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The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

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Greatest common divisor for product traceability and batch definition in continuous biomanufacturing

December 3, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

According to the draft ICH Q13 guideline on continuous manufacturing (CM), the definition of batch established by the ICH Q7 is applicable to all modes of CM, and it may refer to the quantity of output or input material, or to the run time at a defined mass flow rate. Other approaches to batch size definition are also possible and have to be justified taking into consideration their scientific rationale and the characteristics of the specific CM process.

The choice of a range for the batch size has to be justified in the regulatory dossier, including the approach used to define it. To this instance, changes in batch size that fall into the defined range can be managed through the Pharmaceutical Quality System, while variations have to be submitted (based on the availability of supporting data) to manage post-approval changes falling outside the approved range. ICH Q13 also asks manufacturers to define a suitable quantitative metric in order to establish batch-to-batch consistency and system robustness.

A possible approach to answer the complex challenges of batch definition in continuous integrated biomanufacturing has been proposed by an article published in the Journal of Chemical Technology and Biotechnology and signed by researchers of the University of Natural Resources and Life Sciences, Vienna, Austria, and the Austrian Centre of Industrial Biotechnology (ACIB). According to the authors, another important issue to be faced in CM is the ability to trace the raw materials through the entire process.

The usefulness of the greatest common divisor (GCD)

The deep understanding of a continuous manufacturing process is fundamental to support its regulatory acceptability; many are the different parameters to be considered to this instance, both regarding the attributes of input materials (e.g., potency, material flow properties) and process conditions (e.g., mass flow rates), in order to achieve the desired comprehension of the process dynamics.

The definition of the residence time distribution (RTD) for each individual unit operation, as well as for the integrated system, can be used to define the time a certain mass or fluid element remains in the continuous process. Challenges in the use of the RTD for batch definition in CM include the possibility to combine different production runs and the possible occurrence of process failures, which may cause great economic losses in case of batches of large dimensions.

The article by Lali et al. describes the use of the greatest common divisor (GCD) as a new parameter that may prove useful to lower “the spread of the RTD through continuous downstream process chains without the need for a redesign of individual unit operations for narrower RTD”.

Semi-continuous purification as the model example

The process used to model the new approach refers to the conventional semi-continuous purification of monoclonal antibodies using staphylococcal Protein A affinity chromatography, a process that may include runs performed on different columns.

The overall modelled process described in the article consists of six different steps, each characterized by a different RTD, starting from the alternating tangential flow filtration of the output material obtained from the upstream steps. A three-column periodic countercurrent chromatography (PCC) was used for protein capture, giving rise to a discrete output flow. This was collected in a surge tank or a continuous stirring tank reactor, from which a continuous outlet flow feeds the next unit operation, consisting of a fully continuous virus inactivation column. The last step of the process included polishing by flow-through chromatography and final concentration and buffer exchange obtained by ultrafiltration and diafiltration. The simulation first focused on each single step, to then consider the RTD of the integrated process.

The criticality assessed by the authors refers to the time-dependency of the RTD for the semicontinuous steps of the modelled process (whereas continuous steps are time-independent).

This is further complicated by the fact “each semicontinuous unit operation adds a periodic behavior to the product concentration profile, which leads to complex periodic behavior in the outlet of the process”.

The great common denominator is the parameter proposed in order to take into due account the time period of the semi-continuous steps, namely the time difference between elution peaks. A GCD of 2.29 hours was identified for the switching of the inlet flow to the next chromatographic column; this value was used to define batch size in comparison to a fixed arbitrary time (2 h). The same approach was also used to define outlet sections of the process and the resulting batches (also by pooling different outlet sections together to form a larger batch).

“Based on different sectioning in the inlet, when we track the product profile after each unit operation, we see a chaotic pattern when using an arbitrary time of 2 h. However, when the inlets are sectioned based on the GCD of the period for semi-continuous unit operations, we see a predictable, constant periodic behavior in the outlets”, writes the authors.

According to Lali et al., the synchronisation of the semi-continuous unit operations to achieve the largest possible GCD or the smallest possible lower common multiple is the only requirement for this method to define the batch size; every multiple of the GCD can also be used. Authors provide some examples which may typically occur during the management of a CM process and suggest a possible procedure for the implementation of batch definition based on GCD.


Consultation open on the ICH Q13 guideline on continuous manufacturing

October 8, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.