urgently needed.
This chapter breaks down the regulatory requirements of the EU and the U.S. and explains them clearly with the support of original citations from the regulations.
(Dennis Sandkühler, PhD)
Standard operating procedures are instructions on how to work. Their content must therefore be described in a concise, clear and intelligible manner.
The recipients of SOPs are employees who are expected to carry out GxP-relevant work reliably and without errors at the first attempt. Standard operating procedures also serve to demonstrate that there is a goal-oriented approach in place in accordance with defined procedures, to both internal parties (e.g. internal auditors) and external par-ties (e.g. inspectors from authorities). SOPs must always describe the real work process, and must therefore be coordinated with all stake-holders.
If standard operating procedures are to be applied sensibly and effectively, certain requirements must be met: the compilation of the SOP and the training provided for it must closely reflect the reality, and it must be understood by the target group before it is put into effect.
A clear structure and a uniform format or layout for all SOPs improves readability and understanding.
Standard operating procedures must be available in their current version at the workplace at which the activity they describe is carried out. This can be made possible by distributing authorised paper versions or by access to digital systems. Working with outdated versions, drafts or handwritten additions to SOPs is not allowed.
Standard operating procedures must be reviewed on a regular basis throughout their life cycle and their content adapted to changing conditions where necessary. The management of SOPs is made easier by an intelligent identification system. If electronic document management systems are used, they must be validated.
Standard operating procedures are an important part of GMP documentation and must be archived.
(Christine Oechslein, PhD; Cornelia Wawretschek)
The European Commission has revised and well restructured the procedures. In addition to new content and editorial adjustments, the 295-page document has been divided into a Part I for procedural topics and a Part II containing interpretation documents and templates.
The compilation primarily serves a harmonised approach and to facilitate cooperation for inspections within the European Member States. It applies to both, GMP and GDP inspections. The procedures form the basis for national procedures that are part of the quality management systems of the national GMP inspectorates.
New in Part I:
New in Part II:
The European Commission published Version 19 of the Q&A in late December 2021.
What has been updated?
The Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) modernises the existing rules on the authorisation and use of veterinary medicines in the European Union (EU). It contains new measures for increasing the availability and safety of veterinary medicines and should enhance EU action against antimicrobial resistance.
Regulation (EU) 2019/6 repealed Directive 2001/82/EC and amended the provisions of Regulation (EU) 726/2004 relating to the authorisation and supervision of veterinary medicines, which currently governs the centralised marketing authorisation procedure for both human and veterinary medicines. The new veterinary regulation entered into force on 28 January 2022.
EMA has twice updated its Q&A on nitrosamine impurities.
Revision 6 of October 2021, includes an update of
Both questions were amended with the same section stating that testing could be rationalized by testing only the worst-case scenario strength.
During development of an analytical method, a reference standard of the relevant nitrosamine impurity is generally needed. If despite extensive efforts, it becomes apparent that the relevant nitrosamine impurity cannot be synthesized, then this could be an indication that the nitrosamine either does not exist or that there is no risk of it being formed. In such cases, it may not be necessary to conduct confirmatory testing. For both cases, the justification should be documented in the risk assessment in the MAH's pharmaceutical quality system.
Revision 7 of January 2022, comes along with a section on testing and control of multiple impurities in one product and another nitrosamine listed for testing (Q&A 10):
To address the calculation of limit when more than one nitrosamine is identified in the same product two approaches are possible. Both should not exceed the acceptable risk level of 1:100.000 (see ICH M7(R1) guideline):
1. The total daily intake of all identified N-nitrosamines should not exceed the acceptance intake (AI) of the most potent N-nitrosamine identified
2. The total risk level calculated for all identified N-nitrosamines is not to exceed the 1 in 100,000 risk of cancer according to ICHM7(R1). With this option, either a fixed or flexible approach for calculation of AI may be used.
Fixed approach: fixed AI limits (in ppm/ppb) are set for individual nitrosamines and no limit for total N-nitrosamines is needed.
Flexible approach: each N-nitrosamine should be specified at its AI limit in ppm/ppb and an additional limit for total N-nitrosamines is required.
However, the approach chosen needs to be justified by the MAH/applicant. The newly added decision tree (Annex 1) should be helpful for further orientation.