raw materials Archives - European Industrial Pharmacists Group (EIPG)

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

Swissmedic’s technical interpretation of Annex 1

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by Giuliana Miglierini

New insights on the interpretation of the new Annex 1 to Good manufacturing practices (GMPs) comes from the Swiss regulatory authority Swissmedic, that at the end of October 2023 published the first revision of its Q&As document (you can find it on the Swissmedicines Inspectorate webpage)

The technical interpretation refers to the revised Annex 1 to the PIC/S GMP Guide (PE 009), adopted on 9 September 2022 and entered into force on 25 August 2023 (with the exception of point 8.123 on lyophilisation, which will enter into force on 25 August 2024). The Q&As follow the same scheme and chapters of Annex 1.

Scope and Premises

According to Swissmedic, for certain types of advanced medicinal products (e.g. ATMPs or allogenic and autologous cell therapy products) specific considerations are required with respect to the fact they cannot be terminally sterilised or filtered. The unsterile patient material should also be considered. Requirements of Annex 2A, paragraph 5.29(b) should be followed for aseptic processing, that should be maintained from the time of procurement of cells through manufacturing and administration back into the patient.

Exceptions to the application of Annex 1 need to be always justified: the Contamination Control Strategy (CCS) is the appropriate tool to detail all risk analysis performed on the basis of the specific manufacturing processes under consideration.

As for the Premises, segregated unidirectional flow airlocks for material and personnel for grade A and B cleanrooms are expected in the case of new facilities. Temporary separation of the flows in the airlocks is the minimum requirement for existing facilities, together with a detailed risk analysis to assess the need for additional technical or organisational measures.

The transfer of materials in and out of a critical grade A cleanroom should be based on the careful definition of the technical and procedural measures associated with it. For example, prior introduction of materials in an isolator followed by decontamination is considered possible only for small batches and for materials resistant to VHP treatment. In all other cases, materials have to be sterilised before entering the already sterile isolator. The transfer process is also subject to a risk analysis to be included in the CCS, as well as to measures to control the maintenance of the integrity and functionality of the systems (also with respect to aseptic process simulation, APS).

Swissmedic specifies that the cleanroom sequence for the transfer of materials via airlocks or passthrough hatches is expected to be fulfilled for zones A and B. In the case of the passage from grade A to C, qualification is needed to prove adequacy of the established systems and procedures. The corresponding risk analysis has to be included in the CCS.

Updating equipment to reach full compliance with the new Annex 1 may require high investments. According to the Q&As, older barrier technologies should be subject to an in-depth internal evaluation to assess the need for new technical measures. The document underlines that starting from 25 August 2023 all barrier technologies not compliant with the new Annex 1 are considered deficient, thus companies should start projects to evaluate the upgrading of background cleanrooms and to define CAPA plans and interim measures to reduce risks.

The risk assessment should also include the evaluation of all automated functionalities and processes associated with the use of the isolator and the activities taking place in it. To this instance, Swissmedic highlights that robotic systems may help improving the reproducibility of operations and minimising both errors and manual interventions. Automatic processes are also expected for the decontamination of isolators, while for RABS manual processes might be used, provided they are designed to ensure reproducibility and are subject to validation and regular monitoring. The absence of negative effects on the medicinal product associated to the cleaning or biodecontamination substances used should also be validated.

As for barrier technology systems with unidirectional air flow, air velocity must be defined so that uniform airflow conditions prevail at the working positions where high-risk operations take place. Alternative air speed ranges or measurements at different heights in the system have to be scientifically justified in the CCS.

Utilities and Personnel

The section on Utilities offers additional guidance on systems used for water generation, that should be designed to allow for routine sanitisation and/or disinfection. Procedures are needed to define regular preventive maintenance of the reverse osmosis system, including the regular change of membranes. A suitable sampling schedule should be in place to regularly check water quality. More stringent controls are needed for the sampling of water-for-injection distribution systems, including daily microbial and bacterial endotoxin testing. The monitoring of the process gas should be performed as close as possible before the sterilisation filter.

Adequate training and qualification of all people working in grade A and B areas, including aseptic gowning and aseptic behaviors, is essential. According to Annex 1, this should include an annual successful APS. Swissmedic adds that, even if not explicitly required, practical process simulations, including manual interventions, should be carried out under the supervision of qualified trainers/QA; the company can choose if to integrate these process simulations into the APS.

Production and specific technologies

As for lyophilisation, initial loading patterns must be always validated, and revalidated annually. The Q&As specify cases where revalidation can be skipped, adding that a theoretical reference load is not acceptable. Revalidation has also to include temperature mapping for moist heat sterilisation systems.

Should a closed system be opened, this should be followed by cleaning (if required) and a validated sterilisation process. Alternatively, the system can be opened in a decontaminated isolator; a class A cleanroom with a class B background might be considered only for exceptional cases.

Non-aseptic connections can be carried out for coupling closed systems, provided a validated sterilisation cycle (SIP) occurs prior to use. Sterile aseptic connectors can be used if the supplier was checked and validated; data from the supplier can be used to file the relevant documentation, but handling of these parts has to be included in the APS.

Swissmedic also underlines that piercing a septum with a needle is to be regarded as a breach of the sterile barrier, and thus avoided for ascetic steps. Should this not be possible, temporary measures should be undertaken to prevent contamination.

Tube welding has also to be qualified and validated, and included in the APS if it is part of the aseptic filling process. The advice is to use more reliable systems, to avoid risks of undetected integrity deficiencies.

Critical single use systems (SUS) should always be tested for integrity by the end user on site before they are used in production. In case of difficult to test, small single use systems, the decision not to test their integrity must be justified in the CCS, as well as the decision to make use of test results provided by suppliers. To this instance, Swissmedic underlines that the comprehensive assessment (including quality system, etc.) should cover the SUS manufacturer/ s, as well as any subcontractors involved in critical services or processes.

Furthermore, the intended use of a SUS in the specific manufacturing process represents the basis for setting the respective acceptance criteria. The Q&As also detail the modalities for the visual inspection of SUSs and the possible acceptance of validation data provided by their suppliers.

As for extractables, the end user is expected to assess the data provided by the suppliers in order to define the need for additional evaluation or leachable studies. A redundant filtration step through a sterile sterilising grade filter, to be included as close to the point of fill as possible, is also encouraged, and its absence has to be justified. A risk analysis is required to justify the choice not to include pre-use/post-sterilisation integrity testing (PUPSIT) of sterilising grade filters used in aseptically processes.

Environmental and process monitoring

According to ICH Q9 (R1), the frequency of the risk review should be based on the level of risk determined for the specific process under consideration, as well as on the level of uncertainty of previous assessments. The recommendation of Swissmedic for new plants is to review the risk assessment after the first year of operations, so to take into due consideration the acquired experience. The document also suggests cases where more stringent action limits may be needed, and the type of statistics to be used to establish alert levels.

The use of rapid microbiological methods (RMM) requires validation and demonstration of equivalence with more traditional approaches. Details on the frequency of the interventions and their inclusion in the APS are also discussed, as well as the container/closure configuration and the distinction between liquid filling and lyophilisation.

The APS of campaign manufacturing represents a complex case for Swissmedic, for which the start-of-campaign (including aseptic assemblies if the case) and end-of-campaign studies should be both conducted. The Q&As also confirm that any contaminated unit with a contamination > 0 CFU results in a failed APS and requires the activation of the consequent actions. Production should resume only after completion of a successful revalidation.

Quality control

A university degree or an equivalent diploma in the field of microbiology (or other natural sciences, or medicine) together with a good understanding of the manufacturing processes under consideration are required for the person in charge of supporting the design of manufacturing activities and environmental monitoring.

As for raw materials, the need for microbiological testing should be evaluated taking into consideration their nature and respective use in the process. All specifications should be discussed and justified in the CCS.

Swissmedic also confirms that the bioburden has to be tested on each batch of raw material as incoming control as well as on the compounding solution in which it is formulated before sterile filtration. In the case of products with short shelf life, should an out-of-specification (OOS) event appear after release of the batch, a procedure is needed to inform doctors, patients, and health authorities, and to assess the connected risks and define remediation actions.


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

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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.


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.