pharmaceutical production Archives - European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11

This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to Read more

What happens after IP loss of protection

by Giuliana Miglierini What does it happen under a competitiveness perspective once intellectual property (IP) protection for medicinal products expired? And what is the impact of the new entries on generics and biosimilars already in the market? The role of competitor Read more

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

by Giuliana Miglierini A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject Read more

How to approach drug substance supply in new product introduction (NPI) processes

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A key issue to be faced during pharmaceutical development refers to the supply of the active pharmaceutical ingredients and other raw materials to be used for the manufacturing of the first batches of investigational medicinal products, and then up to commercial production once approved.

Changes of specifications can frequently occur during experimentation, thus leading to the need to modify supply requirements for clinical programs. This is more true when dealing with biopharmaceutical investigational products, for which the traditional models for forecasting and demand processes may prove unfitted. The result is a lower robustness and predictability at early stages of the new product introduction (NPI) manufacturing processes. The complexity of the NPI supply chain is also impacting on manufacturing operations, with possible delays in the clinical program and launch schedule.

These issues have been addressed in the document “Guidelines for materials introduction supporting drug substance delivery”, published by the B2B organisation BioPhorum. A summary of its contents has been published in Bioprocess Online.

A good internal communication is fundamental

The ability to produce robust supply forecasts for new product introduction bases on a detailed knowledge of the planning of different activities to be run for a timely launch. Role and responsibilities have to be clear, as well as the information to be collected and timely shared between the manufacturing and commercial departments of biopharmaceutical companies.

The availability of such information is crucial to reduce the variability intrinsic in the NPI process for a biopharmaceutical product, which costs much more compared to a traditional smallmolecule based one. Reducing variability also impacts on the ability to better compete in the often highly dynamic market for biosimilars, or to address the launch of a new biotherapeutic under the correct perspective. Issues may be encountered also with respect to the regulatory approval processes, which may require different time lengths in different geographic areas or countries. This adds another uncertainty factor to estimates of the quantities of product to be manufactured.

Upon this considerations, the BioPhorum document identifies four key issues to be addressed to provide for a timely NPI process, including capacity and lead-time restrictions or oversupply, late change evaluation and implementation, governance issues and network complexity and in-licensed (or non-platform) products.

The availability of a good NPI process may avoid to incur many problems once operations are in place; all the needed master data information to support the use of raw materials should also be present and correct. BioPhorum’s suggestion is to include NPI processes in the creation of master service and supply agreements for the supply of raw materials, as they help to reach clarity on what a supplier can deliver and what it cannot.

A four steps methodology and roadmap

The document by the BioPhorum describes the results of a project aimed to develop a materialsbased methodology and roadmap to support improved NPI processes, on the basis of a collaborative industry approach to identify and implement best practices.

The result is a four steps process referring to the different activities needed to set up materials introduction and supply. The proposed different steps include the establishment of product lifecycle materials requirements, materials evaluation, supplier selection and qualification, and a manufacture and business review. Each of them should be supported by specific tools and checklists to be developed internally by the company. The governance of the process should involve senior supplier/manufacturer nominees to formally approve the package of deliverables at each stage gate.

Establishing product lifecycle material requirements

For each of the four steps of the NPI process, the BioPhorum document offers detailed lists of information to be collected and of expected outcomes.

Stage gate 1 addresses the establishment of product lifecycle material requirements, usually corresponding to the activation of first time in human studies (FTIH). Data to be collected include specifications of raw materials (e.g. order of magnitude, grade, supply options, environmental-health-safety (EHS) or geographic issues, etc.) as well as master data such as recipe information, plant diagram, list of equipment and process information. At the clinical level, information on the demand sensitivities on indication and clinical milestones and decision points should support the first estimates of the supply and demand plan, to be then expanded to agree on lifecycle forecasts.

The output may take the form of a ‘Product Lifecycle Demand and Supply Strategy’, a document discussing the long-term supply, demand and manufacturing of the product. Starting from the initial planning, the strategy should evolve through the creation of a data store specific for biopharmaceuticals, and the execution of gap analysis for in-licensed products. The strategy should also include a rough capacity modelling and description of ownership and the definition of a RACI matrix (responsible, accountable, consult, inform) to clarify roles and responsibilities with respect to each task, deliverable, or action. Information should be also available on high level technology requirements (both at the internal and external level). Strategic suppliers should be involved in early activities and materials risk analysis should be initiated.

Materials evaluation

Stage gate 2 refers to the information to be gathered from suppliers on the basis of requests for information (RFI) on materials. This should include all the different aspects relevant to the selection of the supplier, including capacity and costs, contacts, technical specifications and audit history, availability of samples, EHS aspects and business systems (e.g. availability of an appropriate ERP system).

This information should facilitate the identification of supplier that might be able to support the predicted or proposed growth of the product over its lifecycle. Stage gate 2 is also part of the risk management process to be run to validate the activation of full production.

Outputs include the sharing of forecasts and sensitivities with suppliers as needed, the establishment of a standard industrial master data set for biopharmaceuticals, as well as of business acceptance criteria.

Supplier selection and qualification

Stage gate 3 addresses the qualification process to finally select the most suitable suppliers and close the corresponding material supply agreements. The RFI and other information gathered in the previous step represent the basis of this exercise, aimed to develop a supply chain resilience strategic approach. The signature of the initial contracts is the final mark of formal selection, and should be supported by an agreement with the supplier on forecast and schedule for the supply, as well as of the business acceptance criteria.

Manufacture and business review

Stage gate 4 refers to the assessment of the operational performance of the supply chain for raw materials, a key activity in order to ensure continuity of supply and to promptly intercept any emerging issue on the basis of trends analysis.

Tools needed to this instance include the definition of appropriate metrics to monitor supplies (e.g. adherence to schedule, “On time in full”-OTIF, “Cost of poor quality”-COPQ). Information on the innovation potential of the supplier and the provision of a feedback on its performance is also deemed important. Any issue should be timely discussed between the supplier and the biopharmaceutical company, and confirmation of the production schedule agreed upon.

Consultation open on the ICH Q13 guideline on continuous manufacturing

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.