CMC dossier Archives - European Industrial Pharmacists Group (EIPG)

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

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

ACT EU’s Workplan 2022-2026

by Giuliana Miglierini The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Read more

Key issues in technical due diligences

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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 diligences, assessing the technological platforms and product portfolios to be acquired. A series of articles published in Outsourced Pharma discussed, under different perspectives, the main issues encountered in technical due diligences. We provide a summary of main messages to be kept in mind while facing this type of activity.

Technical due diligence of pharmaceutical products

The third millennium is being highly characterised by the closure of many M&A operations in the biopharma sector as a way to support the transfer of new technological platforms from their originators – usually an innovative start-up or spin-off company – to larger multinational companies. The latter are usually managing advanced clinical phases of development and regulatory procedures needed to achieve market authorisation in the territories of interest.

Furthermore, the acquisition of already marketed products often represents a way to renew the product portfolio or to enter new markets. Should this be the case, an article by Anthony Grenier suggests that a main target is represented by the understanding of how the products were maintained on the market by the seller company.

The restructuring of assets following acquisition may require the transfer of products manufacturing to sites of the acquiring company, or the possibility to use the services of a Contract Manufacturing Organisation (CMO). These are all issues that should enter the technical due diligence, that usually includes the exchange of information about the product, equipment, manufacturing, quality, and regulatory aspects of the deal.

The regulatory and quality perspectives

Regulatory due diligence takes into consideration the approval status of the interested products in target markets. Relevant documentation to be examined include the CMC dossier (Chemistry, Manufacturing, and Controls) and/or the Common Technical Document (CTD), and the current status of approval procedures undergoing, for example, at the FDA in the US or the European Medicines Agency in the EU. A possible issue mentioned by Anthony Grenier refers to the assessment and management of dossiers relative to unfamiliar markets, that may differ as for regulatory requirements and thus need the availability of dedicated internal resources or consultants. This type of considerations may impact also on the selection of CMOs; the transfer of older dossiers is also challenging, as they often do not reflect current requirements and standards and may require significant investments (including the request of additional studies) to support the submission of variations.

A visit to the facility manufacturing the product during the second round of bidding, in order to better understand issues related to the technology transfer, is also suggested. Technical documentation available to assessors should include copies of batch records and specifications for raw materials, active ingredients, and drug products. Analysis of the annual trends in manufacturing may be also useful, as for example a high number of rejected batches may indicate the need for a reformulation of the product.

From the quality perspective, the due diligence should also examine issues with supply or quality agreements, and the date of the last revision of documents. Examples of relevant documentation to be examined include process validation reports, change control lists, stability studies, inspection reports, etc.

The manufacturing perspective

In a second article, A. Grenier examined technical due diligence from the perspective of manufacturing, equipment and logistics.

The manufacturing process is key to ensure the proper availability of the product in the target markets, and it should be correctly transferred to the acquiring company or the CMO. To this instance, executed batch records are important to provide information on actual process parameters, processing times, and yields. Here again, process validation reports and master supply agreements provide information on the robustness of the processes and the steady supply of raw materials.

Consideration should also be paid to the transfer of any product-dedicated equipment involved in the manufacturing or packaging process, including its actual ownership. The time period for technology transfer should be long enough (at least 12 months) to ensure for the proper execution of all operations.

From the logistics point of view, it is important to understand the need to update printed components to reflect the new ownership of the product, a task that may result complex should it be marketed in many different countries and/or in many different dosage forms. Inventories of all raw materials, APIs, and packaging components should be also assessed, paying a particular attention to narcotic products for which specific production quotas may be present in some countries (e.g. the US).

Technical due diligence of entire facilities

M&A deals often involve the acquisition of one or more manufacturing facilities and other complex industrial assets. Anthony Grenier also examined the key factors impacting on this type of technical due diligence.

The “technical fit” between the two companies involved in the deal is a primary target for assessment, in order to evaluate the achievable level of integration and the existing gaps in experience to be filled. This may refer, for example, to the acquisition of a manufacturing plant for non-sterile products that would need to be converted for aseptic manufacturing: a goal that may require the building of new areas, thus the availability of enough space to host them. Experience of the staff is also highly valuable, as well as the successful introduction of new equipment.

Capacity of the plant should also be considered, neither in excess or defect with respect to the effective needs in order to avoid waste of resources or need of new investments. Experience of the seller company in CMO may be also relevant, as it may be used to fill some of the excess capacity. To this instance, the fields of specialisation and the availability of containment capability to avoid cross contamination are important parameters to be considered.

Compliance of the facility to regulatory requirements arising from the different target markets should also be assessed, as it impacts on the positive outcomes of inspections.

Highly complex technical due diligences

Technical due diligence becomes even more complex in the case of multi-site acquisitions. In this case, visits to assess specificities of the single facilities involved in the operation may be needed. The above mentioned parameters of technical fit, capacity and compliance should be always considered, and the take-at-home message from the A. Grenier is for the acquiring companies to “look for the weakest links that would prohibit them from bringing their product or technology to the sites to be acquired”. Capacity optimisation may be needed, for example.

The different steps of technical due diligence have been also examined in another article by Anne Ettner and Norbert Pöllinger published in Pharm. Ind.. They presented a mind map that clarifies the complexity of the items that should enter the due diligence process, and lists typical documents and questions that should be taken into consideration. Examples and case studies are also provided relative to the assessment of starting materials, the evaluation of the pharmaceutical formulations and that of the production process.

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

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.