process analytical technologies Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021


by Giuliana Miglierini The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure Read more

Joint implementation plan for the IVDR regulation


by Giuliana Miglierini Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Read more

Key issues in technical due diligences


by Giuliana Miglierini Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due Read more

Trends in the development of new dosage forms

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by Giuliana Miglierini

Oral solid dosage (OSD) forms (i.e. capsules and tablets) historically represent the most easy and convenient way for the administration of medicines. Recent years saw an increasing role of new approaches to treatment based on the extensive use of biotechnology to prepare advanced therapies (i.e. cellular, gene and tissue-based medicinal products). These are usually administered by i.v. injections or infusions, and may pose many challenges to develop a suitable dosage form, as acknowledged for example by the use of new lipid nanoparticles for the formulation of the mRNA Covid-19 vaccines.

The most recent trends in the development of new dosage forms have been addressed by Felicity Thomas from the column of Pharmaceutical Technology.

The increasing complexity of formulations is due to the need to accommodate the peculiar characteristics of biological macro-molecules and cellular therapies, which are very different from traditional small-molecules. Bioavailability and solubility issues are very typical, for example, and ask for the identification of new strategies for the setting up of a suitable formulation. The sensitivity of many new generation active pharmaceutical ingredients (APIs) to environmental conditions (i.e. temperature, oxygen concentration, humidity, etc.) also poses many challenges. Another important target is represented by the need to improve the compliance to treatment, to be pursued through the ability of patients to self-administer also injectable medicines using, for example, specifically designed devices. The parenteral administration of medicines has become more acceptable to many patients, especially in the case of serious indications and when auto-injectors are available, indicates another PharmTech’s article.

According to the experts interviewed by Felicity Thomas, there is also room for the development of new oral solid dosage forms for the delivery of biological medicines, as well as for OSD forms specifically designed to address the needs of paediatric and geriatric patients.

Some examples of technological advancements

Productive plants based on the implementation of high containment measures (i.e. isolators and RABS) are widely available to enable the entire manufacturing process to occur under “sea led” conditions, thus allowing for the safer manipulation of high potency APIs and the prevention of cross-contamination. Process analytical technologies (PAT), digital systems and artificial intelligence (AI) can be used to improve the overall efficiency of the formulation process. This may also prove true for previously “undruggable” proteins, that thanks to the AI can now become “druggable” targets denoted by a very high potency (and a low stability, thus asking for specific formulation strategies).

Advances in material sciences and the availability of new nanotechnology can support the development of oral formulations characterised by improved efficacy and bioavailability. To this instance, the article mentions the example of new softgel capsules able to provide inherent enteric protection and extended-release formulation. Functional coating, non-glass alternatives for injectables, and new excipients may also play an important role in the development of new formulations, such as controlled-release products, multi-particulates, orally disintegrating tablets, intranasal dosage forms, fixed-dose combinations.

 The ability to establish a robust interaction with the suppliers enables the development of “tailor-made” specifications for excipients, aimed to better reflect the critical material attributes of the drug substance. The ability to formulate personalised dosage forms may prove relevant from the perspective of the increasingly important paradigm of personalised medicine, as they may better respond to the genetic and/or epigenetic profile of each patient, especially in therapeutic areas such as oncology.

Not less important, advancements of processing techniques used to prepare the biological APIs (for example, the type of adeno-viral vectors used in gene therapy) are also critical; to this regard, current trends indicate the increasing relevance of continuous manufacturing processes for both the API and the dosage form.

 Injectable medicines may benefit from advancements in the understanding of the role played by some excipients, such as polysorbates, and of the interactions between the process, the formulation and the packaging components. Traditional techniques such as spray drying and lyophilisation are also experiencing some advancements, leading to the formulation of a wider range of biomolecules at the solid or liquid states into capsules or tablets.

New models for manufacturing

API solubility often represents a main challenge for formulators, that can be faced using micronization or nano-milling techniques, or by playing with the differential solubility profile of the amorphous vs crystalline forms of the active ingredient (that often also impact on its efficacy and stability profile).

As for the manufacturing of OSD forms, 3D printing allows the development of new products comprehensive of several active ingredients characterised by different release/dissolution profiles. This technology is currently represented, mostly in the nutraceutical field, and may prove important to develop personalised dosage forms to be rapidly delivered to single patients. 3D printing also benefits from advancements in the field of extrusion technologies, directly impacting on the properties of the materials used to print the capsules and tablets.

Artificial intelligence is today of paramount importance in drug discovery, as it allows the rapid identification of the more promising candidate molecules. Smart medical products, such as digital pills embedding an ingestible sensor or printed with special coating inks, enable the real-time tracking of the patient’s compliance as well as the monitoring “from the inside” of many physiological parameters. This sort of technology may also be used to authenticate the medicinal product with high precision, as it may incorporate a bar code or a spectral image directly on the dosage form. Dosage flexibility may benefit from the use of mini-tablets, that can be used by children as well as by aged patients experiencing swallowing issues.

The peculiarities of the OTC sector

Over-the-counter (OTC) medicines present some distinctive peculiarities compared to prescription drugs. According to an article on PharmTech, since the mid-‘80s the OTC segment followed the dynamics characteristic of other fast-moving consumer packaged goods (FMCG) industries (e.g., foods, beverages, and personal care products), thus leading to a greater attention towards the form and sensory attributes of the dosage form.

The following switch of many prescription medicines to OTC, in the ‘90s, reduced the difference in dosage forms between the two categories of medicinal products. Today, the competition is often played on the ability to provide patients with enhanced delivery characteristics, for example in the form of chewable gels, effervescent tablets for hot and cold drinks, orally disintegrating tablets and confectionery-derived forms. The availability of rapid or sustained-released dosage forms and long-acting formulations, enabling the quick action or the daily uptake of the medicine, is another important element of choice. Taste-masking of API’s particles is a relevant characteristic, for example, to make more acceptable an OSD form to children; this is also true for chewable tablets and gels, a “confectionery pharmaceutical form” often used to formulate vitamins and supplements.


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.