In the European Union, marketing authorisation holders were asked to review their manufacturing processes to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities. All authorised human medicinal products containing chemically synthesised or biological APls have to be reviewed. The review process is devided into three steps: step 1: risk evaluation, step 2: confirmatory testing and step 3: update marketing authorisations. Future challenges and lessons learned from presence of N-nitrosamine impurities in sartan medicines are also discussed (Ana Mª Castro, PhD, Javier Fernández, PhD).
There is no standard for GMP audits that are not carried out on site at the contractor's premises. Nevertheless, these remote audits have become routine for all those who carry out audits.
In recent months, a lot of information on remote audits has been published and Thomas Peither has followed and analysed some of them. In this current topic’s chapter, he shows the advantages and disadvantages and outlines a future perspective in which combinations of different audit forms (preparation off-site, remote audit, on-site audit) will play a role. (Thomas Peither)
Stability studies are carried out on both APIs and finished medicinal product when the expiry date of a medicinal product is experimentally determined. They can be used to determine suitable primary packaging materials, the shelf life of medicinal products and their storage instructions.
In order to standardise these processes, the guidelines of the WHO, ICH and the respective countries outline the applicable requirements for carrying out and evaluating the stability studies. They also regulate the mandatory requirements that must be met by stability studies when new medicinal products are submitted to the authorities for approval, and the data that must be regularly compiled for those products that already have a marketing authorisation.
Active pharmaceutical ingredients and finished medicinal products must undergo stability testing under stress conditions to determine ageing mechanisms, such as degradation characteristics. Data is then collected under standard storage conditions. This makes it possible to define the recommended storage and transport conditions, protective measures, the re-test period for the API and shelf life of the finished medicinal product.
Stability testing carried out during the development stage is used for describing product characteristics and how they react under the influence of temperature, humidity, light and time. The ICH and WHO guidelines provide detailed information and support.
After authorisation is granted, the product quality must be regularly monitored for consistency using stability studies. The parameters registered with the authorities are checked using designated analytical testing methods and specifications (EU GMP Guidelines Chapters 1 and 6).
The technical requirements for the stability studies include qualified equipment, climatic chambers and analysis devices which are used to ensure that the test conditions remain constant.
Different designs such as bracketing and matrixing can be used to reduce the scope of testing without significant loss of information. This results in considerable savings.
The main purpose of evaluating stability data is to determine the re-test periods (for APIs) the hold times (for intermediates and bulk products) and the shelf life (for finished medicinal products) including the storage instructions.
The entire data collection and evaluation process must be carried out properly in accordance with the GMP requirements and be documented at all times in a traceable way. GMP documentation includes stability reports, results reports, evaluation reports such as PQRs and evaluated overviews of monitoring and calibration data for the climatic chambers and analysis equipment. (Heike Meichsner, Olaf Mundszinger, PhD, Susanne Schweizer)
There is no uniform global definition of the term “counterfeit medicine”. Essentially, it is understood to refer to a medicinal product with false information about its identity, origin and distribution channel.
Counterfeit medicines are of inferior quality and, in the worst case, harmful to health or even life-threatening. In addition to the health risks they present, counterfeit medicines also pose both economic risks and liability and reputational risks for marketing authorisation holders and manufacturers, In the interest of patient safety in particular, defensive measures against counterfeit medicines are therefore essential. In the absence of a uniform definition, available statistics on the scale of the problem must be critically examined and a decision must be made as to which definition is appropriate for the area in question. At the same time, the absence of a uniform definition also hampers the exchange of information on counterfeit medicines.
In Europe, a first step in the fight against counterfeit medicines was taken in 2011 with the EU Falsified Medicines Directive. This directive provides for unique encoding and tamper protection. Specific provisions on the design of these safety features can be found in Delegated Regulation EU 2016/161.
Effective protection against counterfeit medicines can be achieved through counterfeit-proof features, tamper-evident closures and unique encoding with package-specific serial numbers. Coding and serialisation ensure a high level of transparency in the market. Finally, there are numerous possibilities for additional use of these codes. These include for example potential applications for the electronic provision of the package information leaflet or as part of the pharmacovigilance process.
The organisation of the fight against counterfeit medicines in the company comprises four essential aspects: monitoring, knowledge building, prevention and reaction. In terms of monitoring, a globally standardised database has proven to be a suitable tool for recording the global occurrence of counterfeit medicines and for establishing appropriate processes for case processing and notification of the authorities on this basis. A wide variety of sources, associations, committees etc. are available to build up and share knowledge on the phenomenon of counterfeit medicines. Preventive technical measures include the use of safety features and the effective communication of these features to the target groups for which they are intended.
Given that full protection against counterfeited medicinal products is unlikely to be achieved, an appropriate reaction following the discovery of a counterfeit is required on a regular basis. This includes not only the required notification of supervisory or investigative authorities, but also more extensive counteractive measures. The phenomenon of counterfeit medicines is not static, but rather highly dynamic and flexible, necessitating both continuous monitoring and evaluation and the ongoing adaptation or further development of defence mechanisms and internal organisations. (Stephan Schwarze, PhD)
Question 1.14 "Are there mandatory specifications for tamper evidence?" was updated.
The adjustment was made due to the new citation of EN ISO standard 21976:2020 "Packaging – Tamper verification features for medicinal product packaging" as a reference for consideration by manufacturers. The ISO standard has international validity. Previously, the document named the CEN standard EN16679:2014 "Tamper Verification Features for medicinal product packaging" with Europe-wide relevance.
The revision affects questions 3 and 10:
Question 3 refers to the submission templates for Step 2 "Confirmatory testing".
The template "Step 2 – Nitrosamines detected above acceptable intake or new nitrosamine detected response template" should only be used in addition to the "Step 2 – Nitrosamines detected response template" if
Important deadlines for MAHs to submit their confirmatory tests under step 2:
Question 10 newly lists N-nitrosomorpholine, NMOR with a limit of 127 ng/g.