EU Regulatory Flexibility During COVID-19 Pandemic

EU Regulatory Affairs During COVID Pandemic

In these uncertain times it can be challenging to comply with regulatory requirements while maintaining supply demands, but there has been advice published by the authorities to help. This guidance has outlined regulatory flexibility that can be applied to help pharmaceutical companies cope with the consequences of the pandemic, while ensuring a high level of quality, safety and efficacy for medicinal products in the EU.

As current national and international safety measures and travel restrictions likely prevent on-site inspections, the European Commission, the European Medicines Agency (EMA), and national competent authorities have put forth a series of mitigation measures in relation to regulatory inspections to ensure continued availability of medicines with compliance to good manufacturing (GMP) and good distribution practice (GDP) by enabling remote assessments of compliance during the COVID-19 pandemic. The validity of GMP/GDP certificates and Manufacturing and Wholesale Authorisations will also be extended until the end of 2021 and if needed, inspections will be carried out remotely to support extensions, with on-site inspections carried out as soon as is feasible. 1

While not currently permitted across all member states, remote batch certification could be considered under EU GMP rules, provided that the QP has access to all information necessary to enable them to certify the batch.4

The MHRA specifically, have issued guidance to the Qualified Person (QP) and Responsible Person (RP) at this time in relation to GMP and GDP activities. 2,3

Annex 16 has always provided the process for allowing ‘unexpected deviations’ in testing and manufacturing methods and it has been advised that there is scope for QPs to apply the same principles to minor deviations in the finished product specifications where in the professional judgement of the QP, safety and efficacy is not impacted.

This Annex also refers to the ability of QPs to rely upon information on third parties, such as audits, to confirm GMP at sites involved in the manufacture of the product. In the current exceptional circumstances, some flexibility could be applied by QPs in the need for having to repeat all quality control tests on importation from a third country manufacturer. While re-testing on importation should continue whenever possible, if the QP concludes that completion of certain re-testing prior to batch certification of imported products will itself lead to delays and supply chain shortage, flexibility could involve:

  • not carrying out product re-testing on importation if the batch has been fully tested in a PIC/S country
  • performing identity and assay only for products if manufactured in a non-PIC/S territory, if tested by the third country manufacturer.

Where this flexibility is used to omit import analysis, a risk-based, retrospective, alternative-lot approach for full re-testing of imported batches may be undertaken to inform the QP of ongoing quality. For biological products, specialist analysis (e.g. vaccine inactivation tests) should be performed at the point of importation.

When applying the deviations described in relation to re-testing on import, this decision should be recorded as normal in the pharmaceutical quality system.  

Remote audits may also be used to provide confidence that the active substance is fit-for-purpose and may be used to generate QP Declaration for Active Substances. It should be demonstrated that the API will not negatively affect the safety and efficacy of the medicinal product and the QP is expected to justify the controls in place on a scientific basis, recorded in a risk assessment on a product specific basis.4

Under UK guidance, temporary regulatory flexibilities may also be applied to GDP regulations under the current exceptional circumstances, supported by risk assessment and mitigating measures, where necessary.3

Non-temperature-controlled transport may be used when the ambient temperature is less than 20°C and ‘do not refrigerate’ products should be clearly labelled and shipped appropriately when the ambient temperature is less than 8°C. Products may be held for up to 96 hours at a transit hub without a wholesale distribution authorisation (WDA) to facilitate transportation and alternative arrangements may be used to show proof of delivery.

Furthermore, the Responsible Person may act as RP for another company within the same group of companies without variation, provided they have an RP registration number issued by MHRA.

Small changes in various elements of the quality system will be permitted to provide more RP resource and enable focus on supply, again supported by risk assessment as appropriate;

  • periodic supplier and customer requalification may be deferred
  • storage and distribution equipment may be used with limited qualification and validation to allow equipment to be used as soon as possible
  • investigation of ‘minor’ deviations may be put on hold and tracked so that investigations may be raised for identified trends
  • actions to deficiencies classified as ‘Other’ in regulatory inspections may be paused, recorded in the quality system, and corrected after the pandemic
  • SOP reviews, internal audits and GDP refresher training may be put on hold
  • electronic alternatives to wet signatures may be permitted

In these unprecedented times it is refreshing to see some flexibility permitted by the authorities to help companies continue to meet patient needs across the EU. If you would like further information on the impact this may have on your operations, please contact us below.

The information presented within this blog is for illustration purposes only and is not to be considered as professional advice.Any information related to health contained within this article is not a substitute for appropriate medical advice from licensed healthcare professionals.


  1., EU Updates Inspections and Drug-Shortage Systems for COVID-19, April 23, 2020
  2. Exceptional GMP flexibilities for medicines imported from third countries during the coronavirus (COVID-19) outbreak, 31 March 2020
  3., Exceptional good distribution practice (GDP) flexibilities for medicines during the coronavirus (COVID-19) outbreak, 1 April 2020

EU-GMP Guideline of Annex 21 ‘Importation of Medicinal Products’

On 20th March 2020 the EU-GMP Guideline of Annex 21 ‘Importation of Medicinal Products’ was published as a draft.  In addition to the guidance outlined in the main chapters and annexes, it was a thought that there was a need to publish a specific guideline on importation of medicinal products under a dedicated annex of the GMP guideline.

The annex outlines the principles and guidelines applicable to a manufacturing import authorisation (MIA) holder which imports medicinal products (human and veterinary) through the EU/EEA borders

In the guideline, importation refers to the action of physically bringing medicinal product from outside the EEA/EU and implies the requirement for physical importation and customs clearance before certification by the Qualified Person (QP).

When the draft concept paper for Annex 21 was originally published back in May 2015, it was anticipated that the implementation would bring standardised rules for import with an impact on supply chains as well as tax and legal implications. It was thought that the physical and financial flows of product would have to match and that “importation” from a regulatory point of view would be defined as the point in time when the title of goods changed from a non-EEA/EU company to an EEA/EU company.

This draft annex aims to clarify the application of GMP principles in the importation of Medicinal Products and the sites which are considered to have specific responsibilities and required to have a Manufacturing Import Authorisation (MIA) are the:

  • Site(s) of physical importation
  • Site(s) of QP certification of imported products

This draft does not cover unlicensed products nor products which are imported and directly re-exported and the issue of fiscal importation is no longer addressed in this draft. 

This new annex lays out specific requirements for these sites including a documented pharmaceutical quality system, product quality reviews, appropriate premises and equipment, documentation and operational expectations and appropriate systems for handling complaints, quality defects and product recalls. Contractual agreements must also exist between all companies or persons involved in the import activity.

The annex also lays out and clarifies the responsibilities of the QP in conjunction with that already specified in Annex 16. It reinforces the need for maintaining QP oversight of activities performed in the third county; ensuring EU GMP equivalence and MA compliance for manufacturers and exporters through audits and review of documentation. Import testing continues to be a requirement within the EEA/EU unless a Mutual Recognition Agreement or equivalent exists.

The draft will be subject to consultation between March 2020 and June 2020 with a deadline for it coming into operation still to be determined.

Questions you may need to think about

  • What needs to be considered by Marketing Authorisation Holders and MIA Holders?
  • What key considerations should the QP be thinking about?

If you would like to discuss the potential implications for your supply chain, Orphan Drug Consulting would be happy to help. Please contact us below.   

The information presented within this blog is for illustration purposes only and is not to be considered as professional advice.Any information related to health contained within this article is not a substitute for appropriate medical advice from licensed healthcare professionals.


The Impact of Coronavirus (SARS-CoV-2) and COVID-19 on Global Pharmaceutical Supply Chains with Focus on the Indian and Chinese Markets

On 31st of December 2019, a cluster of pneumonia cases with unknown aetiology were reported in Wuhan, China. At the time, healthcare professionals could not identify the causative agent for these seemingly related incidents but on the 7th of January the Chinese authorities confirmed a novel coronavirus (nCoV) was responsible for the disease. This virus is now known as SARS-CoV-2, and the resulting disease presenting in patients infected with this coronavirus is known as COVID-19.

SARS-CoV-2 has gone on to infect more than 200,000 people in 170 countries worldwide, causing over 8,000 deaths, and COVID-19 was officially declared a pandemic by the World Health Organization (WHO) on the 11th of March 2020. In response to the growing infection rates of this virus, we have seen unprecedented measures being brought into countries such as Italy and China where mass quarantine conditions have been introduced to curb the spread of infection. It is too early to quantify the full impact of COVID-19 on the global economy, however recent analysis by McKinsey & Company has predicted three potential scenarios: “quick recovery”, “global slowdown” and “pandemic and recession”. In each scenario, a range of factors are considered such as controlling the spread of COVID-19, individual governmental responses and the transmissibility of the virus over time. The most pessimistic scenario of the three, (“pandemic and recession”) predicts global growth in 2020 falling to between –1.5% and 0.5% with a resulting recession.

Indian and Chinese Pharmaceutical Supply Chains

The distribution of pharmaceuticals is a complex process with materials often being transported to multiple different countries before ever reaching patients. Players involved in this process can include active pharmaceutical ingredient (API) manufacturers, contract manufacturing organizations (CMO’s), primary packagers, secondary packagers, wholesale distributors and patient-facing organizations such as hospitals and pharmacies. While many of the larger pharmaceutical companies may have a large proportion of production in-house, smaller companies may be entirely outsourced for their production needs. This supply chain is also guided by stringent procedures to prevent occurrences like the introduction of falsified medicines and batch failure resulting from uncontrolled environmental conditions, making it even more challenging to navigate.   

Many biopharmaceuticals may be manufactured in USA and Europe but when it comes to generic pharmaceuticals there are two main players in the pharmaceutical manufacturing industry that account for a significant portion of global medicine production – China and India. At present, approximately 20% of the world’s API’s are produced in China which makes it the global leader with an annual production capacity exceeding 2 million tons. India is currently the largest worldwide supplier of generic medicines which account for 20% of global exports in terms of volume, supplying over 50% of worldwide demand for various vaccines, 40% of generic demand in the US and 25% of all medicine in UK.

What is important to consider is that while both countries have not seen the same effects of COVID-19, they are linked through their supply chains so one can impact the other. Currently India has less than 160 confirmed cases of COVID-19, while China has been the worst hit country globally with over 80,000 cases which has led to mass quarantines and restriction of movement of millions of people. The issue with supply comes from the fact that India imports approximately 70% of API’s required for production of medicines from China. The 14-day quarantine period associated with COVID-19 and closure of factories in China poses a risk to this supply chain. In general, Indian pharmaceutical companies keep 2-3 months of safety stock regardless, as a contingency to potential supply issues from China. However, recent restrictions imposed by the Indian government on the export of pharmaceuticals poses a potential risk to global supply chains. Even with pharmaceutical companies in India lobbying to have these restrictions lifted, at present there is a list of 26 different API’s including multiple antibiotics, hormones and vitamins that the government has temporarily restricted export of so that their domestic needs can be accounted for first. The date at which this restriction will be lifted is currently unknown which has led to uncertainty in global markets.

The European Medicines Agency’s Response to Potential Disruptions in Supply Chain

The European Medicines Agency (EMA) has implemented several plans and procedures to support the industry in the fight against COVID-19:

  1. 4th February 2020: the EMA activated its Health Threats Plan in order to coordinate efforts for the fast-track of potential vaccines and treatments for COVID-19.
  2. 10th March 2020: the European regulatory network of national competent authorities began formally assessing the impact COVID-19 could have on pharmaceutical supply chains.
  3. 11th March 2020: to reduce potential spread of infection the EMA begins holding virtual committee and working party meetings in place of face-to-face.
  4.  12th March 2020: fees associated with scientific advice are waived for companies working in treatments and vaccines for COVID-19.

While this is a volatile and unprecedented situation, it is important to note that as of 10th March 2020 there are no reported supply chain disruptions or medication shortages in Europe linked to the spread of COVID-19. As part of the EMA’s efforts to maintain supply chains, an executive steering group is set to identify and coordinate EU-level measures in response to this pandemic. This group is made up of representatives from multiple agencies/departments including the European Commission, the EMA, national medicines agencies, the CMDh (Coordination Group for Mutual Recognition and Decentralised Procedures – Human) and the CMDv (Coordination Group for Mutual Recognition and Decentralised Procedures – Veterinary). Organisations are now being asked to perform risk assessments on their supply chains to identify potential weak spots before they become an issue. The EMA itself is also reviewing manufacturing information on centrally authorised medicines to proactively identify supply risks. In order to maintain a clear and consistent method of communication, the single point of contact network is to be utilised during this outbreak. This network began piloting in April 2019 as a means to improve information sharing between EU member states, the EMA and the European Commission on the supply of medicines.

Business Continuity

Many companies will have business continuity programmes in place already as part of an overall company risk and resiliency programme. These programmes help facilitate the management of and recovery from crises or disruptions such as we are currently experiencing and are there to ensure that essential functions and operations can continue. Larger companies in our industry will often benefit from having a mature suite of standard operating procedures and significant cross training of staff. Smaller companies may often be highly dependent upon key individuals which can present risk.

Orphan Drug Consulting, through its Supply Chain team, are keeping abreast of the current situation and advising its clients accordingly. Having established supply chain strategies for multiple clients, risk mitigation through implementing second source strategies, strategic safety stock programmes and alternate shipping route qualification, such programmes are now demonstrating their value.

Orphan Drug Consulting remains committed to doing all it can to mitigate supply issues for its clients and we encourage any company who would benefit from our guidance to reach out to us and avail of free advice during this challenging period.

The information presented within this blog is for illustration purposes only and is not to be considered as professional advice. Any information related to health contained within this article is not a substitute for appropriate medical advice from licensed healthcare professionals.


Rare Diseases Day 2020: The Importance of Orphan Drugs in Combating Rare Diseases

Rare Diseases Day

An Overview of Rare Diseases:

On February 29th, 2020 the world will observe Rare Diseases Day coordinated by the European Organisation for Rare Diseases (EURODIS). Now in its 13th year, this special day aims to spread awareness of rare diseases and the patients whose lives are impacted by them. But what exactly is a rare disease and what role do orphan drugs play in treating them?

What is a Rare Disease?

The exact definition of a rare disease can vary per region, however in Europe it is defined as being a condition which affects less than 5 in 100,000 people. To put this into perspective, these conditions can affect 30 million European Union (EU) citizens. There are over 6,000 different diseases/disorders that are classified as being rare and the number of people affected by each condition can vary hugely with some diseases affecting less than 1 in 1,000,000 people. Some of the main characteristics of a rare disease are as follows:

  • Often chronic, progressive, degenerative and life-threatening
  • No existing cure
  • High number affecting children (75%)
  • 4 out of 5 rare diseases have a genetic origin

Patients and their families face many challenges due to the rarity of their conditions. Because of the small populations being affected by these diseases, there can be little scientific information available and limited, if any, options for treatment. This makes both diagnosis and medical intervention difficult, with the standard course of action often being to treat the symptoms of the disease rather than the cause of the condition itself as curative or disease-modifying options are not always available. 

What are Orphan Drugs?

Simply put, an orphan drug is a classification given to therapies that aim to treat rare diseases. The exact definition of an orphan drug in regulatory terms can vary slightly, however in order to receive this designation the European Medicines Agency (EMA) has criteria that must be met:

  • it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
  • the prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
  • no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

Once a medication has been granted an orphan drug designation, there are several ways in which the EMA can help companies to launch their medicine. These include providing clinical protocol assistance, access to the centralised authorisation procedure, extended market exclusivity and licensing/submission fee reductions. While the EMA itself does not offer research grants to orphan drug sponsors, there are alternative sources available such as Horizon 2020 and E-Rare. 

These incentives and programs, along with ongoing research and development, have helped contribute to an increase in the number of orphan drugs reaching the market, with 20% of recommended approvals by the EMA from 2015-2019 being orphan drug products, compared to 12% from 2010-2014. With this increasing trend, coupled with ongoing scientific research, we hope to see more rare diseases being treated in the future.   

Orphan Drug Consulting remains committed to assisting innovative orphan drug companies in getting their medicines access to as many markets and patients as possible.


The information presented within this blog is for illustration purposes only and is not to be considered as professional advice.

Advanced Therapy Medicinal Products (ATMPs)

With the rise of new therapeutic modalities, regulators have had to adapt to the changing environment with one of these adaptions being the introduction of Advanced Therapy Medicinal Products (ATMPs). ATMPs are those medicines for human use based on genes, tissues or cells and offer ground-breaking opportunities for disease and injury treatment. Cell and gene therapies are relatively new additions to the techniques employed by health professionals to fight specific diseases and conditions. A form of immune deficiency called adenosine deaminase (ADA) deficiency was the first condition to be treated in a trial with a gene therapy approach in the early 1990s. More recently, the European Medicines Agency (EMA) approved a gene therapy treatment for this same condition in 2016 named Strimvelis™, highlighting the importance and urgent need for these unique medications

These specialised products have introduced a host of new terms into the modern pharmaceutical era that previously were not considered. The below gives a quick summary of some of these “buzz words” that frequently appear when discussing ATMPs.

DNA: a large molecule made up of nucleotides that contain the “code” for living organisms within each cell.

Genes: snippets of DNA that code for specific proteins required for human life to function.

Chromosomes: strands of genes wrapped together around support structures known as histones.

Vector: used to insert a new gene, the ‘transgene ‘into a cell and is usually a modified non-disease-causing virus. The process of using a vector to insert a transgene into a cell is called transduction.

Stem cells: naturally occurring cells in the body that can divide and produce a range of different cell types important in the growth and development and repair of the body. These cells become ATMPs when they are manipulated as Somatic Cell Therapy medicines or Tissue Engineered medicines depending on how they work in the body.

In gene therapy, genes or genetic materials are introduced into target organisms i.e. they alter the genes in the body’s cells by either replacing a mutated gene that causes disease with a healthy copy of the gene, inactivating, or “knocking out,” a mutated gene that is functioning improperly or introducing a new gene into the body to help fight a disease. This is in contrast to stem cell therapy, where stem cells are transplanted into target tissues.

Companies may need to consult the European Medicines Agency (EMA) to determine whether a medicine they are developing is an ATMP. The procedure allows them to receive confirmation that a medicine, which is based on genes, cells or tissues, meets the scientific criteria for defining an ATMP.

The MHRA have also issued a useful guide titled “Flowchart for Determining the Regulatory Status of Tissue and Cell-Based Products (Version 5) which can help companies establish whether their new drug is an ATMP.

The complete Good Manufacturing Practice (GMP) guide for ATMPs is then outlined in Eudralex Volume 4, Part IV. These guidelines very much rely on a risk-based approach for manufacture of these products recognising a certain level of flexibility. One of the key messages from this guidance is “The quality, safety and efficacy attributes of the ATMPs and compliance with GMP should be ensured for all ATMPs, regardless of whether they are developed in a hospital, academic or industrial setting”.

Once it has been established that the product is an ATMP it’s then down the more familiar path for product approval and launch with supply chain oversight, MA compliance, batch certification and release all considered uniquely for these complex drugs and manufacturing processes which can all be supported by Orphan Drug Consulting.


The information presented within this article is for illustration purposes only and is not to be considered as professional advice.


Brexit Orphan Drug Consulting

The United Kingdom (UK) voted in a referendum on June 23rd, 2016 to leave the European Union (EU), by 52% to 48%, leaving the Single Market and the Customs Union. While the referendum was not legally binding, the UK government at the time promised to honour the result.  The UK has population of over 66 million. The makeup is, England (84.25%), Scotland (8.2%), Wales (4.7%), and Northern Ireland (2.8%). Interestingly, both Northern Ireland and Scotland voted in the referendum to remain in the EU.

This ‘Brexit’ (exit of the UK from the EU) was due to happen on 29 March 2019. That was two years after then Prime Minister Theresa May triggered Article 50, the formal EU process to leave. However, the Brexit date has been delayed twice. The UK (led by Theresa May) and the EU agreed a deal in November 2018, but Members of Parliament (MPs) voted to rejected it three times. Since then there has been an extension to the Brexit deadline out to the 31st October 2019.

The single market refers to the EU as one territory without any internal borders or other regulatory obstacles to the free movement of goods, services and people between all 28 EU member states (as well as Iceland, Norway, Liechtenstein and Switzerland, who are members of the European Economic Area). Countries in the single market apply many common rules and standards. The EU Single Market currently accounts for 500 million consumers and 21 million small and medium-sized enterprises. The single market is at the heart of the EU project.  Its aim is to stimulate competition and trade, improve efficiency, raise quality, and helps to cut prices.

The customs union ensures that all EU countries charge the same taxes on goods coming in from outside. They do not charge taxes on each other’s goods, but members cannot strike their own trade deals. This is a crucial point and part of the reason parliament voted not to accept the agreed deal.

The EU is the world’s largest trading block. Its GDP was estimated to be $18.8 trillion in 2018, representing about 22% of the global economy.  Together with the United States and China, the EU is one of the 3 largest global players in international trade. It has significant trade deals with other economies around the world having recently done trade deals with Japan and Canada. These trade deals can sometimes take years to negotiate.

The deal that was agreed between the UK and EU (the withdrawal agreement) but not approved by the UK parliament, covers the following critical areas (and many more):

  • Citizens’ rights, both of UK citizens in EU countries and vice-versa,
  • Border arrangements and customs, particularly along the border between the UK and the Republic of Ireland
  • The law, and the mechanisms for resolving disputes, currently vested with the European Court of Justice

The agreement also sets up a transitional period, which lasts until 31 December 2020 and can be extended once by mutual consent. During the transitional period, the UK would remain a member of the European Economic Area, the single market, and the customs union, EU laws would continue to apply to the UK, and the UK would continue to pay into the EU budget. However, the UK would not be represented in the decision-making bodies of the EU. The transition period would give businesses time to adjust to the new situation and time for the British and EU governments to negotiate a new trade deal between the EU and UK.

Without a parliamentary approved agreement or a further extension there would be a hard Brexit on 31st October 2019, i.e. a no-deal scenario and the UK would immediately leave the EU. Overnight, the UK would leave the single market and customs union. No deal also means immediately leaving EU institutions such as the European Court of Justice and Europol, its law enforcement body. Membership of dozens of EU bodies that govern rules on everything from medicines to trademarks would end. There would be no transition period and the UK would effectively become like a third country to the EU without any trade deal in place and it would mean that the UK service industry would lose its guaranteed access to the EU single market.

Continuity of supply of medicines to patients in both the UK and the rest of the EU has long been one of the major areas of concern in the context of Brexit. The European Medicines Agency (EMA), which has relocated from London to Amsterdam, has called on all biopharmaceutical companies across the EU to continue their preparedness for the UK’s withdrawal. It says it is well prepared for Brexit and has finalised authorisations for nearly all the 400 drugs under its watch that required further clearing because of Britain’s impending departure.Over 37 million patient packs are supplied from the EU-27/EEA to the UK each month.

In the UK, the Department of Health and Social Care (DHSC) has determined that around three-quarters of the medicines and over half of the clinical consumables used in the UK come from or via the EU.  Following an analysis, DHSC has put in place processes to minimise any supply disruption, through a combination of securing freight and warehousing space, building up safety stocks and providing regulatory flexibility. The impact on medical supplies will also be felt beyond the UK. About 45 million packs of medicines are shipped from the UK to the rest of the EU27 every month, in trade worth nearly 12 billion GBP in 2016.

Many biopharmaceutical companies have been building up safety stocks of raw materials and finished goods where possible (and shelf life permitting) as a contingency. Investing in trusted trader accreditations e.g. Authorised Economic Operator (AEO) has also been a wise move for companies who have achieved this. If queues of trucks build up at Dover or Calais for example, prioritisation will be given to companies who have a trusted trader status.

The other key areas that will be impacted by Brexit for biopharmaceutical manufacturers and marketing authorisation holders are:

  • GMP certification
  • Qualified Person (QP) release
  • Clinical trials
  • Product coming from the UK (including Active Pharmaceutical Ingredients)
  • Release testing
  • Sample storage

In the event of a hard Brexit there may be other areas or issues that become problematic for all the actors in the biopharmaceutical supply chain and it is these unknowns that are of most concern.

Understanding and aligning your supply across the differing legal, tax, customs, finance, regulatory and compliance framework to ensure successful supply can be challenging.  Orphan Drug consulting is here to navigate these legislative frameworks on your behalf and ensure that your patients receive seamless product first time and every time across the world.


The information presented within this article is for illustration purposes only and is not to be considered as professional advice.