BIA Archives - European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11


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

What happens after IP loss of protection


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

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


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

Current inspection trends and new approaches to the monitoring of post-inspection activities

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by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years,  a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.


A record year for biotech investments in UK, a year after the Brexit

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by Giuliana Miglierini

One year after the Brexit, the UK’s economic landscape is far from being suffering for leaving the European Union. On the contrary, 2021 has been a record year for many sectors, including UK’s biotech and life sciences. A recent report from the BioIndustry Association (BIA) and Clarivate shows that £4.5 billion was raised in public and private financings in the field, £1.7 bln (60%) more than in 2020.

There is an obvious gap that we must plug in the UK’s financing environment. The large fundraises seen in 2021 are largely the result of welcome overseas investment, meaning that significant value creation will also be offshored. History has handed the UK two world-leading sectors: life sciences and finance. A symbiosis should exist between these two, but it doesn’t, yet. There is great opportunity to turbo-charge the UK’s biotech and life sciences sector and capture more of its economic value for the UK by building better connections between the UK’s financial institutions and our innovative scaling businesses”, said Steve Bates OBE, Chief Executive of the BIA.

A higher attractiveness than the US

More in detail, UK companies attracted more than half of all biotech venture capital in 2021, for a total value in the period 1 December 2020 – 30 November 2021 of £2,518 million (+81%from 2020; 56% of total investments). Even higher has been the increase of Initial Public Offerings (IPOs), for a total of £1,304 million (+434% from 2020; 29% of total); all other public financings raised £684 million (15% of total). Thirteen investment deals were more than £100meach (vs 3 in 2020), and a further 27 raised more than £20 million each (vs 12 in 2020).

The positive trends of investments marked in 2021 are not unique to the UK; the level of venture capital investments raised 10% in the last year compared to 2020, reaching the global value of £28.1 billion for the biotech sector. The attractiveness of the UK reached 79%, compared to 49% for the US’s Boston Massachusetts cluster, while the San Francisco one marked -21%; total investments in the US reached £18.8 billion (+11%). Negative trends characterised Europe (-12%venture investments, for a total of £5 billion) and China (-12%, £3.4 bln).

We value the significant investment that comes from overseas, but we must complement it with the full financial firepower of the City of London so that more companies stay in the UK. This is why our ambitious 2021 Life Sciences Vision sets out our firm commitment to helping UK life sciences and biotech firms access long-term scale-up capital from investors here at home, who are committed to building successful companies. Scaling up UK companies will help both grow our economy and improve access to innovative diagnostics and treatments.”, added George Freeman MP, Minister for Science, Research and Innovation.

Venture capitals looking for new opportunities

The UK has been a key point of innovation during the pandemic, generating many new vaccines and treatment opportunities. The interest of investors in UK’s science is acknowledged by the£128 million invested into startup companies, more than four times the amount seen in previous years. A trend that paralleled later-stage rounds of financings into mature projects.

The bigger deal (£195 mln fundraise prior to the London IPO) involved Oxford Nanopore, a company specialised in the development of innovative sensing techniques based on the use of nanopores embedded in high-tech electronics. These can be used to sequence small or large fragments of DNA and RNA, for example; the platform may be also adapted for the detection of other types of molecules, e.g. proteins.

At the second place is the Exscientia’s deal (£158 mln, round D). The company offers AI-driven drug discovery services aimed to deeply innovate how new medicines are developed. Its AI platform is being used to completely design from scratch new molecules; algorithms are used also to optimise properties in parallel, rather than sequentially, and to reduce the overall development time thanks to the higher capacity of analysis of complex data.

Vaccitech attracted the third deal (£118 mln, round B); the company is the spin-off of the Oxford University specifically created to commercialise the technology platform behind the Oxford/AstraZeneca Covid-19 vaccine.

IPOs reached record values

Oxford Nanopore and Exscentia also represent the higher values for IPOs operated by UK biotech companies in 2021. The former deal worth £350 million, representing the largest amount raised in a listing on the London Stock Exchange by a biotech company. Exscentia attracted a £256mln value at Nasdaq; the total amount raised by UK biotech through IPOs in 2021 reached £1.3billion (42.8% of all the money raised by UK biotechs at IPO in the past decade, a huge amount if compared to the £244 million raised in 2020).

Three companies were listed at the London’s Alternative Investment Market (AIM): Poolberg Pharma (£25 mln) is a clinical stage infectious diseases pharmaceutical company, aiming to become a “one-stop shop” to find Phase II ready products for development and commercialisation. Arecor Therapeutics (£20 mln) has developed a proprietary platform for the reformulation of already available medicines, while BiVictriX Therapeutics (£7,5 mln) is developing new targeted cancer therapies.

When looking at the international scenario, 133 companies raised £19 billion in IPOs in 2021 at the global level (+30% vs 2020). In the US, 86 companies raised £9.7 billion; the most attractive biotech clusters were again Boston Massachusetts and San Francisco. The number of IPOs in Europein creased to 29 (vs 12 in 2020), for a total of £3.3 billion raised (+218% vs 2020); to this instance, according to BIA’s report the UK accounted for 31% of the European IPOs and 40% of the capital raised. No significant changes involved listed companies in China (14), but on this market the average IPO was three-times larger than that achieved by the average American or European listing.

Follow-on financing of quoted biotech companies almost halved in 2021 compared to the previous, record year (£684 million vs £1.18 billion raised, respectively).

A main contribution came from Blackstone’s investement in Autolus at the Nasdaq (£183 million) to support the development of the company’s CAR-T cell therapy currently in Phase III stage of development. A strategic investment of £50 million in Oxford Biomedica, received from the Serum Institute of India, will support the expansion of the advanced therapy manufacturing facilities near Oxford.

Mergers & Acquisitions and Licensing deals

Jazz Pharmaceuticals acquired in 2021 GW Pharma, a company specialised in the development and commercialisation of cannabinoid-based epilepsy treatments. The biotech Kymab, thoseplatform is used for the development of fully-human monoclonal antibodies, was acquired by Sanofi in a deal involving £1,073 million upfront payment and up to $350 million in milestone payments.

The licensing deal signed between AstraZeneca and VaxEquity would allow the multinational company to use the University College London spin-out’s saRNA platform for the development of up to 26 drug targets.

Early-stage biotech companies are often supported by research grants; to this instance UK’s biotech received in 2021 over £50m in non-dilutive grant funding.


A golden era for UK’s life sciences and a new Code of practice for its pharmaceutical industry

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by Giuliana Miglierini

Less than a year has gone since the Brexit, and the UK innovation landscape is experiencing a new, vivid era of expansion under the stimulus of a strong demand from global investors. According to recent data of the BioIndustry Association (BIA) and Clarivate, the second quarter of 2021 (March – May) saw £1.56 billion investments, a record value for a quarter since the trade association began recording this data.

A record year for investments
The first semester has registered a total of £2.39 bln investments, almost the same amount raised in the entire 2020 (£2.81 bln). “The scale of these financings suggests 2021 will be another record year of investment into UK biotech companies. We continue to see deals being driven predominantly by investors from outside of the UK. Our hope is that the Government’s impending Life Science Sector Vision will be a platform for the UK’s financial institutions to add further fuel to take this sector into a golden age.”, said Dr Martin Turner, Head of Policy and Public Affairs at the BIA.
More in detail, UK biotech and life science companies raised £1,07 billion in venture capital; thirteen deals overcame £20 million, and four of them even £100 mln. The 60% of the total biotech venture capital invested in Europe is represented by UK companies; furthermore, £431 million was raised through three NASDAQ IPOs and £58 mln in follow-on public financings. “These figures show that our life sciences sector is booming, demonstrating the confidence that global investors have in the UK. The extraordinary innovation underway in the sector will not only increase our resilience against future healthcare challenges, but will boost the economy, create highly skilled jobs across the country, and enhance our status as a science superpower”, said Life Sciences Minister Nadhim Zahawi.
Biotech shares on the London Stock Exchange also continued to out-perform the wider market in the first half of 2021, according to the report prepared by Radnor Capital Partners on behalf of the BIA.

A new Vision of the life sciences sector
The UK government published it’s new Life Science Vision on 7 July, a 10-year strategy for the sector which builds on the success of the previous 2017 Life Sciences Industrial Strategy.
The same approach used to fight the Covid-19 pandemic will be used as a blueprint to tackle some persisting health issues such as dementia and cancer, for a total of seven critical missions. The others include early diagnosis and treatments, comprehensive of immune therapies and cancer vaccines, vaccine discovery, treatment and prevention of cardiovascular diseases and its major risk factors (i.e. obesity), reducing mortality and morbidity from respiratory disease, addressing the underlying biology of ageing, increasing the understanding of mental health conditions and redefining tools to fight them.
The new strategy also includes planned investments for a total of £1 billion, to be dispensed under the Life Sciences Investment Programme (LSIP). The programme is expected to boost further private sector investment, and the creation of a world leading UK life sciences venture capital ecosystem. The investments will be delivered through British Patient Capital (BPC), part of the government-owned British Business Bank, which will allocate the £200 million to specialist funds. Some other £800 mln will result from the collaboration between BPC and Abu Dhabi’s Mubadala Investment Company, one of the world’s leading sovereign investors. The LSIP will have access to a scientific advisory panel composed of leading industry figures, chaired by Professor Sir John Bell and in charged to share insight on key scientific trends.
“We are indebted to the ingenuity of UK life sciences and its pioneers, with the discovery of the Oxford-AstraZeneca vaccine and the seamless collaboration between our scientists, industry, regulators and NHS saving millions of lives during the pandemic. We must make sure this is the norm and use this new way of working to search for life-changing breakthroughs against diseases such as cancer, dementia and obesity, as we have done with Covid”, said Prime Minister Boris Johnson.
“Crucially, we’re going to build a pro-enterprise environment where our life sciences firms can access the finance to grow, are incentivised to onshore manufacturing, and can commercialise breakthrough products right here in the UK – rather than elsewhere – as we cement the UK’s position as a science superpower”, added Business Secretary Kwasi Kwarteng.
Central to the new Vision is the emulation of the approach used by the UK Vaccines Taskforce to fully exploit the private sector expertise while removing unnecessary bureaucracy. New regulatory freedoms and opportunities are expected for the UK life science business sector as a result of the country’s new position outside the EU. The UK’s regulatory agency MHRA is expected to act as an independent, sovereign regulator with great agility and with a focus on getting vaccines, drugs, and technologies to patients as safely and quickly as possible.
“The BIA’s focus will be to increase the expert pool of UK based capital needed for innovative UK life science firms to grow to scale. This will enable UK investors and pension savers, to secure the economic benefit from this burgeoning golden age for UK life sciences while at the same time enabling NHS patients to secure the health benefit of global biotech innovation”, said BIA’s Chief Executive and former member of the Vaccine Taskforce Steve Bates.

A new Code of Practice for the pharmaceutical industry
The renewal of the UK’s landscape in life sciences also pass through the new Code of Practice for the Pharmaceutical Industry, which has become operative since 1st July 2021 without transition period, with the exception of companies wishing to continue with ongoing Medical and Educational Goods and Services where the transition period will close on 31 December 2021.
The Code published by the Association of British Pharmaceutical Industry (ABPI) is operated under the supervision of the Prescription Medicines Code of Practice Authority (PMCPA), established by ABPI in 1993 as an independent organism. The previous version of the code was released in 2019.
The Code provides indication on the acceptable practices for the promotion of prescription medicines to both health professionals and other relevant decision makers. Requirements for interactions with health professionals and standards for the provision of information about prescription medicines to the public and patients (including patient organisations) are also included.
There are four principles inspiring the document, first among which the benefit and safety of patients. Integrity and commitment towards responsible, professional, ethics and transparent relationships, transparency and respect will guide the future activities of the UK pharmaceutical industry in the promotion of medicines.
Even if the Code refers only to activities carried out by the industry, its indications should also inspire individuals and organisations in their interactions with the pharmaceutical environment.
Training of personnel and robust operating procedures to review all materials and validate their compliance to the rules highlighted by the Code and other legal requirements are other principles inspiring the document. The Code incorporates some other references important in the field of the promotion of pharmaceutical products, among which those contained in the Codes of Practice of the International Federation of Pharmaceutical Manufacturers and Associations’ (IFPMA), the European Federation of Pharmaceutical Industries and Associations’ (EFPIA), the WHO’s Ethical Criteria for Medicinal Drug Promotion, the EU’s Directive 2001/83/EC and 2004/27/EC on human medicinal products, and the Human Medicines Regulations 2012 No. 1916.