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The containment of highly potent active pharmaceutical ingredients

Giuliana Miglierini
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The containment of highly potent active pharmaceutical ingredients

Pharmaceutical production has deeply changed since the last two decades, and highly potent active pharmaceutical ingredients (HPAPIs) play now a increasing central role in the fight against many diseases, i.e. cancer. The flip side of the game is represented by the need to protect workers who handle HPAPIs along the entire life cycle of the drug product manufacturing, from synthesis of the pharmaceutical active ingredient to distribution of the finished medicinal product. A further degree of complexity is represented by the fact that highly toxic substances are often available in the physical form of combustible powders. As explained by Sonia Ricci, past president of Ispe Italy Chapter, «there is need to integrate the good manufacturing practices (GMP) – at the base of quality requests for medicinal products and of their safety and efficacy – with the protection of the workers’ and environmental health, according to applicable laws. Many HPAPIs’ containing drugs are, for example, oncology products. There is an increasing demand of these medicines especially from emerging countries such as India or China, where a great part of the population asks to access advanced therapies made available by research».

The first Manual on HPAPIs’ containment

Based on these considerations, in 2010 the Containment Community of practice (CoP) of the Ispe DACH Chapter (Germany-Austria and Switzerland) started to draft a Containment Manual, the first of its kind at the international level. «We had never thought it would have become an Ispe’s best seller, with more than seven hundred copies sold in one year and a half – tells the coordinator of the initiative, Richard Denk –. The motivation to draft the Manual has been that there was quite nothing available on the topic of containment, and the pipelines of pharmaceutical companies indicated that many highly active products would have entered the market. Together with the Containment Manual, the Ispe Smepac Good practice guide is also available on the measurement of containment and the RiskMaPP guideline on the risk-based manufacturing of medicinal products».The manual explains the basis of containment and risk analysis, to then discuss in deeper detail containment measures along the entire life cycle of the product, as well as those for oral solid dosage forms and for active pharmaceutical ingredients (API). The document gives also an overview of the primary and secondary technical solutions available to contain HPAPIs, on validation procedures for occupational hygiene and for cleaning and waste management. «The Manual offers many useful information that should be included into every user requirements specification (URS)», adds Richard Denk. He also explains how the drafting of the document followed a different procedure than the normal one used by Ispe to develop new guidelines. At the beginning the document was thought for the German market only, thus it was drafted in German without involvement of the Ispe’s Guidance document committee (GDC),that is usually the responsible for the development of the guidelines of the Association. «We followed the procedure in any case, and after finalisation the document was sent to experts from the industry for their revision and comments – tells Denk -. The introduction of the Manual on the German market went very well, thus we have been asked for an English translation just after the publication of the German text. The English version has been sent to the Ispe’s GDC Committee for a revision, but without implementation of the comments we received. This because the English translation had to be identical to the German one already published». The Ispe DACH group coordinator also explains how – after the generally very good comments received by the GDC – the second edition of the Manual should become a true Ispe’s Good practice guide. «The document is now available also in the library of the European Directorate for the Quality of Medicines and Health (EDQM) of the European Council. EDQM is the editor of the European Pharmacopeia and the responsible for the release of the Certificate of Conformity. We are thus very proud of this, because it reflects the importance of the Ispe DACH’s Containment Manual», further tells Denk.

The critical points for a correct containment

The life cycle of a medicinal product is very complex, and there are many issues to be considered to develop containment measures specific for each single case, which have to be based on a preliminary risk assessment. The analysis should always proceed in parallel from three different points of view: the safety of workers, the evaluation of exposure limits and those of the risk of explosion for HPAPIs’ powders. «The base for a correct risk assessment is always the knowledge of the process and of how to manipulate substances that might determine a potential exposure of the operator: only so it is possible to identify really effective protective measures – explains Sonia Ricci, who coordinated Ispe Italy’s working group on the safety of pharmaceutical processes using combustible and highly active powders -.The identification of the strategy for protection and risk control, in particular, requires to consider the quantities of the manipulated substances, the length of exposure and the characteristics of the product, especially the capacity of the substance to disperse into the environment».

Containment measures start from the primary ones, related to the characteristics of the equipment used to manipulate the substance. Secondary containment measures are those related to the characteristics of the buildings (i.e. HVAC systems). «The application of operative procedures (which can be subject to human errors) or the use of DPI (i.e. protective clothing or rebreathers)  must always be considered as additional protection measures – never as the only one – because they force to work under difficult conditions», adds the Ispe Italy’s past-president.

The validation of the entire approach

Sonia Ricci, Ispe

According to the current legislation, the employer is called to demonstrate the efficacy of the chosen containment systems by mean of periodical measurements of the concentration of airborne substances into the environment. «The frequency should be determined by the categorisation defined for the specific risk. The mode for execution of the measurements are defined by the SMEPAC guideline (Standardized measurement of equipment particulate airborne concentration)», Sonia Ricci explains.

The more widely used parameters to determine the exposure risk to HPAPIs for the operators are the occupational exposure limit (OEL) or the occupational exposure band (OEB). OEL’s values depend upon the route of administration of the HPAPI (oral, parenteral or by inhalation) and represents the maximum concentration in air at the working place to which the worker can be exposed during a time interval defined as the work shift (8 hours TWA) or the short term exposure (15 minutes, STEL limit). OEL may vary upon the specific manufacturing situation (including buildings, equipments and workers). OEB is based on the toxicity of the pure substance and classify the highly active ingredient into a specific category (tabella 1) according to its potency and the outcomes for the health of workers. «To determine the hazard of a particular substance some methods refer to the OEL, while others are based on the categorisation of risk phrases. Risk analysis methodologies generally refers to the exposure to the substance by inhalation, and differentiate among solid substances (airborne powders) or in the liquid form (that might generate vapours). Specific methods are available for the risk assessment in case of exposure by contact», explains Ricci.

How to contain the risk

A good risk analysis allows to design the production plant taking into consideration containment systems suitable to provide and adequate level of exposure, lower to the ones known to be dangerous for workers’ health. Containment strategies (i.e general ventilation, localised vacuum systems, manipulation into isolators with open or closed systems) are ranked according to their efficacy level. In the case of multi-product plants, it should be also considered the risk of contamination between different production campaigns, according to the guidelines published by the European medicines agency. «Guidelines ask to run a risk analysis to identify protection measures suitable to provide a certain level of segregation between different productions (if they are run simultaneously) and to provide effective cleaning of the production plant between different batches», further explains Ispe Italy’s representative. In some instances, the containment strategy has to be applied to already existing plants, or it should be evaluated since the first steps of the design of a new one. Pharmaceutical production is continuously evolving, and it might  occur to manage changes of production on existing plants which had not been designed to manipulate HPAPIs. «Should this be the case, specific solutions should be considered, also taking into consideration the number of batches per year. The use of single use containment systems is a possible example suitable for already existing plants. The design of a new plant requires to think to flexible solutions to manage future productions», tells the expert. But the first solution to be always considered, also suggests Sonia Ricci, should be the possibility to use a less toxic substance for the process instead of the HPAPI. An alternative to containment might also be represented by a process modification to avoid exposure of workers, for example by use of pre-dosed substances or lower concentrations to minimise the risk. Cleaning of the plant should also be managed appropriately. «A closed process eliminates the risk of exposure to the dangerous substance for workers only when an efficient and automatic cleaning process (CIP) of the plant is put in place at the end of each production batch. It is essential to validate the cleaning process to ensure that the system had been cleaned, to avoid exposure of the operator to traces of dangerous/toxic substances during the following phases of the plant’s maintenance», explains Ricci. The employer is also responsible to inform workers about the risks connected to the manipulation of chemical substances and to provide training on the procedures that should be applied to manage it.

The containment pyramid

API potency OEL OEB
> 100 mg/die 1000-5000 mg/m3 1 – scarcely dangerous
10-100 mg/die 100-1000 mg/m3 2 – moderately dangerous
1-10 mg/die 10-100 mg/m3 3 – dangerous
0,1-1 mg/die 1-10 mg/m3 4 – highly dangerous
< 0,1 mg/die < 1 mg/m3 5 – extremely dangerous

 

 

 

Gene editing. The first recommendations on allowed use

Giuliana Miglierini
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Gene editing. The first recommendations on allowed use

The new report “Human genome editing: Science, Ethics and Governance“ was released in January 2017 under the auspices of the US National Academy of Sciences and National Academy of Medicine, the Wellcome Trust and the British of Chinese Academy of Sciences. It represents the first, albeit very cautious, opening of the international scientific community towards the possibility to use gene editing techniques to also modify germ line cells, and not only the somatic ones. The working group that drafted the first recommendations for the governance of this rapidly growing emerging field included representatives of research and medicine as well as philosophers and experts of bioethics and social sciences and representatives of the different cultures and religions, such as the head of the Library of Alexandria (Egypt).

The permanent members of the working group met all the different stakeholders, including industry, biotechnology, religions, patient organizations and minorities. The final document, published on this website, summarizes and mediates among all different opinions that emerged during consultations. «It was a complex process: it has been difficult to reach an unanimous consensus of the recommendations on issues such as the possibility to modify the germ line», tells NCF geneticist Luigi Naldini, the member of the working group representing Italy. «In general, many respondents showed prudence or even closure, while others were far more open. What matters is the final result: we managed to clearly limit the possible way to proceed. There is a very cautious opening: as a scientist, it is always difficult to close the door to new technologies and possibilities, but it was necessary to take into account all the positions».

Research on germ lines only under many safeguards

«This has been the most controversial topic we faced. The current techniques of gene editing make no longer inconceivable to avoid the transmission of a genetic disease to offspring. This would represent no longer the treatment of a disease, but a form of prevention», underlines the geneticist, who heads the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget). Research on germ line cells would impact on procreation and on the transfer of the genetic inheritance, a sphere of the human life that is traditionally considered “off limits” by all cultures. «In any case, it is necessary to start from the scientific basis in order to assess the implications: today we are not ready, technologies are not sufficiently proven and safe, but we expect them to be available quite soon», says Naldini.

Experiments on in vitro models are already ongoing in countries where research on human embryos is permitted, such as Britain, China or the United States (in this latter case without public funding from the National Institutes of Health). The question to be answered to determine whever there is a real opportunity to use germ line cells regards the actual existence of a medical need, tells Naldini.

«There is no patient to be treated; there is the need of a person carrying a disease who wants to have a genetically-related child and to prevent the transmission of the disease. The great part of these cases is currently managed through pre-implantation genetic diagnosis and possibly with the therapeutic abortion. As per now, the indication for gene editing on the embryo is very modest, even if the technique was safe», says Naldini. According to the expert, the few cases in which this could be possible might enjoy an ethical justification, based on the prevention of the transmission of the defective gene.

«We left the door ajar to these applications, under a very strict control. Research targeted at modifying the human germ lines is still prohibited by law in many European countries. With this respect, Great Britain is so far the more open ones. The situation is quite varied among nations, the diversity of approaches can also represent a value. The primary concern addressed in the document is to open the door to a technology which might then escape control», adds Naldini. The group of experts long debated the various options that might be used to hold such an event and the risks related to a possible drift, tells the Italian representative in the task force. «Today we are protected in any case, because the technology is not yet ready. But in a relatively short time discussion will start about the use in confined areas, and our recommendation is that a very strict control mechanism has to be put in place in order to prevent the spread to only justified uses».

Somatic cells for clear indications

The situation of the research on somatic cells is very different, and several projects have already reached the clinical stage. «In this case – says the geneticist – our message is first of all to reassure the society and to show enthusiasm for somatic applications targeted to a clear therapeutic indication. There are mechanisms available for the governance and a solid scientific rational to move forward, we are at the beginning but we can expect considerable benefits. The gray area of enhancement, however, can still wait for the time being». The therapeutic use of gene editing falls in the general regulatory framework of the development of a new gene therapy, that is already regulated both from the legislative and regulatory point of view. Issues concern the so called “genetic doping”: the purpose of the genetic modification falls outside the therapy a serious disorder or a serious disability, to be rather directed to the strengthening of certain characteristics of the individual. «There we raised a red card. This is not the way to be followed, as per today. On this type of not-directly-medical applications we need at first to define a social consensus, which doesn’t currently exist. The risk-benefit evaluation should prevent these types of applications, but in any case we issued the recommendation not to pursue this path, at least to date», adds Naldini, who is also a member of the Italian National Committee for Biosafety, Biotechnology and Life Sciences. He further explains to NCF-Pharma World that, from the social perspective, enhancement might also involve unequal access for privileged individuals. «There are issues with fairness, about the ability to enhance differences rather than alleviate them», underlines the geneticist. In the United States, a formal mechanism is in place for discussion and acquisition of all social issues: the Recombinant advisory committee (RAC) examines all new gene therapy and genomic editing strategies in an open debate, where even the members of the non-scientific society have the possibility to express their opinion.

The genomic editing on somatic cells has opened new important therapeutic frontiers: today it is possible, for example, to inactivate a gene in a somatic cell to make it more resistant to infection by a virus (the application is undergoing clinical studies on patients with Hiv chronic infection of lymphocytes), or to produce more robust lymphocytes for adoptive immunotherapy of cancer. Gene editing might also allow to in situ correct a mutation, or to insert a new sequence at an exact point of the genome. «It is ambitious because it is more difficult compared to the inactivation of the gene, that is only the first step. The following repair by homologous recombination is more complex. This is the true, corrective, precision medicine, but it is still relatively inefficient. We are still in the field of laboratory research, new techniques are behind the corner and we expect to reach them soon», says Naldini. This is the reason why the institutions involved in the project worked for the development of recommendations to direct gene editing technologies for therapeutic applications. This type of applications, further tells the geneticist to close the interview, are absolutely acceptable when used on somatic cells of an individual bearer a serious disease or a genetic defect, because the inserted modification exhausts itself with the treated person.

 

Not only CRISPRs

The daily news of the last two-three years reports a the huge growth of gene editing applications following the development of the techniques known as CRISPR-Cas 9, very easy to apply and inexpensive. The modification of the targeted DNA is actually something already existing well before CRISPRs techniques, and used for over a decade in many laboratories world-wide.  Many different technological platforms are available, all based on artificial nucleases that cuts the DNA at a specific site. Among the most commonly used are the zinc finger nucleases (ZFN) and the technique known as Talen. The birth of the CRISPR-Cas9 has made the generation of these targeted enzymes easier, as it uses an RNA probe. «It is not yet clear whether the CRISPRs are more specific than previous approaches. The dissemination of technology requires the need to direct its use, even the therapeutic one, which becomes more accessible – explains Luigi Naldini -. Today we dispose of a range of reagents, CRISPRs are probably the most versatile ones and it is likely that they will expand in the future»

The recommendations of the task force

The report “Human genome editing: Science, Ethics and Governance” recommends a set of principles that all countries should follow for the governance of research in the field of gene editing and its clinical applications:

  • Health promotion: provide benefits and prevent harm to patients;
  • Transparency: provide clear, accessible and useful information to patients, families and stakeholders;
  • Caution: proceed only if solid scientific support data are available;
  • Responsible research: follow the highest standards in conducting research, in line with the international best practices;
  • Respect for individuals: recognize the dignity of each individual and respect their decisions;
  • Fairness: treat all cases the same way, with a fair balance between risks and benefits;
  • Transnational cooperation: conduct research under a collaborative approach, while respecting cultural differences.

The projects of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)

The research team of the SR-Tiget began working on gene editing well before the appearance of the CRISPRs techniques, and developed a strong expertise especially on the use of zinc finger nucleases and applications on blood cells. The group directed by Luigi Naldini is currently working to develop one of the first gene therapies for the correction of blood stem cells to be used in the treatment of rare diseases. Gene editing is also applied to lymphocytes T, for use in the immunotherapy of cancer. «In collaboration with the group of Chiara Bonini, we produced one of the first evidences on how to use gene editing to enhance their action, an approach that has been further developed in UK to treat children suffering from leukemia», tells Naldini.

Neurodegenerative diseases. The role of dopaminergic neurons

Giuliana Miglierini
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Neurodegenerative diseases. The role of dopaminergic neurons

The death of dopaminergic neurons might represent a possible cause of the Alzheimer disease, as well of Parkinson, tells the neurophysiologist Marcello D’Amelio. His team at the Campus Bio-Medico University, Rome made important discoveries that might have a future impact on the treatment of many neurodegenerative diseases

«The idea that different types of neurodegeneration might have a common basis is not new: our results open new and interesting perspectives. The midbrain may play a fundamental role, common to both Parkinson and Alzheimer diseases». Neurophysiologist Marcello D’Amelio is the leader of the team at the Campus Bio-Medico University, Rome and Fondazione S. Lucia those results might represent a final blow against neurodegenerative diseases. Alzheimer and Parkinson (Highlights on dementia) are two among the main health emergencies affecting the world population and their impact is progressively growing due to ageing.

A new role for the dopaminergic system

According to the research group, the leading cause of the Alzheimer disease would be an alteration of the dopaminergic system. This represents a marked difference with respect to the currently accepted cause of the disease, i.e. a degeneration of brain areas related to memory. According to the new results, the first brain area interested by the degeneration would be the ventral tegmental area (VTA) of the brain. Its degeneration would occur much prior the appearance of the formation of amyloid plaques, which is a typical anatomic-pathological characteristic of the disease.

The VTA area is populated by neurons responsible for the production of the neurotransmitter dopamine. Its early degeneration thus implies a reduced flux of dopamine towards the hippocampus and the nucleus accumbens, as well as towards other cerebral areas. When these two structures are functionally altered they might cause problems similar to those observed during the first stages of the disease: apathy and memory failure. «The identification of the derailment of the dopaminergic circuit represents the new item of our research, that put together all the current literature – explains Marcello D’Amelio. – Dopamine is no longer available to the different cerebral areas, as the one producing it is facing degeneration». D’Amelio is professor of Neurophysiology ad the Campus Bio-medico University and director of the Laboratory of Molecular Neurosciences at the IRCCS Fondazione Santa Lucia, Rome. His team studies the molecular and functional modifications that occur in the course of neurodegenerative diseases. The group published in April 2017 in Nature Communications1  the results obtained on the murine model of Alzheimer Tg2576: the mice overexpressed a mutated precursor of the human amyloid protein (APPswe) and it represents one of the more robust research model to study Alzheimer. According to the paper, the typical symptoms of the disease – i.e. loss of memory, anxiety, apathy and reduced appetite – would be the result of a loss in the synaptic plasticity.

Marcello D’Amelio, Campus Bio University, Rome

 

The challenge is still open

The new mechanism proposed for the Alzheimer disease is only the first step towards the practical applications on patients: the way is long and full of new challenges still to be solved. New neuro-diagnostic methods are required for an early and firm diagnosis of the disease at VTA level. D’Amelio’s group is collaborating with neuro-radiologists at the IRCCS Fondazione S.Lucia (http://www.hsantalucia.it/) and other specialised hospitals in order to better investigate the ventral tegmental area of the midbrain in early phases of the disease using functional magnetic resonance. «We want check that this area is actually disconnected in patients from the rest of the encephalon, thus loosing its normal projections with the other areas of the brain», tells D’Amelio.

But the main challenge remains therapy: the identification of a new cause for neuro-degeneration may lead in coming years  to the development of a new and effective treatment for Alzheimer. The disease is currently addressed only with symptomatic drugs, in order to slow down its progression. As Marcello D’Amelio tells NCF Pharma World, the researchers in Rome have very clear ideas on how it works the mechanisms of neurons’ death in the midbrain. «We now have to understand how we can protect them. There are many different molecules under clinical development for the Parkinson disease: we are validating their efficacy in our Alzheimer model. Clinical development for the two pathologies might proceed in parallel in the future». Such an hypothesis would be much easier to become true as the new data from functional magnetic resonance will confirm that the protection of dopaminergic neurons shall be the common therapeutic target for the two different type of senile dementia. According to D’Amelio, a couple of years are still needed to reach firm neuro-radiological evidence on the role and extent of the ventral tegmental area in the development of the diseases. The pre-clinical screening of candidate molecules should require further two-three years of investigation. Another line of clinical investigation is centred on the possible use of dopamine’s agonists (Main dopamine agonists). «We are studying the therapeutic efficacy of molecules able to increase the dopaminergic function of the brain, so to slow down the memory loss and improve its functioning in Alzheimer’s patients», tells Marcello D’Amelio.

Another challenge for the group in Rome implies the identification of the so called “sporadic forms” of the disease, that do not have a genetic basis. They represent 95% of the diagnosed Alzheimer cases. D’Amelio tells about the possible role of the VTA area studied in animal models of the sporadic forms.  «Such models are obtained through exposure to particular toxins or by use of protocols that replicate some of the risk factors of the disease. The important role paid by the beta-amyloid and the fact that VTA neurons are easily liable to death are the more interesting features of the research. We are not surprised, as from the functional electrophysiological point of view they are very labile and delicate neurons».

The new paradigm

The rapid death of dopaminergic neurons represents a completely new point of view on the Alzheimer disease. Prior to the publication of the paper from D’Amelio’s group, the more scientifically sounded hypothesis on the origin of Alzheimer was based on a central role played by the hippocampus, the cerebral area controlling memory. The new data shift the attention of the deep midbrain area, which controls both the hippocampus and the limbic system (that controls mood and motivational impulses). «All the dopamine in the brain is produced into the midbrain, that is divided into the VTA area and the substantia nigra pars compacta. The Parkinson disease also relates to dopamine, in a symmetrical way with respect to Alzheimer», explains the expert. Classical motor symptoms that are observed in Parkinson’s patients are in general attributed to the early degeneration of the substantia nigra pars compacta, thus resulting in a reduced dopamine’s release into the striatum that leads to the typical tremors. Neurons in the VTA area undergo degeneration in a later phase of the disease, with appearance on the no-motor symptoms of the Parkinson disease (i.e. reduced emotions). «According to our data on Alzheimer, it appears to be the exact opposite:  the first neurons undergoing degeneration are the VTA’s ones. In a more advanced stage of the disease neurons of the substantia nigra pars compacta also partially degenerates. Some patients with severe Parkinson disease present also motor symptoms», tells Marcello D’Amelio.

The rational of the new vision

D’Amelio’s research group based its initial assumptions upon several fragmented information already reported in the scientific literature. Some studies of transcranial magnetic stimulation on Alzheimer’s patients2, for example, have demonstrated a role for the cerebral plasticity of the primary motor cortex. «This plasticity is completely restored upon administration of rotigotine (a dopamine agonist used to treat Parkinson) for four weeks – tells D’Amico -. The TVA area richly innervates the primary motor cortex: the data obtained from the transcranial magnetic studies were interpreted up to now as the result of a degeneration within the projection areas of dopaminergic nerve terminals. No prior investigation was made on the possibility that the dopamine producing area might itself degenerate, and dopamine might no further reach projection areas».

Another starting point is represented by a seven years long longitudinal clinical study carried on patients affected by dementia in the course of their life. The results published in Neurology3 showed a progressive reduction of the memory function coupled with the alteration of mood (anxiety, apathy, agitation) and appetite modification in patients with Alzheimer. The working hypothesis of D’Amelio’s group was based on a parallel impairment of both memory and motivational cerebral areas and on the early degeneration of a common area able to activate them both: the ventral tegmental area. VTA projects dopamine both into the hippocampus and the limbic system, as well as in the primary motor cortex. «This hypothesis explains the recovery of transcranial magnetic stimulation upon administration of dopamine and the parallel deterioration of the memory and motivational functions», tells D’Amico. The loss in memory and motivation has been studied in animal models, the second one using chocolate consumption as the stimulus, and confirmed the parallelism. This relates further to a massive death of VTA’s dopaminergic neurons. The hippocampus and the limbic system did not showed any sign of degeneration. «We measured dopamine levels into the hippocampus and the nucleus accumbens, demonstrating that this area are reached by less dopamine as a consequence of the early dopaminergic neurons’ death», explain the team leader. A further confirmation of this hypothesis has been obtained by administration of dopamine precursor levo-dopa and selegiline (an inhibitor of monoamine oxidase enzymes that degrade dopamine): in both cases an increase of dopamine availability has been observed in the hippocampus as well as in the limbic system. Memory and motivational functions were both restored. «Our model allowed to verify that the main damage occurs in the VTA area. This damage impacts at a secondary level of projection area, hippocampus and limbic system», concludes Marcello D’Amelio.

 

References

 

Highlights on dementia

Alzheimer represents the 50-60% of all forms of dementia.

  • there are more than 47 million patients affected by dementia at the global level;
  • this number is expected to double in the next twenty years;
  • Economic and social costs to treat dementia counted for $ 818 billion in 2015;
  • They are expected to reach $ 1 trillion by 2018;
  • Parkinson disease affects approx. 4 per thousand of the general population and approx. 1% of the over-65.

Fonte: Federazione Alzheimer Italia e Parkinson Italia

 

Main dopamine agonists

·         bromocriptine
·         lisuride
·         di-hydroergocriptine
·         pergolide
·         apomorphine
·         cabergoline
·         ropinirole
·         pramipexole

·         rotigonine

Fonte: Parkinson italia

 

Figure 1 -The illustration reproduces the VTA area, where dopamine is produced. Arrows indicates the release of the neurotransmitter in the two areas related to memory (the hippocampus) and motivational function (nucleus accumbens). These areas, together with some other not present in the illustration, constitutes the mesolimbic pathway.

Marcello D’Amelio group demonstrated that the VTA undergoes an early degeneration, thus causing a reduction in the release of dopamine followed by degeneration of memory and motivational functions of the brain.

 

 

Regulatory challenges of CAR-T cell therapies

Giuliana Miglierini
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Regulatory challenges of CAR-T cell therapies

The first-in-class new chimeric antigen receptor T cell (CAR-T) cell therapy – Novartis’ Kymriah™ (tisagenlecleucel, CTL019) for children and young adults with B-ALL cell that is refractory or has relapsed at least twice – has received FDA approval at the end of August 2017.

The new approach is based on the reprogramming of autologous T cells, obtained from the patient by leukapheresis, through insertion of a viral vector encoding for molecules able to recognize cancer cells and other cells expressing a specific antigen (CD19). Once administered to the patient, CAR-T cells have the potential to recognize and bind to the cancer cells and other cells expressing the specific antigen, a process that initiate direct cell death.

The challenges of a complex manufacturing

Kymriah’s suspension for intravenous infusion is obtained though a complex process that starts in hospital, where patient’s blood containing T cells is collected, to then continue in the cGMP facility where reprogramming, quality and batch  controls take place, to finally end again in hospital with the administration of the therapy to the patient. According to Novartis, the first CAR-T cell therapy on the market will be manufactured for each individual patient at the Novartis Morris Plains, New Jersey facility. The integrated manufacturing and supply chain platform operates on a global scale and manages many critical steps, including viral production, genetic modification, cell expansion, quality control and analysis and cryopreservation of the cells.

The high variability of cells deriving from different patients poses many technical and regulatory challenges along this pathway, such as the definition of specifications and the characterisation of the final product. Batch failure is a concrete possibility in CAR-T cell manufacturing, according to the paper signed by Shirley M. Bartido and published in Cell & Gene Therapy Insights.

Manufacturing requires ‘more than minimal manipulations’ (MTMM) on the cell product, argues the paper, thus it is regulated in the U.S. under the Public Health Service Act (PHSAct) section 351. The paper also reports details of U.S. and ICH guidelines relevant to cell therapy development.

According to an editorial by Frederick L. Locke and Marco L. Davila published in the Expert Opinion on Biological Therapy (you can access it here) the accelerated approval of such kind of therapies is based on surrogate endpoints.

It thus requires a deep post-marketing development phase, inclusive of new trials and surveillance activities in order to define the morbidity, mortality, and efficacy of the therapy and its overall survival compared to standard salvage therapy. Other points needing further attention are the production failure rate of autologous CAR-T cells and the impact of the type of virus (lentivirus or gammaretrovirus) used for the reprogramming. Shirley Bartido also evidences the need to test for the possibility of having a replication competent ret­rovirus (RCR) during the transduction of T cells with the viral vector. The intended modification delivered by the vector is generally  inserted using gene editing techniques, a further point that requires great attention with respect to undesired target- related effects. According to Bartido, traditional preclinical pharmacokinetic  studies are usually not feasible for this kind of therapeutics, as well as the use of animal models to determine cytotoxicity.

Among risks typical of the clinical development of CAR-T cell therapies (that significantly differs from the standard one), Bartido identifies the potential for prolonged biological activity after a single administration, a high potential for immunogenicity or the need for relatively invasive procedures to administer the product: all aspects to be kept in mind since the very beginning of early clinical development. Locke and Davila estimates some 10,000 patients undergoing the new therapy each year in the United States, a number that requires to address the possible emergence of rare, but potentially severe toxicities. Juno Therapeutics reported five deaths for cerebral edema during the phase 2 “Rocket” trial with JCAR015 therapy, which was thus ended up.

Guidelines to assess and manage CAR-T cell related toxicity have been reported among others by Lee et al. (Blood 2014; 124: 188–95) and Brudno et al. (Blood 2016; 127: 3321–30)

The Foundation for the Accreditation of Cellular Therapy (FACT) and the Joint Accreditation Committee ISCT – EBMT (JACIE) jointly developed international standards for immune effector cell therapies, which include CAR T cell therapies. Locke and Davila suggest that the accreditation, even if not compulsory, might represent a quality identifier useful both for patients, payers and manufacturers assurances.

Long term safety monitoring might benefit of conservation of biological samples: the paper suggest several already existing database, such as the one of the C.W. Bill Young Cell Transplantation Program  and the Stem Cell Therapeutic Outcomes Database (SCTOD) as examples possible repositories external to the manufacturing companies.

The financial impact of innovation

The CAR-T cell therapy is currently available in the U.S. and it can be delivered only by the network of certified treatment centers established by Novartis. The FDA has approved also a risk evaluation and mitigation strategy (REMS) for Kymriah, to inform and educate healthcare professionals about the risks that may be associated with the treatment. According to Bartido, cytokine release syndromes (CRS), macrophage activation syndromes (MAS), on-target off-tumor toxicity, neurotoxicity and TL are among the most frequent adverse effects.

According to Novartis, a new collaboration with Medicare and Medicaid Services (CMS) will focus on improving efficiencies in current regulatory requirements and it should provide access to patients on the base of indication-based pricing. Payments shall be outcomes-based.

 

 

 

 

The new ICH E11 (R1) on pediatric studies

Giuliana Miglierini
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The new ICH E11 (R1) on pediatric studies

After the public consultation phase in 2016, the ICH E11(R1) Addendum on Clinical Investigation of Medicinal Products in the Pediatric Population closed step 4 of the ICH procedure in August 2017  and is now undergoing the implementation period (Step 5) (click here to download the document).

The Addendum has ackowledged the new scientific and technical advances in pediatric drug development that have occured since the first release of the ICH E11 Guideline in 2000 and provides clarification and current regulatory perspective on topics in pediatric drug development. The harmonisation of data requested by the regulatory authorities of different geographic regions should allow, according to the document, to reduce the likelihood that substantial differences will exist for the acceptance of data and ensure a timely access to new medicines for children.

The contents of the ICH E11 (2000) have been amended with the new section 2 on “Ethical considerations”, section 4 on “Age classification and paediatric subgroups including neonates”, and section 7 on “Pediatric formulations”. Section 3 addresses the “Commonality of scientific approach for peadiatric drug development programs” and discusses scientific issues that might occur at various stages of pediatric drug development in different regions. Section 5 “Approaches to optimize pediatric drug development” deeply addresses pediatric extrapolation and introduces modelling and simulation (M&S) procedures. Section 6 on “Practicalities in the design and execution of pediatric clinical trials” considers feasibility, outcome assessments and long-term clinical aspects of studies on pediatric populations.

How to identify a pediatric population

Pediatric studies are often conducted on patient populations smaller that the ones typical of the development of medicines for adults. Ethical considerations are at the base of this difference, as children should be enrolled in a clinical study only when strictly necessary to achieve an important pediatric public health need, as explained by the new ICH E11 (R1). The disease under investigation has to affect the young patients, which should  exposed to lower risks compared to a classical clinical study. Section 3 of the new guideline addresses the possible differences that might occur in the selection of the relevant pediatric population for the study among different geographic regions. “A common scientific approach, not common regional requirements, is at the cornerstone of efficient pediatric drug development and timely delivery of safe and effective medicines for children”, writes the ICH E11 (R1).

The common practice to divide pediatric patients in specific age-related categories may not have a scientific basis for some conditions, argue the guideline, and the subsequent limitation of the study population might delay the development of new medicines. “Physiological development and maturity of organs, pathophysiology and natural history of the disease or condition, available treatment options, and the pharmacology of the investigational product are factors to be considered in determining the subgroups in pediatric studies”. Particular care should be paid to the selection of neonatal patient populations.

FDA wants to close the loopholes

Rare diseases often affect patients in the pediatric age, with the result that the development of dedicated drugs can be classified under the “orphan drug” designation. Pharmaceutical companies are increasingly investing in research for orphan diseases (defined in the U.S. as affecting less than 200,000 patients), as the “orphan drug” designation qualifies for tax incentives for clinical trial costs, relief from prescription drug user fees and grants a potential seven years of marketing exclusivity after the drug is approved. The Food and Drug Administration published its new “Orphan drug modernisation plan” in June 2017. 

FDA Commissioner Scott Gottlieb recently announced from the Agency’s blog the intention to “fully eliminate a backlog of about 200 orphan drug designation requests that were pending review with FDA”. Among the various loopholes the FDA Commissioner wants to close the post mentions the one that “allows sponsors to avoid an obligation to study drugs in pediatric indications” with a particular regard to pediatric subpopulations of diseases typical of the adult. Under such circumstances, new formulations under development for the pediatric age become exempt from the requirements of Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (PREA). “It’s a loophole that is in direct opposition to what Congress intended”, writes Scott Gottlieb, announcing also the issuing of a draft guidance document aimed at closing the loophole.

 

 

 

Biosimilars to provide better access at sustainable costs

Giuliana Miglierini
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Biosimilars to provide better access at sustainable costs

In the era of the personalisation of therapies, a better access to cure closely relates to the ability to sustain the very high costs of medicines that are far more sophisticaded than just some twenty years ago. The third millenium is characterised by the exploitation of biological medicines, which allows to better tailor the therapeutical intervention on the specific pathological subtype that affect each single patient (and for the determination of which dedicated biomarkers and in vitro tests are required). The other side of the game most of the Western governments have to face is represented by the financial restraints typical of the majority of Western healthcare systems.

Oncology is the new frontier for biosimilars

This is especially true in oncology, as anticancer drugs will account for € 140 billion costs by 2020, according to the position paper on  biosimilars published by the European Society of Medical Oncology (ESMO) in 2016. There were 23 biosimilar products approved in 2016 in the European Union.

The experience and knowledge gained in more than 10 years of biosimilars use is summarised in the “Biosimilars in the EU. Information guide for healthcare professionals” published this year by the European Commission and the European Medicines Agency.

A short summary on the industrial perspective to biosimilars, reporting a plenty of useful links, has also been given in a presentation by Adrian van den Hoven, director general of Medicines for Europe, the Federation of national associations of generics producers. “Biosimilar medicines are a real game changer for better health. They can transform oncology care, by prioritising greater and equal patient access to biologic medicines treatment, supportive care and other needed health services”, commented van den Hoven during the works of the ESMO 2017 Congress.

Biosimilars represent an important opportunity to help reducing health expenditure. A special session of the Congress, that took place in Madrid at the beginning of September, discussed how to act in order to build a better confidence towards the prescription of biosimilars, exploring the issue from all the different perspectives of physicians, specialist nurses, patient and the regulatory authority.

In Ireland, the Department of Health of the local government lauched in August a public consultation on the new “National biosimilar medicines policy”, aimed to promote the rational use of this category of drugs and to create a sustainable environment in the country.

According to the document, the cost of the community schemes and the High Tech Arrangement has been relatively stable at about €1.7 billion since 2012. But “this apparent headline stability masks a change within the total”, warns the Consultation paper, as the reduction in the amount of the GMS scheme (€1.2 billion in 2013 vs. €875 million in 2016) was paralleled by the increase of the High Tech funds (€442 million in 2013 vs €597 million in 2016)

The importance of HTA

The current European reference framework for biosimilars has been deeply analysed in the survey “2017 Market Review. European Biosimilar Medicines Markets – Policy Overview” conducted by Medicines in Europe among its national associates and relevant companies of the sector.

The document investigates, with respect to each single country, the availability of biosimilars, the pricing system, tendering, reimbursement system, physician and pharmacist policies, patient policies.

 

 

 

The new FDA guidelines on Quality Metrics

Giuliana Miglierini
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The new FDA guidelines on Quality Metrics

The new Food and Drug Administration (FDA) guideline “Submission of quality metrics data – Guidance for industry” was published at the end of November 2016. It represents a proposed, new risk-based tool to help both companies and the FDA to better define the timetable for inspections according to articles 704-706 of the US Food and Drug Administration Safety and Innovation Act (FDASIA). FDA and ISPE International collaborated over the last three years to conjunctively build the new approach to inspections, which will base upon predefined and harmonized quality indicators. No more biennial deadlines for companies to host inspectors: FDA’s target aims to an increased flexibility of the entire process on the basis of the quality indicators (“quality metrics”) the companies themselves will send to the Agency as a result an internal self-evaluation process. Other joint goals of FDA and ISPE include the ability to prevent and mitigate episodes of drug deficiency on the market and to encourage the adoption of innovative and last-generation quality management systems.

The first phase of implementation of the new draft guideline will see the launch by FDA of a voluntary reporting scheme of quality metrics, focused on the three indicators described in the document. The US Agency expects that the initiative will see the initial adhesion of manufactures of “covered drug products” finished pharmaceutical forms or of the corresponding active pharmaceutical ingredients. The voluntary implementation phase will not include manufacturers of biological products, blood derivatives, vaccines, in vitro diagnostics, allergen extracts and products for gene or cell therapy.

ISPE International, the international association of professionals operating in the field of pharmaceutical engineering, started the ambitious project in 2013, acting as the connection link between FDA’s requests and proposals developed by a group of about thirty companies (mostly big pharma), for a total of eighty manufacturing sites involved at the global level. The pilot project aimed to demonstrate the sustainability of the quality metrics approach and to the identification of a preliminary set of proposed standard indicators. Two representatives of ISPE Italy, Francesca Maienza and Boris Gabani participated at the working group and tell NCF Pharma World about the initiative.

The meaning of “quality metrics”

«The term “quality metrics” means all those indicators that give an idea of ​​the collective quality characteristics of a certain production site. The number of rejected batches per year compared to the total number of batches produced, or the number of out-of-specification results found by a QC lab, and which are then not confirmed with respect to the total number of batches tested, are examples of generic indicators already used by most companies and that may provide an idea of ​​the quality management of a site», explains Boris Gabani, QC Raw Materials Lab Manager at Roche, who followed the pilot project for the company’s Italian Segrate production site. FDA’s intention in 2013 was to establish a self-evaluation process to identify useful indicators for a preliminary assessment of the qualitative performance of a certain production site. The process should have produced a sufficient set of data to support the Agency decision to increase or decrease the inspection frequency. «The initiative born to address the significant increase of inspection requests received by the FDA. Its target was the collection of standardized data among companies to be used to calculate the risk for each site upon which take the decision if to increase or decrease the frequency of inspection – tells Gabani -. The translation into reality of this need has been possible only now, with the publication of the guideline. ISPE’s supported this need, in order to ensure that indicators were usable in practice and could be applied in a standardized way».

The pilot project

«ISPE acted as an intermediary, as the FDA could not directly interact with individual companies, and run the project over three years in two successive phases», says Francesca Maienza, QC manager of Farmila-Thea and Operation support director of ISPE Italy. The data referred to individual participating sites were collected with the help of a consulting company, which then analysed them under a confidentiality framework. The final data were shared with the company that generated them. The project’s global data were then transferred to the FDA, which used them to decide what were the most appropriate quality metrics to be included into the guideline under preparation. The first phase, conducted in 2014 on a limited number of companies, focused on quantitative quality metrics and run surveys to help evaluate process capability and quality culture within the various participating sites.

«The second wave, in 2015, involved more companies with the goal of identifying the optimal quality metrics indicators to measure the quality level in a harmonized way among different sites. This was also the most difficult aspect, not yet resolved. The collection of data and numbers needed to understand which were the most significant and useful indicators has been very demanding», says Maienza.

«Quality culture-related indicators can be considered to be quantitative, because the collected data are in numerical form. But they identify a parameter – quality culture – which is difficult to measure», tells Boris Gabani. To solve this problem surveys have been used, and interviews to employees and managers were collected in each company to specifically assess the perceived quality culture. «Collection of this kind of indicators could not use numbers, it has been necessary to use percentages relative to the level of agreement on individual questions», adds Gabani.

Phase 2 included also an evaluation of the effort and logistics needed by a company in order to collect data, as well as the development of appropriate tools for the optimal management of quality culture and process capability.

FDA chose three indicators

The second phase of the project started with the identification of a wide set of indicators (Indicators used during the pilot project) to evaluate the sustainability of the approach across different companies. The final data transmitted to FDA led the Agency to select three of them, which were used as the basis for the new guideline. They are the Low acceptance rate (LAR), the Product quality complaint rate (PQCR), and the Invalidated out-of-specification rate (IOOS) (Indicators included into the FDA guideline). «Many of the indicators that were evaluated were real challenges in order to check the site’s reaction and the kind of results that would have been possible to achieve: for example, if big differences were present between different sites, or if data between biotechnological, chemical, or active substance production sites might have been aggregated. The data obtained showed that this type of approach is often unsustainable in order to obtain data to be sent to the FDA, as it is too complex to attribute a precise meaning to the results obtained», tells Boris Gabani.

Low acceptance rate is a performance indicator of the production process that shows the number of batches released compared to the number of batches produced in a certain time unit. Customer satisfaction is assessed through the product quality compliant rate, an indicator of the number of complaints received compared to the number of total batches released in a defined time unit. «The “customer” is both the patient and the buyer, whether it is a health authority or another companies in the case we are working with third parties», says Roche’s expert. Quality control is monitored by the use of the invalidated out-of-specification rate: in this case, the indicator highlights the number of unspecified out-of-specification data, an important factor to assess the goodness of the operations performed by QC labs. «All out-of-specification which are traced but unconfirmed are usually laboratory errors, which solve upon the identification of an error in the analytical process, not in the batch itself. The lower the number, in a given time frame, the more the laboratory works well», adds Gabani.

The future of the project

The FDA draft guideline represents just a first proposal of indicators that can be used by companies around the world. These are still free to send further proposals of new quality metrics to the Agency. «The project is still open, there are many questions and doubts – tells Francesca Mazienza -. We have focused on three quality indicators because we have come to the conclusion that the simpler they are, the easier they can be standardized between different sites to provide comparability between one site and another. They must be simple numbers to calculate, based on very clear parameters and defined time units».

Each company sets its own quality system and identifies the key performance indicators (KPIs) needed to monitor its activities on the basis of the company’s specific features. This heterogeneity made difficult to identify a set of homogeneous indicators to be reproduced across companies that participated in the pilot project. «The FDA guideline suggests the three main indicators identified by the work done with ISPE, which were found to be the most univocal, simple to interpret and use. The guideline is open to use other indicators, as well as to the proposal of the companies to publish reports to suggest other indicators that are understandable and validated», adds the ISPE expert.

Quality metrics self-monitoring tools should not represents a shock for major pharmaceutical companies, already used to operate according to this type of approach. Many of them, in fact, have taken the opportunity of the pilot project as a specific exercise to better target their KPIs in accordance to the work done with ISPE and finalised to the FDA. «Companies were interested in participating to the pilot as they had the opportunity to play a primary role in defining the new indicators, thus helping themselves to measure and understand how to move», says Maienza. The new guideline could also serve as inspiration for the European regulatory authorities, which, according to the experts, might eventually implement a similar instrument also in Europe based on the US’s results. «FDA proved to have a very practical approach to the project, as it chose only three indicators among the twenty identified during the second pilot phase. FDA’s decision has been based on the feedback received, the three indicators are the ones that need less effort from the companies», tells Boris Gabani. According to the expert, FDA realized that multinational companies would be able to afford the costs for a dedicated person to manage the indicators, but smaller companies may not.

To start implement the entire process, a data sharing platform generated by pharmaceutical companies is by now still missing. Boris Gabani assumes the transmission of data to the FDA could occur through a form sent to an online mailbox, or a web-based system with a password-based access for individual companies. This model would allow the transfer of data directly into the system to be consulted by the Agency on the other side of the interface. «To start the process, it is necessary that the guideline diffusion is not only restricted among companies selling their products in the US, but also in Europe. There is also need for some more practical detail in order to communicate these numbers», adds Gabani.

Culture is a must

«All the companies participating to the pilot project accepted to play the game, as activities could have shown some weakness, or new parameters could have emerged which until now no one had ever thought, or new KPIs or recalculated in a different way», says Francesca Maienza about the  practical experience of the companies. The project also had an immediate impact to implement the needed actions to promote knowledge and dissemination of information across all departments. «We realized that sometimes actions decided by few people sitting around a table are not acquired and known by everyone in the company. A shared knowledge of issues by everyone helps to improve», says Maienza.

Boris Gabani tells about Roche’s experience, where a QC lab resource has been devoted entirely to the improvement activities: «We reviewed instruments’ position, workflows and document management in order to improve the process. Although it was not a direct consequence of the FDA quality metrics project, the execution of these activities allowed us to highlight some areas of improvement to work on. For example, we have identified a new indicator, the number of batch records waiting for approval for more than 30 days. It could happen that a batch record of a product that was not to be shortly shipped remained for a long time waiting for approval, while others were moving forward thus invalidating the average of release». Boris Gabani also tells that the new performance self-evaluation modalities helped towards the regular publishing and discussion of KPIs in each department. «The project has increased the self-awareness of values ​​and the desire to share improvements: a positive outcome of the FDA and ISPE project for all companies» concludes Boris Gabani.

QUANTITATIVE METRICSCULTURE’S INDICATORSSURVEYS’ BASED METRICS
Total complaints rateCAPAs with preventive actionsQuality culture survey
Critical complaints ratePlanned maintenanceProcess capability
Recall eventsWorkforce’s turnover Drug shortages
Lot acceptance rateDeviations from human errors
Invalidated OOS rateDeviations without an assigned root cause
Right first time rateCAPAs requiring new formative actions
Deviations rateAPR’s approvals
Recurring deviations rateAttempted lots pending disposition

Indicators included into the FDA guideline

  • LAR– Lot acceptance rate – indicator for the performance of the manufacturing process;
  • PQCR – Product quality compliant rate – indicator of the feedback from customers or patients;
  • IOOS – Invalidated out-of-specification rate – indicator describing the operativity of QC labotarories.

 

Manufacturing classification system

Giuliana Miglierini
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Manufacturing classification system

«The proposal coming from the Manufacturing classification system (MCS) working group represents a “guideline” for the formulator, that might be used as far as possible adapting it to the specific active ingredient to be formulated and inserting its description into the pharmaceutical development section of the dossier».

Piero Iamartino coordinates the new AFI’s Pharmaceutical Technology working group, together with professor Andrea Gazzaniga of the University of Milan. He summarizes for Pharma World the history and final goals of the MCS initiative, originally proposed in 2014 by a British university-industry mixed working group led by representatives of three big pharma, Bristol-Myers Squibb, GlaxoSmithKline and AstraZeneca. AFI’s Pharmaceutical Technology group accepted the invitation of the authors of the paper published in Pharmaceutical Development and Technology1 aimed to review the potential of the proposed approach and how it could benefit the pharmaceutical industry.

«The introduction of a manufacturing classification system could help explain the quality-by-design approach to the regulatory authorities, highlighting that the manufacturing process has been developed taking into account quality criteria and the critical quality attributes of the active ingredient. The MCS would have no direct impact from the regulatory point of view: it would rather enrich the knowledge of the formulator, to be briefly explained in the dossier», explains Iamartino.

Figure 1- MCS’s four classes of manufacturing methods. Source:  M. Leane et al. Pharmaceutical Development and Technology, 20:1, 12-21 (2015)

The Manufacturing Classification System represents a hierarchical organization of the different production methods to obtain solid oral formulations, discussed in comparison to the chemical-physical and mechanical characteristics of the individual active pharmaceutical ingredients (APIs) and to the specific formulative requirements (figure 1). The deeper understanding of the factors leading to the choice of the production technology could help, according to the authors, to better assess the risk associated with the different approaches, based on past experiences. «The proposal represents an attempt to rationalize the approach of the pharmaceutical development of solid oral forms. I also see it as the result of the progressive knowledge about physical characteristics of active ingredients, pharmaceutical formulations and processes which accumulated in the past decades», says Iamartino.

The challenges of solid oral forms formulation

The proposed classification of manufacturing methods according to APIs’ characteristics also responds to the need of identifying the bottlenecks that may be encountered during development, such as uniform blends that flow without adhesion to the surfaces and that can be easily compressed or inserted into the capsules.

«Application of this approach could reach a double result: first of all, it could induce suppliers of active ingredients to better evaluate the physico-chemical characteristics of the APIs and to discuss them with the formulator». This would represent a silver lining, according to Piero Iamartino, to improve the communication between chemists and formulators, and the quality of the final product thereof. «It is something that goes in the same perspective of the currently more applied approach – quality-by-design – those target is to achieve project’s quality in the development of a pharmaceutical formulation. With the introduction of the Manufacturing Classification System, a more robust formulation might be obtained, optimized with regards to the quantity of excipients used. And produced using the simplest manufacturing process, which is also the less costly from an economical point of view».

Complementarity with the Biopharmaceutics Classification System

The Biopharmaceuticals Classification System (BCS) was introduced about two decades ago with the aim of classifying the active ingredients based on their solubility and intestinal permeability (figure 2), i.e. the main parameters that influence bioavailability (figure 3). The British working party emphasizes in its article that such classification does not take into account other important parameters of the active ingredients. Particle size or the crystalline form of the APIs are only a few examples of parameters that can affect the biopharmaceutical properties of a solid formulation for oral use.

Figure 2 – The BCS classification. Source: FDA

The proposal of the new Manufacturing Classification System would complement the already existing BCS, providing for a more comprehensive view of pharmaceutical development both from the patient safety and efficacy point of view and the choice of the production method. Collecting and grouping under a unique reference system the today fragmented evidence could also allow, according to the authors, to guide solid oral form development based on the specific physical characteristics the APIs, i.e. particle size, surface characteristics and bulk properties. «The introduction of the Biopharmaceuticals Classification System was an attempt to rationalize the evaluation of the biopharmaceutical properties of active ingredients. The BCS is closely linked to the chemistry of the activity molecule, it takes into consideration an inherent property such as solubility or parameters such as log P or liposolubility. BCS system is now undergoing a phase of further refinement – tells the coordinator of the Pharmaceutical Technology group -. The proposal of an MCS system, however, ignore this to focus on the manufacturing process at the pharmaceutical technology level. It is intended to highlight APIs’ properties that might impact on formulative choices, such as excipient composition. It works alongside the BCS system, but they remain distinct». According to Piero Iamartino, the greater knowledge currently available on the physical properties of the APIs is also a consequence of the greater availability of instrumentation to measure them accurately. «This is the first pillar of the proposal. The second pillar is the manufacturing process», adds AFI’s group coordinator.

Figure 3 – Criteria to define BCS’ parameters. Source: FDA

Four classes at increasing complexity

There are four different classes, according to the proposal of the MCS working group, to describe the production process of a solid oral form. They are denoted by an increasing complexity, starting from direct compression (Some properties related to Class 1, 2 and 3), dry and wet granulation (Some properties for direct compression) up to the production methods needed to address the formulation of active ingredients that can not be managed with the previous ones (Some properties for wet granulation). The progression takes into account the increase in the number of processing steps, resulting in an higher complexity and higher costs. This is counterbalanced by the growing ease to formulate also “difficult” APIs. «The evaluation of the strategy to be chosen should start from the simplest process, with an open mind towards the adoption of more complex criterion where necessary. Physical characteristics of the active ingredient and the drug loading play an essential role. The article apparently pays less attention to APIs’ chemical characteristics, such as chemical stability or reactivity. But of course they must be taken into account, as they represent a preliminary condition for developing a solid oral formulation», says Iamartino. The authors of the MCS proposal also introduced the concept of “developability” to assess how the chemical-physical properties and the dosage of an active ingredient impact on a certain development strategy.

A particular formulative problem is represented by poorly soluble active ingredients, which often require the use of complex, difficult to classify technologies within the rigid framework of MCS. In this case the fourth category (“Other Technologies”) should be the reference, even if direct compression or dry granulation might work well from the point of view of obtaining a product of good quality. But they do not solve the problem of solubility of the active ingredient. «Methods such as hot melt extrusion, melt granulation or spray drying should be considered», adds Iamartino.

Excipients and drug loading

MCS classification system also pays a particular attention to drug loading, the amount of active ingredient that must be included in the formulation according to the pharmacologically active dose. It directly affects the choice of excipients and the size of the solid formulation. «The article refers to a scarcely known theory – percolation – developed more than ten years ago. It is a physical theory that tries to define the threshold that impacts on the formulation», explains Iamartino. Percolation addresses the possible passage of the active ingredient through the solid matrix formed by excipients and directly impacts the processability of the chosen method of manufacturing. The percolation threshold is defined as the API’s level that influences the final properties of the pharmaceutical finished form and is influenced by the surface, mass, volume and mechanical properties of the active ingredient. When the dosage of the API or its physical characteristics exert a strong effect on the formulation, the percolation threshold is low. «There is an influence on the robustness of the formulation, whereas if the threshold is high this impact is less important. A classic example of an active ingredient with a low percolation threshold is a micronized product, which could not flow and distribute well, or an high dosage», adds the coordinator of the Pharmaceutical Technology group. The MCS working group emphasizes in the article that it is necessary – for each active pharmaceutical ingredient – to confirm its specific percolation threshold. It suggests also that, ideally, the robustness of the formulation should be based on a formulative design that includes an appropriate “buffer zone” away from the percolation threshold.

Multistep processes also require more attention, because this type of process often induce more stress on the molecule of the active ingredient, which may result in its modification and/or unwanted reactions. Friction forces during milling and grinding, exposure to moisture in wet granulation, or the heat required for drying or coating may all be possible causes of variation of the APIs’ characteristics. Once again, according to the article, if parameters remain within the percolation threshold the formulation is robust compared to its ability to accept any changes to the active ingredient.

The MCS working group also explains that this could lead to a greater difficulty in identifying the root causes giving rise to manufacturing defects during the production process. «This work highlights how an increase of the complexity of the process creates higher risks in terms of quality. The use of this knowledge systematically and according to these criteria should help the formulator to choose the best solution. The evaluation should not start from the more complex process, but rather begin considering how the characteristics of the active ingredient impact on the robustness of the formulation», adds Iamartino.

The proposal of a manufacturing classification system is not free from points of weaknesses, which require further reflection according to the AFI’s Pharmaceutical Technology working group. First of all, the extreme diversity in the molecular structures of active ingredients that could make difficult to standardise the applicability of the system. «The attempt by the authors of the article is laudable, and also very intriguing and stimulating. But undoubtedly I have some reservations about its possible application to all the active ingredients», concludes Piero Iamartino.

1) M. Leane, K. Pitt, G. Reynolds & The Manufacturing Classification System (MCS) working group (2015), A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms, Pharmaceutical Development and Technology, 20:1, 12-21

Some properties related to Class 1, 2 and 3

  • Melting point
  • Contact angle with water
  • Moisture uptake
  • Dose number
  • Bulk density
  • Stability / Compatibility
  • Particle size
  • Morfology
  • Form

Source:  M. Leane et al. Pharmaceutical Development and Technology, 20:1, 12-21 (2015)

Some properties for direct compression

  • Particle size and shape
  • Blend uniformity
  • Powder flow
  • Powder density
  • Tableting performance
  • Compact mechanical properties

Source: M. Leane et al. Pharmaceutical Development and Technology, 20:1, 12-21 (2015)

Some properties for wet granulation

  • Low density
  • Poor wettability
  • Moisture sensitivity
  • Morfology
  • Deformation mechanism
  • Solubility interactin
  • Hydrates/polymorphs formations
  • Melting range
  • Poor flow
  • High tendency to segragate

Source:  M. Leane et al. Pharmaceutical Development and Technology, 20:1, 12-21 (2015)

 

Germany: The Rx-mail order German affair

Giuliana Miglierini
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Germany: The Rx-mail order German affair

In Germany since 2004 pharmacies, both retail and on-line, are allowed to sell medicines upon receipt of a mail order. Free market-price is allowed for non prescription medicines, while a fixed price is used for the prescription ones, which are subject to the Drug Price Ordinance.

According to the German law, foreign pharmacies are also allowed to ship human medicines to Germany only if located in the following countries: Iceland, the Netherlands (only if also an associated retail pharmacy exists), Sweden (for prescription medicine only), the Czech Republic (for non-prescription medicine only), the United Kingdom. Veterinary medicines may currently be shipped to Germany from the Czech Republic (for non-prescription medicine only) or the United Kingdom.

On October 19th, 2016 the European Court of Justice (ECJ) sentenced against Germany’s fixed prices for prescription drugs (Judgment in Case C-148/15), as they may represent an unjustified restriction of the free movement of goods in the European Union.

“In doing so, the ECJ has deviated from previous health care related rulings and also overturned leading decisions made by the German court system”, states the position paper published after the sentence by ABDA, the Federal Union of German Associations of Pharmacists.

The Union is now working together with the German Parliament and Government to safeguard the domestic pharmaceutical supply system.

A possible action suggested by the position paper could be the general ban on the mail-order trade of prescription pharmaceuticals, which would reflect the situation already in place in the vast majority of EU Member States.

The sentence of the ECJ refers to the cause promoted by the Zentrale zur Bekämpfung unlauteren Wettbewerbs (an association for protection against unfair competition) against the Deutsche Parkinson Vereinigung, a patient association those members used mail orders to buy medicines from the Dutch-based on-line pharmacy DocMorris on the basis of a special bonus system agreed upon the two parts.

A first judgement of the Regional Court, Dusseldorf, upon which the bonus scheme should have been ended up, was first appealed at the Higher Regional Court to finally end up at the European Court of Justice, which inverted the decision stating that fixed prices could prevent competition from other EU countries to enter the German market.

According to Abda, fixed prices avoids patients to compare the cost of Rx-drugs at different pharmacies, both in doctors’ practices as well as in hospitals. But the main impact would be for German pharmacies, which are facing many economical challenges and suffer from the general reduction of their density on the German territory. According to the position paper, the price maintenance system is also the cause of the sustainability of the benefits-in-kind principle within the statutory health insurance (SHI) system.

As the result of the entering into force of the European “falsified medicines” directive (2011/62/EU), each website selling human medicinal products per mail order should be registered into a national register and should be easily identified by consumers thanks to a special security logo. These prescriptions have been implemented also in the German Drug Law since June 2015 (section 8 of paragraph 67): the German Register of Online Medicine Retailers and the EUsecurity logo – both provided by the German Institute of Medical Documentation and Information (DIMDI) on behalf of the Federal Ministry of Health – are the operative measures set in place in Germany to fullfill EU’s obligations.

Many new clinical guidelines from EMA

Giuliana Miglierini
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Many new clinical guidelines from EMA

The European Medicines Agency (EMA) recently released several new guidelines related to the clinical aspects of pharmaceutical development. Compliance of the trial master file (TMF) to Good clinical practices is the object of the draft guideline EMA/15975/2016, issued by the GCP Inspectors Working Group (GCP IWG) on March 31st, 2017.

The document discusses the main requirements posed by the new “Clinical Trials Regulation” (EU) No 536/2014 and ICH-GCP E6 and that impact the preparation and filing of the TMF, both in the paper and electronic format.

Content and management of the trial as well as archiving of all relevant documentation, audit by the sponsor and inspection by the health authorities of Member States are all taken into consideration in the new EMA’s guideline. The document also clarifies retention times, and expectations in case of digitization and consecutive destruction of paper documentation.

It includes also a revised version of the reflection paper on TMF previously published by EMA, whithin which have been also inserted the comments collected during the public consultation phase (01 February – 30 April 2013).

The European Commission has released on March 24th, 2017 the implementing regulation detailing arrangements for the good clinical practice inspection procedures (C(2017) 1812 final).The document refers to clinical trials conducted in the UE – or referring to in MAA in the EU – and provides detailed information about the timeframe for inspections, the quality system that has to be set in place by Member States to ensure their quality, as well as qualifications, training and experience of the workforce employed as inspectors. Powers of inspectors and recognition of inspection conclusions are also discussed.

Requirements to comply with EMA’s policy on the publication of clinical data are the topic of other two newly published guidelines. The first one (EMA/90915/2016 Version 1.2, published on April 12th, 2017) provides readers with the last updates on clinical reports submitted as part of other regulatory procedures, informed consent applications and duplicate marketing authorisations.

The guideline discusses also all procedural aspects related to the submission of clinical reports as well as issues related to their anonymisation (with inclusion of a template for the anonymisation report). The identification of commercially confidential information in clinical reports and the redaction of the relative documentation is covered in the last chapter of the guideline, which also provides a Justification table template to be used by the sponsors.  An expanded questions-and-answers (Q&A) document (EMA/14227/2017) is also available to assist the interested companies in the drafting of applications.

 

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