control strategy Archives - European Industrial Pharmacists Group (EIPG)

Patient involvement in the development, regulation and safe use of medicines


by Giuliana Miglierini The Council for International Organizations of Medical Sciences (CIOMS) has published the CIOMS report on “Patient involvement in the development, regulation and safe use of medicines”. The report marks an important step forward towards a harmonised approach to Read more

Webinar: Implementation of Contamination Control Strategy Using the ECA template


The next EIPG webinar will be held in conjunction with PIER and University College Cork on Friday 21st of October 2022 (16.00 CEST), on the implementation of Contamination Control Strategy (CCS) using the ECA* template. This is the second Read more

Real-world evidence for regulatory decision-making


by Giuliana Miglierini Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world 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.


Consultation open on the ICH Q13 guideline on continuous manufacturing

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by Giuliana Miglierini

The new ICH Q13 guideline on the continuous manufacturing of drug substances and drug products aims to harmonise at the international level this rapidly growing sector of pharmaceutical production, providing manufacturers with a flexible approach for the implementation of innovative technologies and ensuring compliance to Current Good Manufacturing Practices (CGMP) specific to continuous manufacturing.

The draft guideline was released in July 2021 and is currently subject to the public consultation phase, which will remain open for comments until 20 December 2021. Comments should be forwarded by e-mail to EMA at the address [email protected] The process to develop the new guideline started in November 2018 with the publication of the final Concept paper on continuous manufacturing.

The new ICH Q13 guideline is expected to support the adoption of continuous manufacturing systems by the pharmaceutical industry, thus providing innovation of manufacturing methods and availability of more robust and efficient processes, in order to increase options available in case of public health needs and to implement new approaches to Quality Assurance. The new provisions shall also contribute to the reduction of risks for operators, and to resource consumption and waste generation.

The key principles

The guideline on continuous manufacturing builds upon the existing ICH Quality guidelines to specifically address the production of drug substances and drug products for chemical entities and therapeutic proteins, and the conversion of batch manufacturing to continuous manufacturing modalities for existing products. It may also apply to other biological/biotechnological entities. The discussion takes into consideration both scientific and regulatory elements, with respect to the entire lifecycle management of the continuous manufacturing process.

This manufacturing technique is characterised by the continuous feeding of input materials into the productive flow, the transformation of in-process materials within, and the concomitant removal of output materials from the flow. A special attention is paid by the guideline to continuous manufacturing systems in which two or more unit operations are directly connected.

More in particular, Part I of the document addresses general aspects of continuous manufacturing not specific to the technology, dosage form or molecule type under consideration. Many illustrative examples are provided in Part II (Annexes) to support the implementation of the provisions to different operative setups.

Among available modes to run continuous manufacturing, the guideline discusses the combination of traditional approaches inclusive of units operating in a batch mode and integrated continuous manufacturing unit operations, the situation in which all unit operations are integrated and operate in a continuous mode, and the possibility the drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single continuous manufacturing process.

Part I: How to approach continuous manufacturing

The main part of the guideline is composed of six different sections aimed to provide a general vision of possible issues found in continuous manufacturing, under complementary points of view. The Introduction describes the guiding principles that inspired the document, including scientific and regulatory considerations to be taken in mind for the development of a new continuous manufacturing system.

Section 2 focuses on key concepts, among which is batch definition: according to the guideline, the ICH Q7 definition of a batch is applicable to all modes of continuous manufacturing, for both drug substances and drug products. Different options are available to define the size of a batch produced by continuous manufacturing, i.e., in terms of quantity of output material, quantity of input material, and run time at a defined mass flow rate. Other approaches to batch definition can be also considered upon justification, on the basis of the characteristics of the single process. For example, a batch size range can be established by defining a minimum and maximum run time.

Control strategy, changes in production output and continuous process verification are the key scientific principles addressed in Section 3, being the last item a possible, alternative approach for validating continuous manufacturing processes.

Principles described in ICH Q8-Q11 have always to be taken into consideration while developing the control strategy, using a holistic approach to properly consider aspects specific to continuous manufacturing.

The guideline takes into consideration all items which are part of the control strategy, starting from the state of control, according to ICH Q10, to provide assurance of continued process performance and product quality. Mechanisms should be in place to evaluate the consistency of the operations and to identify parameters outside the historical operating ranges, or signs of drifts/trends indicative the process could be at risk of falling outside the specified operating range. Knowledge of process dynamics is also important to maintain the state of control in continuous manufacturing. To this instance, a useful parameter may be represented by the characterisation of the residence time distribution (RTD). Furthermore, process dynamics should be assessed over the planned operating ranges and anticipated input material variability using scientifically justified approaches.

The guideline provides detailed examples of material attributes that can impact various aspects of continuous manufacturing operation and performance, with specific reference to a solid dosage form process, a chemically synthesised drug substance process, and a therapeutic protein process. Not less important is the design of equipment and the integration to form the continuous manufacturing system. Examples are provided as for the design and configuration of equipment, connections between equipment and locations of material diversion and sampling points.

Process analytical technologies (PAT) developed according to ICH Q8 are suited to implement real-time automated control strategies aimed to promptly detect transient disturbances that may occur during the continuous process. In-line UV flow cells, in-line near-infrared spectroscopy and in-line particle size analysis are possible examples. PAT’s measurements also support traceability of all materials that enter the process and diversion of the potential non-conforming ones.

The different definitions of batches in continuous manufacturing impact also on change management activities. The optimisation of the process may require changes of different parameters; examples discussed by the guideline include changes in run time with no change to mass flow rates and equipment, increase mass flow rates with no change to overall run time and equipment, increase output through duplication of equipment (i.e., scale-out), and scale up by increasing equipment size/capacity.

The above-mentioned critical aspects are also considered in Section 4 as part of the regulatory expectations the development of a continuous manufacturing process should fulfil. A sequential narrative description of the manufacturing process should be included in the Common Technical Document (CTD) and supported by suitable pharmaceutical development data. The description of the continuous manufacturing operational strategy should include operating conditions, in-process controls or tests, criteria that should be met for product collection during routine manufacturing, and the strategy for material collection and, when applicable, diversion. Other information also includes a description of how the material is transported from different pieces of equipment, a flow diagram outlining the direction of material movement through each process step, details about the locations where materials enter and leave the process, the locations of unit operations and surge lines or tanks, and a clear indication of the continuous and batch process steps. Critical points at which process monitoring and controls (e.g., PAT measurement, feedforward, or feedback control), intermediate tests, or final product controls are conducted should be also provided, together with a detailed description of any aspects of equipment design or configuration and system integration identified during development as critical with respect to process control or product quality. Sections 5 and 6 provide, respectively, a Glossary of terms used in continuous manufacturing and a list of useful references.

Part II: Five Annexes to illustrate different fields of continuous manufacturing application

Each of the five Annexes that form Part II of the ICHQ13 guideline addresses issues specific to the application of continuous manufacturing to the target domains typical of the pharmaceutical manufacturing process.

Annex I refers to drug substances for chemical entities. It provides an example of a process containing both continuous and batch operations, where the segment run under continuous conditions consists of a series of unit operations for reactions, liquid phase extraction, carbon filtration, continuous crystallisation, and filtration. A second intermediate synthesised in batch mode enters the continuous flow to participate to the second step in the synthesis of the final drug substance.

Annex II describes a possible implementation of continuous manufacturing for the production of a solid dose drug product.

Here too, a flow diagram exemplifies the different steps of the process, including the blending of different materials followed by direct compression of the tablets and a final step of batch-mode film coating. The guideline also addresses the use of PAT technologies to monitor blend uniformity and trigger tablet diversion. The batch size range is defined on the basis of a predefined mass flow rate.

The manufacturing of therapeutic protein drug substances (e.g., monoclonal antibodies) is discussed in Annex III. This type of process may be used to produce intermediates for the manufacturing of conjugated biological products, and it could be integrated partially or in full of the continuous manufacturing system. The process described in the guideline includes a perfusion cell culture bioreactor with continuous downstream chromatography and other purification steps to continuously capture and purify the target protein. As regard to viral safety and clearance, the guideline specifies that the general recommendations of ICH Q5A remain applicable also for continuous manufacturing; alternative approaches need to be justified.

Many continuous processes integrate in the same flow the manufacturing of both the drug

substance and drug product. This type of circumstance is approached in Annex IV with reference to the production of a small molecule tablet dosage form. The two parts of the overall process may differ under many aspects, e.g., the prevalence for liquid or solid input material addition, different run times, different frequency of in-process measurements. This impacts on the choice of the equipment and the design of locations of in-process measurements and material diversion.

Annex V discusses some possible examples for the management of transient disturbances that may occur during continuous manufacturing, potentially affecting the final quality of the product. Three different approaches are provided, based on the frequent/infrequent occurrence of the disturbance and on its amplitude and duration with respect to predefined acceptance criteria.