FDA Archives - European Industrial Pharmacists Group (EIPG)

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS


by Giuliana Miglierini The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents Read more

The transition towards EMA's new Digital Application Dataset Integration (DADI) user interface


by Giuliana Miglierini The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface. The European Medicines Agency (EMA) has Read more

IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics


by Giuliana Miglierini The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important Read more

Revision of the CDMh’s Q&As document on nitrosamine impurities

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by Giuliana Miglierini

The review process of medicinal products started in 2018 to assess the presence of nitrosamine impurities is still ongoing. The Coordination Group for Mutual Recognition and Decentralised Procedure (CMDh) last updated in December2021 its Questions & Answers document (Q&A) proving guidance on how to approach the revision procedure.

The US’s Food and Drug Administration (FDA) also updated its guidance on how to minimise the risks related to nitrosamine through formulation design changes. We summarise the latest news of the topic of nitrosamine impurities.

The CMDh’s update of the Q&A document

The CMDh Questions & Answers document (CMDh/400/2019, Rev.5) specifically refers to the implementation of the outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. According to the indications released in November 2020 by EMA’s human medicines committee (CHMP), these outcomes should now be aligned with those issued for other classes of medicines. This provision impacted on the allowed limits for nitrosamines, which are now applied to the finished products instead than to the active ingredient. The limits are determined on the basis of internationally agreed standards (ICH M7(R1)).

Companies are called to implement an appropriate control strategy to prevent or limit the presence of nitrosamine impurities as much as possible and to improve their manufacturing processes where necessary. A risk assessment should be run to evaluate the possible presence of N-nitrosamines in medicinal products, and tests carried out if appropriate.

Four different conditions (A-D) are set for the marketing authorisation (MA) of tetrazole sartans, with specific dates to be met for their fulfilment by marketing authorisation holders (MAHs). Revision 5 of the Q&As document specifically addresses conditions B and D.

Condition B asks the MAH to submit a step 2 response in the general “call for review”. To lift the condition on the risk assessment for the finished product, and provided no nitrosamine was detected in step 2 or levels are below 10% of acceptable intake (AI), submission of the step 2 response must now be followed by the submission of the outcome of the risk assessment. To this instance, the relevant template “Step 2 – No nitrosamine detected response template” should be used to fill a type IA C.I.11.a variation.

A further amendment to Condition B refers to nitrosamines being detected in step 2 above 10% AI. In this case, a variation application should be submitted as appropriate to support changes to the manufacturing process and the possible introduction of a limit in the specification of the finished product.

Condition D now specifies that it applies only to N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) impurities. Thus, to lift the condition on the change of the finished product specification, and if the MAH wants to apply for omission from the specification, supporting data and risk assessments should be submitted via a type IB C.I.11.z variation referring only to these two impurities. Should any other nitrosamine impurity be potentially present, data should be submitted under separate variation (also grouping them together). Conditions A and C remain unchanged. The former refers to the three different possibilities for lifting the condition on the risk assessment for the active substance and with specific reference to the manufacturing process used to prepare it, the second to lifting the condition on the control strategy.

The guidance from the FDA

The US regulatory agency Food and Drug Administration (FDA) released in February 2021 the first revision of the “Guidance for Industry Control of Nitrosamine Impurities in Human Drugs”, establishing a three-step process to demonstrate the fulfilment of requirements.

The guideline widely discusses the structure of nitrosamine impurities and the possible root causes for their presence in medicinal products. While not binding for manufacturers, recommendations contained in the document should be applied in order to evaluate the risk level for the contamination of both active ingredients and finished products. This exercise should be run on the basis of a prioritisation taking into consideration the maximum daily dose, the duration of treatment, the therapeutic indication, and the number of patients treated.

The FDA provides also the acceptable intake limits for a set of different nitrosamine impurities (NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA); the approach outlined in ICH M7(R1) should be used to determine the risk associated with other types of nitrosamines.

Manufacturers do not need to submit the results of the risk assessment to the FDA, the relevant documentation has to be made available just upon specific request.

The second step refers to products showing a risk for the presence of nitrosamine impurities. In this case, highly sensitive confirmatory testing is needed to confirm the presence of the impurities.

The implementation of all changes to the manufacturing process for the API or final product have then to be submitted to the FDA in the form of drug master file amendments and changes to approved applications.

The Agency also provides specific guidance for API manufacturers to optimise the route of manufacturing in order to prevent the possible formation of nitrosamine impurities. API manufacturers should participate to the risk assessment run by the MAH; this last exercise should include the evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage.

Additional points to be considered

A Communication issued in November 2021 by the FDA specifies the terms for the recommended completion dates of the above mentioned three steps and adds some additional points to be considered in the evaluations. MAHs should have already completed by 31st March 2021 all risk assessments, while there is time up to 1st October 2023 for confirmatory testing and reporting changes. According to the FDA, the time left is enough to include in the development of the mitigation strategies also new considerations on how formulation design may prove useful to control nitrosamine levels in drug products.

More in particular, manufacturers are asked to evaluate the presence of nitrosamine drug substance-related impurities (NDSRIs), that may be produced if nitrite impurities are present in excipients (at parts-per-million amounts) or may be generated during manufacturing or shelf-life storage. Should NDSRIs be present, FDA recommends the mitigation strategy should include a supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and excipient lots.

Formulation design is another possible approach to solve the issue. This may use, for example, common antioxidants – such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) – that according to the scientific literature inhibit the formation of nitrosamines in vivo. The kinetic of the reaction leading to the formation of nitrosamine impurities may be also addressed by using a neutral or basic pH for formulation, to avoid acidic conditions which favours the side reaction.

Formulation changes may be submitted to the FDA through supplements or amendments to the applications, also following a preliminary meeting with the Agency to better discuss the approach to be used. Should this be the case, applicants or manufacturers are asked to prepare a comprehensive meeting package with the appropriate regulatory and scientific data on the selected approach to be submitted to the FDA in advance of the meeting.


Automation of aseptic manufacturing

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by Giliana Miglierini

The pharmaceutical industry is often the last industrial sector to implement many new manufacturing and methodological procedures. One typical example is Lean production, those concepts were developed in the automotive industry well before their adoption in the pharmaceutical field. The same may also apply to automation: it appears time is now mature to see an increasing role of automated operations in the critical field of aseptic manufacturing, suggests an article by Jennifer Markarian on PharmTech.com.

The main added value of automation is represented by the possibility to greatly reduce the risk of contamination associated to the presence of human operators in cleanrooms. A goal of high significance for the production of biotech, advanced therapies, which are typically parenterally administered. Automation is already taking place in many downstream processes, for example for fill/finish operations, packaging or warehouse management.

The advantages of the automation of aseptic processes

The biggest challenges engineers face when designing isolated fill lines are fitting the design into a small, enclosed space; achieving good operator ergonomics; and ensuring all systems and penetrations are leak-tight and properly designed for cleanability and [hydrogen peroxide] sterilization,” said Joe Hoff, CEO of robotics manufacturer AST, interviewed by Jennifer Markarian.

The great attention to the development of the Contamination Control Strategy (CCS) – which represents the core of sterile manufacturing, as indicated by the new Annex 1 to GMPs – may benefit from the insertion of robots and other automation technologies within gloveless isolators and other types of closed systems. This passage aims to completely exclude the human presence from the cleanroom and is key to achieve a completely segregated manufacturing environment, thus maximising the reduction of potential risks of contamination.

The new approach supports the pharmaceutical industry also in overcoming the often observed reluctance to innovate manufacturing processes: automation is now widely and positively perceived by regulators, thus contributing to lowering the regulatory risks linked to the submission of variations to the CMC part of the authorisation dossiers. High costs for the transitions to automated manufacturing – that might include the re-design of the facilities and the need to revalidate the processes – still represent significant barriers to the diffusion of these innovative methodologies for pharmaceutical production.

The elimination of human intervention in aseptic process was also a requirement of FDA’s 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing and of the related report on Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. According to Morningstar, for example, the FDA has recently granted approval for ADMA Biologics’ in-house aseptic fill-finish machine, an investment aimed to improve gross margins, consistency of supply, cycle times from inventory to production, and control of batch release.

Another advantage recalled by the PharmTech’s article is the availability of highly standardized robotics systems, thus enabling a great reduction of the time needed for setting up the new processes. The qualification of gloves’ use and cleaning procedures, for example, is no longer needed, impacting on another often highly critical step of manufacturing.

Easier training and higher reproducibility of operative tasks are other advantages offered by robots: machines do not need repeated training and testing for verification of the adherence to procedures, for example, thus greatly simplifying the qualification and validation steps required by GMPs. Nevertheless, training of human operators remains critical with respect to the availability of adequate knowledge to operate and control the automated systems, both from the mechanical and electronic point of view.

Possible examples of automation in sterile manufacturing

Robots are today able to perform a great number of complex, repetitive procedures with great precision, for example in the handling of different formats of vials and syringes. Automatic weighing stations are usually present within the isolator, so to weight empty and full vials in order to automatically adjust the filling process.

This may turn useful, for example, with respect to the production of small batches of advanced therapy medicinal products to be used in the field of precision medicine. Robots can also be automatically cleaned and decontaminated along with other contents of the isolator, simplifying the procedures that have to be run between different batches of production and according to the “Cleaning In Place” (CIP) and “Sterilisation In Place” (SIP) methodologies.

The design and mechanical characteristics of the robots (e.g. the use of brushless servomotors) make the process more smooth and reproducible, as mechanical movements are giving rise to a reduced number of particles.

Examples of gloveless fully sealed isolators inclusive of a robotic, GMP compliant arm were already presented in 2015 for the modular small-scale manufacturing of personalised, cytotoxic materials used for clinical trials.

Maintenance of the closed system may be also, at least partly, automated, for example by mean of haptic devices operated by remote to run the procedure the robotic arm needs to perform. Implementation of PAT tools and artificial intelligence algorithms offers opportunities for the continuous monitoring of the machinery, thus preventing malfunctioning and potential failures. The so gathered data may also prove very useful to run simulations of the process and optimization of the operative parameters. Artificial intelligence may be in place to run the automated monitoring and to detect defective finished products.

Automated filling machines allow for a high flexibility of batch’s size, from few hundreds of vials per hour up to some thousands. The transfer of containers along the different stations of the process is also automated. The implementation of this type of processes is usually associated with the use of pre-sterilised, single-use materials automatically inserted within the isolator (e.g. primary containers and closures, beta bags and disposal waste bags).

Automation may also refer to microbial monitoring and particle sampling operations to be run into cleanrooms, in line with the final goal to eliminate the need of human intervention.

Comparison of risks vs manual processes

A comparison of risks relative to various types of aseptic preparation processes typically run within a hospital pharmacy and performed, respectively, using a robot plus peristaltic pump or a manual process was published in 2019 in Pharm. Technol. in Hospital Pharmacy.

Production “on demand” of tailor-made preparations has been identified by authors as the more critical process, for which no significant difference in productivity is present between the manual and automated process. The robotic process proved to be superior for standardised preparations either from ready to use solutions or mixed cycles. A risk analysis run using the Failure Modes Effects and Criticality Analysis (FMECA) showed a lower level of associated risk.


The opportunity for repurposing of oncology medicines

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by Giuliana Miglierini

Rare cancers, which account for approx. 22% of new cases in Europe, represent an area of low business interest for the pharmaceutical industry, due to the limited number of patients compared to the very high costs to develop targeted treatments. It is thus important to consider the possibility for already existing medicines to be repurposed for a new indication. Lower costs of development and risk of failure, and a shorter time frame to reach registration are upon the main advantages of repurposing compared to de novo development, highlights the Policy Brief presented during the Joint meeting of EU Directors for Pharmaceutical Policy & Pharmaceutical Committee of 8 and 9 July 2021.
The experts addressed more specifically the possibility to achieve non-commercial repurposing of off-patent cancer medicines, which are commonly used off-label to treat patients not responsive to other more innovative types of therapies.

The issue of non-commercial development
The request of a new indication for an already marketed medicine has to be submitted by the Marketing authorisation holder (MAH). This greatly hampers the access to noncommercial repurposing by independent research institutions, as they would need to find an agreement with the MAH, the only responsible for all the interactions with regulatory authorities, at the central (EMA) or national level.
Considering the issue from the industrial point of view, this type of external request may prove difficult to be answered positively, when taking into consideration the very low return on investment that can be expected from a repurposed off-patent medicine. Even EU incentives schemes, such as those on data exclusivity and orphan designation, may not be sufficiently attractive for the industry. Current incentives schemes, for example, allow for an additional year of exclusivity in case of a new indication for a well-established substance, a 10-year market exclusivity
plus incentives in case of an authorised medicine granted with orphan designation, or the extension of the supplementary protection certificate for paediatric studies (plus 2 years market exclusivity for orphans).
The following table summarises the main issues and potential solutions involved in the setting of a specific reference framework for the repurposing of off-patent medicines for cancer, as reported in the WHO’s Policy Brief.

Table: Short overview of issues and solutions in repurposing of off-patent medicines for cancer
(Source: Repurposing of medicines – the underrated champion of sustainable innovation. Copenhagen: WHO Regional Office for Europe; 2021. Licence: CC BY-NC-SA 3.0 IGO)

Many projects active in the EU
The European Commission started looking at the repurposing of medicines with the 2015-2019 project Safe and Timely Access to Medicines for Patients (STAMP). A follow-up phase of this initiative should see the activation in 2021 of a pilot project integrated with the new European Pharmaceutical Strategy.
Several other projects were also funded in the EU, e.g. to better train the academia in Regulatory Science (CSA STARS), use in silico-based approaches to improve the efficacy and precision of drug repurposing (REPO TRIAL) or testing the repurposing of already marketed drugs (e.g. saracatinib to prevent the rare disease fibrodysplasia ossificans progressive, FOP). A specific action aimed to build a European platform for the repurposing of medicines is also included in Horizon Europe’s Work programme 2021 –2022; furthermore, both the EU’s Beating Cancer Plan and the Pharmaceutical Strategy include actions to support non-commercial development for the repurposing of medicines.

According to the WHO’s Policy Brief, a one-stop shop mechanism could be established in order for selected non-commercial actors, the so-called “Champions”, to act as the coordination point for EU institutions involved in the funding of research activities aimed to repurposing. This action may be complemented by the support to public–private partnerships involving research, registration and manufacturing and targeted to guarantee volumes for non-profitable compounds.
Among possible non-profit institutions to access funding for repurposing research in cancer are the European Organisation for Research on Cancer (EORTC) and the Breast Cancer International Group. An overview of other existing initiatives on repurposing has been offered during the debate by the WHO’s representative, Sarah Garner.

How to address repurposing
Looking for a new indication is just one of the possible points of view from which to look at the repurposing of a medicine. Other possibilities include the development of a new administration route for the same indication, the setup of a combination form instead of the use of separated medicinal products, or the realisation of a drug-medical device combination.
A change of strategy in the war on cancer may be useful, according to Lydie Meheus, Managing Director of the AntiCancer Fund (ACF), and Ciska Verbaanderd.
Keeping cancer development under control may bring more efficacy to the intervention than trying to cure it, said ACF’s representatives. The possible approaches include a hard repurposing, with a medicine being transferred to a completely new therapeutic area on the basis of considerations about the tumor biology and the immunological, metabolic and inflammatory pathways, or a soft repurposing within the oncology field, simply looking to new indications for rare cancers.
From the regulatory point of view, a possible example for EMA on how to address the inclusion of new off-label uses of marketed medicines is given by the FDA, which may request a labeling change when aware of new information beyond the safety ones.

The Champion framework
The Champion framework, proposed as a result of the STAMP project, is intended to facilitate data generation and gathering compliant to regulatory requirements for a new therapeutic use for an authorised active substance or medicine already free from of intellectual property and regulatory protection.
A Champion is typically a not-for-profit organisation, which interacts with the MAH in order to include on-label what was previously off-label, using existing regulatory tools (e.g innovation offices and scientific and/or regulatory advice). The Champion shall coordinate research activities up to full industry engagement and would be responsible for filing the initial request for scientific/regulatory advice on the basis of the available data. The pilot project to be activated to test the framework will be monitored by the Repurposing observatory group (RepOG), which will report to the Pharmaceutical Committee and will issue recommendations on how to deal with these types of procedures.

AI to optimise the chances of success
Artificial intelligence (AI) may play a central role in the identification of suitable medicines to be repurposed for a target indication, as it supports the collection and systematic analysis of very large amounts of data. The process has been used during the Covid pandemic, for example, when five supercomputers analysed more than 6 thousand molecules and identified 40 candidates for repurposing against the viral infection.
AI can be used along drug development process, making it easier to analyse the often complex and interconnected interactions which are at the basis of the observed pharmacological effect (e.g drug-target, protein-protein, drug-drug, drug-disease), explained Prof. Marinka Zitnik, Harvard Medical School.
To this instance, graphic neural networks can be used to identify a drug useful to treat a disease, as it is close to the disease in “pharmacological space”. The analysis may also take into account the possible interactions with other medicines. This is important to better evaluate the possible side effects resulting from co-prescribing; annual costs in treating side effects exceed $177 billion in the US alone, according to Prof. Zitnik.