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Regulatory Focus™ > News Articles > 2020 > 5 > Drug shortages in Germany ‒ A critical appraisal

Drug shortages in Germany ‒ A critical appraisal

Posted 28 May 2020 | By Ralf D. Hess, MSc, PhDHenric WassmerSiegfried Schmitt, PhDMartin Hug, PhDAnmar Marouf, PhDDominik M. Aumer, MBAMoritz Haucke, MBASimon Schulz, MSc, PhD 

Drug shortages in Germany ‒ A critical appraisal

The article discusses drug shortages in Germany the root causes of production problems with active pharmaceutical ingredients and drug product manufacturers. The authors offer analysis from a medium-sized generic drug manufacturer’s perspective. They offer a variety of reasons, all of which point to a “broken marketplace.” The article concludes with a discussion of mitigation activities and in an epilog address the current COVID-19 pandemic, warning that drugs and active ingredients from China and India may be in short supply because of the disruption caused by the pandemic.
 
Introduction
 
All pharmaceutical manufacturers aim to meet market demand in a timely manner while maintaining the highest possible standards of quality. Nevertheless, drug shortages occur to varying degrees in most countries, although the root causes can vary substantially. It makes a great difference for patients whether a shortage of their medication is temporary and limited, with alternative medicines available, or whether there is no available substitution for the duration of the shortage last.1 Figure 1 shows the complexity of the supply chain by showing the various stakeholders/economic operators involved in drug supply and how they interact.
 
Figure 1. Drug supply chain Stakeholders and economic operatorsHess_Figure1_png.png

API, Active Pharmaceutical Ingredient, DS, Drug Substance, CDMO, Contract Developing Manufacturing organization, DP, Drug Product, MAH, Marketing Authorization Holder

Drug shortages in Germany
 
As of 6 January 2020, the German Federal Institute for Drugs and Medical Devices (BfArM) listed 280 human pharmaceuticals (not including vaccines) for which there were transient supply shortages. By comparison, there were only 176 such shortages reported in the whole of 2019.2 By 28 April 2020, 444 pharmaceuticals had already been listed.
 
The list of medications in short supply includes, but is not limited to, therapies for hypertension, pain killers, lipid-lowering drugs, antibiotics, chemotherapeutics, H2-receptor antagonists, antidepressants, and medications for asthma. These drug shortages mean there is an urgent need for prescription medications for patients who depend on a smoothly operating supply chain.
 
The shortages also impact the drug stockpile for manufacturers, wholesalers and hospitals. To a large extent, pharmacies and hospitals are supplied by drug manufacturers through purchasing associations and wholesale distributors. Having sufficient stocks of drugs to meet market demand is a regulatory requirement in Germany for drug wholesalers and marketing authorization holders, according to the Medicinal Products Act, Section 52b, Supply of Medicinal Products3 and for pharmacies, according to the pharmacist work ordinance.4
 
Production problems
 
Table 1 below provides an example of 11 selected drugs in short supply because of production problems for the active pharmaceutical ingredients as the root cause. The list was compiled by the supervisory higher authority in Germany, the BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte).5 There are no alternative medicines available for 6 of the 11 medicines listed, for example, for specific H2-receptor antagonists (Table 1/ No. 4) and medicines for hypertension (Table 1/No. 6) next to other medicines (Table 1/No. 7, 9, 10, 11).
 
Table 1. Examples of drug shortages registered BfArM, and the corresponding list of APIs6
 Hess_Table-1.png

Where are the active pharmaceutical ingredients?
 
To produce a finished drug product, some medicinal product manufacturers use APIs that are not manufactured in-house but at another manufacturing facility or by a contract development and manufacturing organization (CDMO). It is not mandated to obtain a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP)7 or an active substance master file (ASMF)8 for APIs, but these two commonly used regulatory formats/certification for APIs invaluably facilitate API trading.
 
Many, but not all, medicinal products or generic medicinal product manufacturers, source APIs or drug substances, come from a variety of API manufacturers. From our generic drug manufacturing perspective, resourcing CEP-certified APIs, or ASMF-APIs, is a valid, cost-efficient and suitable approach for resourcing quality-controlled, CEP-certified APIs, or ASMF-APIs needed for producing drug products.
 
Supervisory authority surveillance
 
As part of the CEP application, manufacturers involved in the production of active substances and their intermediates are requested to declare they have complied with EU GMP Part II and are willing to be inspected. Based on these declarations and a risk-based approach, the EDQM may or may not inspect the sites. If they do carry out an inspection, it takes place either before or after the CEP is issued.9
 
The EDQM (The European Directorate for the Quality of Medicines & HealthCare), a Council of Europe organization, is the European Supervisory Authority responsible for checking compliance with both good manufacturing practice (GMP) and the CEP application and any updates at the manufacturing/distribution sites covered by CEPs. The EDQM inspection program is an integral part of the CEP certification procedure and is detailed in the context of the mandate given to the EDQM by the European Commission in the application of Directives 2001/83/EC and 2001/82/EC as amended.
 
In addition, a drug manufacturer must be authorized by national competent authorities (NCA) for drug production according to Directive 2001/83/EC, Article 6.10 Once the GMP certificate has been granted, surveillance inspections by NCAs are performed regularly to verify sustained compliance to applicable European GMP (good manufacturing practice) regulations. These are stipulated in Directive 2001/83/EC, Article 46 b, which says “the manufacturing plant concerned is subject to regular, strict and transparent controls and to the effective enforcement of good manufacturing practice, including repeated and unannounced inspections, to ensure protection of public health at least equivalent to that in the Union.”11
 
CEP-API suspension, withdrawal
 
Tables 2 and 3 show that APIs certified by the EDQM in principle could have been resourced from various API manufacturers from different countries for the production of drug products (including those listed in Table 1/No. 4 and 6, with no alternative medicines available), while for ranitidine, there are 15 sites in India (Table 2) and for valsartan, 17 sites are located in India (Table 3). The ranitidine CEP-certified APIs are either suspended, expired, or withdrawn by the holder (Table 2).12, 13 The Valsartan CEP-certified APIs are either valid, suspended or withdrawn by the holder (Table 3). The list of drug shortages, as provided in Table 1, does not allow tracing back to the respective API manufacturers involved in the manufacture of the medicines affected. Thus, it remains speculative as to whether API suspension or withdrawal may contribute as a root cause for the drug shortage reported production problems. Nevertheless, Tables 2 and 3 illustrate that primarily, India and China represent a majority of CEP-certified API manufacturers, which indicates a dependency for some APIs used in drug products marketed in Germany and elsewhere.
 
Case study
 
We have a potential drug shortage because a European API manufacturer depends on an intermediate API manufacturer in Italy who is facing compliance issues. Despite the compliance issues, the national authority agreed it was necessary to deliver the drug with restricted indications and an explanatory “Dear Healthcare Professional Communication,” to avoid drug shortages for this medication, which is urgently needed in clinical hospitals14 (Eudra-GMP Database Report No.: IT/NCR/API//1/2018). There are only two drug product manufacturers in Germany providing the drug, and both manufacturers have been affected. This situation illustrates the complexity of the supply chain for generic drug manufacturers and demonstrates that, even for an urgently needed medication, there may be only two drug manufacturers in Germany who, unfortunately, get the same API from the same source. A key factor impacting the supply of medicines is the limited range of ingredients (key raw materials or APIs) that originate from ‒ or are manufactured in China, India or Europe.
 
Table 2. Ranitidine CEP holders15

 Hess_Table-2.png
 

Table 3. Valsartan CEP holders16

Hess_Table-3-PNG.png
Information of a commercially or personally confidential nature is not made public, search for “ Valsartan”, modified*: site name and site address and revisions to CEP omitted, SN: 2423, 19 x IN (2x2 same site), 6x CN, 1x S, 1x MX, 1x CH, 2x IL.
 
The complexity of supply chain disruption
 
Supply chain disruption can be complex, involving manufacturing capacity; GMP compliance issues; withdrawal of GMP certificates; suspension of manufacturing authorizations; suspension/ voiding of CEPs; prohibition of supply; recalls; and compliance with new regulations.
 
What are the contributing factors for these API shortages? A common reason for API shortages comes with a variety of problems that can be faced at facilities. These issues can range from a fire or  a lack of production capacity (as illustrated in Table 1), or they can be related good manufacturing practice (GMP) or other quality issues. The result of any of these may be that factory must temporarily suspend production (as illustrated in Table 4).17
 
Likely root causes of temporary drug shortages of medicines can also be attributed to non-GMP compliance of drug manufacturers and the resulting actions taken by NCAs resulting from GMP compliance surveillance inspections. These have led to withdrawal of GMP certificates (Table 4/No. 11, 13 -18, 21, 23, 25, 26, 31); suspension of the manufacturing authorization (Table 2/ No. 11-21); suspension or voiding of CEP (Table 4/ No. 1-10) for drug substances/APIs, or prohibition of supply (Table 4/ No. 2-5, 7, 10, 19, 20, 22, 23, 31,32); or even issues with secondary packaging (serialization) as seen in Table 4/ No. 5, 15/16, 24.
 
Table 4. EudraGMDP, non-GMP compliance reports, Jan. 2018-Dec. 201918

 Hess_Table-4-PNG.png
Intentional omission of the EudraGMDP document reference number (related to Table 4), site name and city (also Tables 2 and 3) and of revision numbers to CEP do not allow for the affected APIs to traced back to the manufacturer. However, there are strong indications that the revocation of CEPs by key suppliers of the same API can lead to drug shortages as illustrated by API CEP holder for ranitidine hydrochloride (Table 2) and valsartan (Table 3), and as reported in case study for EudraGMDP Database Report No.: IT/NCR/API//1/2018, falling into the observed period.
 
The information provided is based on publicly available information in the European EudraGMDP database in the selected period from January 2018 to December 2019, while API manufacturing countries involved in suspension or voiding of CEP are illustrated in Tables 2 and 3.
 
Table 5. Actions taken/proposed by NCAs as a result of non-GMP compliance inspection outcomes, Jan. 2018-Dec. 2019 (n = 32)19
Hess_Table-5_fina;.png
GMP non-compliance issues, which primarily concern sterile manufacture and cross-contamination, can also include non-compliance to new GMP requirements for secondary packaging, such as serialization/labeling/tamper seal device of products). Issues, such as found during NCA surveillance inspections and the respective actions taken by NCA, can contribute to drug shortages in Europe (including Germany) with European as well as Indian and Chinese manufacturing sites affected.
 
Price pressures, reimbursement and price caps
 
In addition to issues medicine manufacturers in API supplies, another important drug shortage can be “price pressuring.” The European Medicines Agency defines a generic medicine as one that is “developed to be the same as a medicine that has already been authorized ‒ the reference medicine.” A generic medicine contains the same active substances as the reference medicine and used at the same dose. When generic versions of a reference medicine are on the market, the market is referred to as “multi-source market,” in contrast to a situation where only one manufacturer is supplying a specific medicine.20
 
As the marketing authorization holder (MAH), the generic drug product manufacturer does not necessarily need to be the drug substance manufacturer. These regulations also allow involving CDMOs to produce either drug substances and/or finished drug products, as illustrated in Figure 1. Regardless, the finished drug product MAH takes full responsibility for the medicinal product placed on the market and the quality control of the active substance, but that responsibility is associated with additional costs.
 
Price finding of drug products in Germany
 
Fundamentally, a German drug or generics drug manufacturer serves two market segments, the hospital sector and the retail sector (i.e., wholesalers and pharmacies). The prices for prescription drugs are determined in a catalog that is “binding” for wholesalers and retail pharmacies,21 but hospital pharmacies may freely negotiate prices.
 
Tendering of drug products
 
Once a medicine has entered the public domain, its original manufacturer loses market exclusivity and becomes part of a multi-source market. The tendering process is used when payers, such as governments or hospitals, procure medicines from the multi-source market. The practice of procurement involves bidding on the price to be paid for a medicine. As things stand, but for in a few cases, tenders for medicines in Europe are most often issued based on price.22
 
Pricing in Germany
 
On 1 August 2010 a drug “price moratorium” came into effect in Germany. The moratorium stipulates drug manufacturers must pay price increases for drugs not subject to a fixed amount as discounts to statutory and private health insurance companies and other cost units. In other words, since August 2009, substantial price increases for these drugs have been effectively excluded and represent a problem for the supply of drugs not to be underestimated. The regulators have now extended the price moratorium until the end of 2022. The extension is part of the Drug Supply Reinforcement Act (AM-VSG), which was passed in March 2017. The AM-VSG also permits price adjustments for all drugs falling under the moratorium, effective August 2018.23
 
Rebate contracts
 
Since 2003, it has been legally possible for statutory health insurance companies to negotiate individual discount agreements or rebate contracts for drugs with pharmaceutical companies. Initially, this regulation had little practical significance. Since April 1, 2007, however, this instrument has been significantly upgraded. Since 2007, pharmacists have been obliged to give priority to dispensing a discounted drug. The conclusion of discount contracts, especially in the generic sector, is considered an essential instrument for cost containment of pharmaceutical expenditures.24
 
Discussion
 
The impact of the 2008 financial crisis is still with us. The crisis prompted European governments to apply strict cost-containment policies on generic medicines to lower their costs. However, this initiative has reduced the number of companies supplying the market and resulted in a decline in the number of manufacturers willing to supply certain generic medicines. This decrease in production has been a trend for complex, older, generic medicines, such as injectable forms of hospital medicines, injectable antibiotics, injectable oncology products and anesthetics. As these are difficult to manufacture, companies are restricted from earning profits due to the aforementioned government measures, so fewer companies are willing to continue to invest in this kind of manufacturing. The result is an over-reliance on just a few manufacturing sites. In addition, even the generic players have realized their revenues can be much higher in the more costly segment of biologics and biosimilars. Therefore, many big companies have shifted their investments to the production of large molecule biologics, rather than small molecule drugs.
 
German medium-sized (SME) generic drugs manufacturer ‒ disincentives
The regulatory system for older complex generic medicines is burdensome and costly from the perspective of a German SME pharmaceutical generic drug manufacturer, and factors such as those tend to remove incentives for companies to keep their products on the market.25
 
As an example, drugs with the API epirubicin are used in chemotherapies for breast, stomach or ovarian cancer, as well as for certain lung tumors. The US pharmaceutical company Pfizer references a temporary issue in production at the Italian drug manufacturer Actavis Generics. The German company Aqvida no longer produces this drug because production costs exceed healthcare insurance reimbursement levels. Another German drug manufacturer, Puren Pharma GmbH & Co KG, Munich, is about to take that drug out of their portfolio because it is no longer economically viable. Manufacturing costs for this drug within the EU is disproportionate to the reimbursement situation in Germany, as reported by Bendalis GmbH, a manufacturer of generic oncology drugs, whose yearly drug product stock sold out within a few days, Although the API could be replaced in principle by other APIs with a similar activity, other APIs may have an impact on treatment procedures and therapy strategies.26
 
Thus, the success of chemically produced API by SME generic drug manufacturers is limited to high drug volumes, which are difficult to achieve, such as under conditions such as temporary lack of licensed EDQM-certified API (see Tables 2 and 3) that may affect the drug manufacture and stockpiling of drugs and at the low pricing/reimbursement levels as found currently in Germany.27
 
Tendering
Tenders for medicines in Germany are most often based on price.28 Larger generics companies are able to offer lower prices as compared to SME generic drug manufacturers, sometimes knowingly accepting contractual penalties in case of temporary out-of-stock situations, to win the bid for a contract.
 
Pharmaceutical purchasing groups (on average representing 30 hospitals in Germany) additionally put pressure on pricing, which is only possible so long as there are competing interests among suppliers.
 
Contracts between pharmaceutical purchasing associations and drug manufacturers assume specific transaction volumes. That can put a financial burden on drug manufacturers because they would have to maintain larger stocks than they would otherwise. Anecdotal evidence suggests that stock volume reductions by hospitals is often not followed by financial penalties.
 
Tenders resulting in binding commitments of the MAH are prospectively affecting finished drug product procurement, stockpiling and supply. Thus, at the time of a specific drug/API shortage, especially if the drug has a short shelf-life, the MAH is fully incapable to clear the situation, although an alternative API would be available. Fast situation clearance is impaired by regulatory provisions of submission of variations whenever the API manufacturer changes and by long lead times for production of validation batches, and ultimately by considerations regarding whether the drug is economically viable.
 
Rebate contracts
Through exclusive discount/rebate contracts between health insurance companies and pharmaceutical companies (other than non-contracted pharmaceutical companies), de facto is subject to a delivery stop for the health insurance in question. Additionally, if one of the companies winning the bid fails to deliver, the other contractors usually cannot cover the sudden additional demand, especially when health insurance companies have only one manufacturer discount or rebate contractor. This raises the risk for drug shortages.29
 
In Germany, there is a legally binding price moratorium for a drug product for the public sector,30 which means that prices are essentially “frozen” for years. Cost pressures on generic drugs are highest in Europe and are combined with increasing costs for authorization of drugs. Additional costs are incurred by preventing falsified medicines from entering the supply chain and by providing regulatory serialization requirements and tamper-proof seal devices.31 Moratorium prices may only be adjusted to compensate for the annual inflation rate.
 
The increasing demand for drugs and the low market prices for generics, combined with higher costs, are resulting in unfavorable situations. Consequently, only a small number of pharmaceutical production plants, primarily based in China and India, supply the world with the bulk of APIs found in medicines. If a surge in demand arises in Europe or elsewhere, it puts a strain on these manufacturers who already have a limited production capacity.32
 
Lack of ability to plan production in line with demand
The manufacture of medicinal products cannot be adapted, converted or increased "on-demand." The regular lead times from production planning to delivery of pharmaceuticals are, on average, about six months. If health insurance funds enter into supply agreements with companies within the framework of discount contracts, then other companies will de facto receive a delivery stop for the fund in question. Those companies will then attempt to have their production facilities engage in the manufacture of other drugs. If one of the rebate contract companies fails, the others will usually not be able to cover the additional sudden demand.33
 
Drug shortages are not limited to the German or EU market
The US Food and Drug Administration (FDA) additionally considers root causes of shortages involving economic factors driven by private and public-sector decision-making. In 2018, at the request of the US Congress, FDA convened an interagency Drug Shortages Task Force to study the problem. The task force analyzed 163 drugs in short supply from 2013 to 2017 and compared them with similar drugs for which there was adequate supply. Of the 163 drugs in the sample, 63% were sterile injectables, and 67% were drugs that have a generic version on the market. They were also older drugs with a median time since first approval of almost 35 years.34
 
Summary
 
Temporary or permanent drug shortages affect the largest marketplaces, such as in the EU and the US, and undoubtedly also affects patients who may subsequently suffer from insufficient care. Temporary solutions can be adequate, although time-consuming for those attempting supply shortage management, such as hospitals and pharmacies.35
 
Several root causes are known for drug shortages have been outlined above and most prominently identified as stemming from production problems and GMP compliance issues. For APIs, which are CEP certified, the GMP compliance issues may necessitate withdrawal, voiding or suspension of CEPs, limiting the availability of these APIs. When generic versions of a reference medicine are on the market, the market is referred to as a “multi-source market,” in contrast to the situation where only one manufacturer is supplying a specific medicine.
 
“Downstream” consequences of the lack of availability of APIs, whether for generic medicines or reference medicines, impact the stockpiles of drug products and foster the inability of companies to timely serve binding tenders, affecting pharmacies, hospitals and wholesalers. The result is that there are drug shortages in the marketplace.
 
Given the dynamics of regulatory provisions and GMP regulations and guidance, it is important to mention that all manufacturers of APIs and drug products will face GMP and regulatory requirements, which is associated with additional work and costs that affect company profitability. Challenges result from these provisions and some manufacturers do not seem to adequately cope, as evidenced by GMP-compliance issues (Tables 2-5).
 
Pricing and reimbursement regulations for drugs contribute to a situation in which manufacturers can no longer offer certain drugs or dosage forms in both the outpatient and hospital sectors. This leads to a narrowing of the market for some drugs. It also means that only a few companies will continue to offer these drugs. We provided an example for an urgently needed intensive care unit medication, a generic medicine for which there are only two manufacturers serving the German market. However, with fewer suppliers for a specific drug, the supply chain becomes more susceptible to disruption. In Germany, the price and discount pressure on drugs has been increasing steadily for many years, with the cost pressure in the generics sector being among the highest in Europe.36
 
The root causes discussed above include a lack of incentives for manufacturers to produce less profitable drugs. Also, drugs in short supply are likely to be relatively cheap and financially unattractive to companies. Manufacturers may also stop production of drugs before a shortage for commercial reasons, such as loss of profitability. Additionally, the market does not recognize and reward manufacturers for "mature quality systems" that focus on continuous improvement and early detection of supply-chain issues. Once more, logistical and regulatory challenges make it difficult for the market to recover from a disruption. Shortages often occur because of disruption in supply. During shortages, production typically does not increase enough to restore supply to pre-shortage levels. Taken together, this suggests a "broken marketplace.” Absent major changes to this marketplace, it is likely that drug shortages will continue to persist.37
 
Drug and generic drug manufacturers cannot raise prices as they wish for their products, because the pricing is governed by regulatory controls. Rebate contracts and tender participation of manufacturers require to continuously monitor if drugs can be offered at economic terms.38
 
To mitigate drug shortages, the German federal regulatory authority that is charged with evaluating and approving drugs and medical products has provided recommendations on delivery and supply shortages and for drafting contracts between operators of hospital pharmacies, pharmacies supplying hospitals, and pharmaceutical companies. The goal is to improve the delivery excellence of relevant medicinal products in hospitals.39 This came into force 11 July 2019.
 
The European medicines regulatory network aims to minimize the impact of medicine shortages on patients by working with pharmaceutical companies to resolve manufacturing and distribution issues; sharing information with international partners about alternative sources of supply; seeking input from patients and healthcare professionals on the impact of medicine shortages; and supporting decision-making regarding measures for allowing alternative medicines or suppliers to be used.40
 
Medicines for Europe, an association of generic manufacturers, is currently investigating ways to adjust some of the cost containment measures to make it more attractive for companies to re-engage in markets. Measures could be put in place to incentivize companies to expand manufacturing capacity, either by building new manufacturing plants or expanding existing ones, reviewing the European Commission directive on procurement, or introducing guidelines on how to modulate applications for tenders to medicines and introduce a flexible process for reward systems. For example, a company maintaining multiple active API suppliers for a single product could pay lower fees or undergo a faster approval procedure. As suggested by Adrian van den Hoven, director-general of Medicines for Europe, these regulatory changes could be introduced into the European Union within a year or two, as legislation would not be required.41
 
Epilogue: The COVID-19- pandemic
 
The world is currently suffering under the devastating COVID-19 pandemic, which likely originated in China, one of the important medicine-manufacturing countries. On 28 February 2020, and as the spread of the coronavirus intensified, FDA issued a warning about potential shortages of at least one drug manufactured in China.42 Europe could face more drug shortages as the coronavirus crisis stalls supplies because many active pharmaceutical ingredients are produced in China, and the virus outbreak is affecting the manufacturing capacity and stability of the supply chain.43 Moreover, India, as the other global source of drug production, has restricted export of several essential medicines, thus aggravating the situation. Taken together, these are strong arguments for fostering European medicine drug manufacturing.
 
The European Medicines Agency and its partners in the European medicines regulatory network are closely monitoring the potential impact of the outbreak of COVID-19 on pharmaceutical supply chains into the European Union.44,45
 

References
  1. Bundesverband der Arzneimittel-Hersteller. Lieferengpässe, https://www.bah-bonn.de/unsere-themen/lieferengpaesse/. Accessed 21 February 2020.
  2. Bundesinstitut für Arzneimittel und Medizinprodukte. Aktuell offene Lieferengpässe für Humanarzneimittel in Deutschland (ohne Impfstoffe). BfArM website. http://lieferengpass.bfarm.de/ords/f?p=30274:2:609130577714::NO. Accessed 7 January 2020.
  3. Medicinal Products Act (Arzneimittelgesetz – AMG) https://www.gesetze-im-internet.de/englisch_amg/englisch_amg.html. Accessed 20 February 2020.
  4. “Apothekenbetriebsordnung”, ABO, section 15 (https://www.giz-nord.de/giznord/toxinf/ABetrO.htm. Accessed 20 February 2020.
  5. Op cit 1.
  6. Ibid.
  7. EDQM homepage, CEP, background and legal framework. https://www.edqm.eu/en/certification-background-77.html. Accessed 27 December 2019.
  8. Active substance master file procedure. https://www.ema.europa.eu/en/active-substance-master-file-procedure. Accessed 27 DEC 2019.
  9. EDQM, The Inspection Program. https://www.edqm.eu/en/inspection-programme-certification-159.html. Accessed 21 February 2020
  10. Consolidated text: Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (26/07/2019). https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0083-20190726&from=EN. Accessed 7 APR 2020.
  11. Op cit 10.
  12. EDQM homepage, CEP (Certificate of Suitability to European Pharmacopeia) database searches. https://extranet.edqm.eu/publications/recherches_CEP.shtml. Accessed 23 December 2019.
  13. EDQM homepage/ Actions on CEP. https://www.edqm.eu/en/actions-ceps#CEP%20suspension. Accessed, 23 December 2019.
  14. DAZ: Missstände in italienischem Herstellbetrieb. https://www.deutsche-apotheker-zeitung.de/news/artikel/2018/08/17/missstaende-in-italienischem-herstellbetrieb. Accessed 8 APR 2020.
  15. Op cit 12.
  16. Ibid.
  17. EudraGMDP, Non-Compliance Report, data base. http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do?ctrl=searchGMPNCResultControlList&action=Page&param=2. Accessed 23 December 2019.
  18. Op cit 17.
  19. Ibid.
  20. The Economist, Addressing medicine shortages in Europe: Taking a concerted approach to drive action on economic, manufacturing and regulatory factors. http://graphics.eiu.com/upload/topic-pages/medicine-shortages/Addressing-medicine-shortages-in-Europe-EIU.pdf. Accessed 18 February 2020.
  21. Allgemeine Deutsche Lauer Taxe. https://www.lauer-fischer.de/LF/Seiten/Verwaltung/Kundencenter/1.aspx. Accessed 25 APR 2020.
  22. Op cit 20.
  23. BfArM homepage/ Preismoratorium. https://www.bah-bonn.de/de/unsere-themen/preismoratorium/. Accessed 14 January 2020.
  24. B.A.H homepage. https://www.bah-bonn.de/de/unsere-themen/rabattvertraege/. Accessed 3 March 2020.
  25. Rees V. Resolving and mitigating medicine shortages in the EU, 10 February 2020. https://www.europeanpharmaceuticalreview.com/article/112301/resolving-and-mitigating-medicine-shortages-in-the-eu/. Accessed 17 February 2020.
  26. Der Spiegel Nr 5/ 25.1.2020, Seite 65: Pharma: Engpass bei Krebsmedikament. Accessed 25 January 2020.
  27. Op cit 20.
  28. Ibid.
  29. Gemeinsame Position der Pharmaverbände zu Lieferengpässen. https://www.bpi.de/fileadmin/user_upload/Downloads/Publikationen/Positionen/2019-12-13_Gemeinsames_Positionspapier_Verbaende_zu_Lieferengpaessen.pdf. Accessed 20 February 2020.
  30. Op cit 23.
  31. Op cit 29.
  32. Hyde R. Europe faces worsening medicine shortages, www.thelancet.com Vol 395 February 15, 2020. https://www.abstream.me/entries/576469/world-report-europe-faces-worsening-medicine-short/. Accessed 18 February 2020.
  33. Op cit 29.
  34. 'Broken Marketplace' Behind Ongoing Drug Shortages, FDA says. https://www.medscape.com/viewarticle/920565. Accessed 27 December 2019 .
  35. PGEU Survey on medicine shortages 2019 (Pharmaceutical group of the European Union (PGEU), https://www.pgeu.eu/wp-content/uploads/2019/03/PGEU-Medicine-Shortages-Survey-Results-2019.pdf. Accessed 18 February 2020.
  36. Op cit 29.
  37. Op cit 34.
  38. Op cit 29.
  39. BfArM homepage.  https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Zulassung/amInformationen/Lieferengpaesse/Protokolle/Recommendations_on_delivery_and_supply_shortages_190711.pdf?__blob=publicationFile&v=2. Published 8 October 2019. Accessed 27 December 2019.
  40. EMA hompepage/ Medicine shortage. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines#medicine-shortages-section. Accessed 27 December 2019.
  41. Op cit 25.
  42. Coronavirus outbreak causes first drug shortage in U.S., FDA says. https://www.cbsnews.com/news/coronavirus-human-drug-shortage-food-drug-administration/. Accessed 5 March 2020.
  43. Europe could face more drug shortages as coronavirus squeezes supplies. https://www.reuters.com/article/us-health-coronavirus-eu-idUSKBN20S1R2. Accessed 18 March 2020.
  44. EMA on Potential Impact of Coronavirus. https://www.gmp-compliance.org/gmp-news/ema-on-potential-impact-of-coronavirus?utm_source=Newsletter&utm_medium=email&utm_campaign=ECA+GMP+Newsletter+-+2020+-+KW12+-+PEU. Accessed 18 Mar 2020.
  45. Addressing the potential impact of novel coronavirus disease (COVID-19) on medicines supply in the EU. https://www.ema.europa.eu/en/news/addressing-potential-impact-novel-coronavirus-disease-covid-19-medicines-supply-eu. Accessed 18 March 2020.
 
About the Authors
 
Ralf D. Hess, MSc, PhD, is a principal project consultant and member of the task force at Entourage in Munich and Basel, CH, providing quality compliance and regulatory consulting services in the medical device, pharmaceutical and biopharmaceutical industry. He is a virologist/immunologist and has more than 30 years of experience in drug and device development. He can be contacted at ralf.hess@theentourage.de.
 
Henric Wassmer, is a cofounder and CEO of Inresa Arzneimittel GmbH, Germany.
He is a pharmaceutical specialist with experience of about 20 years in the hospital business responsible for the clinical field service and after 10 years he took over the General Management at Inresa Arzneimittel GmbH. He can be contacted at henric.wassmer@inresa.com.
 
Siegfried Schmitt, PhD, is Vice President, Technical at Parexel. He provides consulting services to the regulated healthcare industry on all aspects of regulatory compliance, particularly the design and implementation of Quality Management Systems and Competitive Compliance. He can be contacted at siegfried.schmitt@parexel.com.
 
Martin Hug, PhD, Chief pharmacist, Freiburg University, Medical Center, studied Pharmacy at Freiburg University, where he also completed his Ph.D. After 10 years of research in epithelial and cardiovascular Physiology in both academia and industry he became Hospital pharmacist. He continued his line of research at Freiburg University Medical Center and is now Chief Pharmacist at the Medical Center and Professor of Clinical Pharmacy at the Institute of Pharmaceutical Sciences, Freiburg University. Prof. Hug can be reached at martin.hug@uniklinik-freiburg.de.
 
Anmar Marouf, PhD, is Director of Quality, Scientific and Regulatory Affairs at Inresa Arzneimittel GmbH and Regulatory CMC expert with focus on small molecules. He is pharmacist with round 20 years of experience in the pharmaceutical industry. He can be contacted at anmar.marouf@inresa.com.
 
Moritz Haucke, MBA, is an independent entrepreneur and founder of Entourage GmbH. He studied information science, philosophy and economics and graduated as M.A. in Saarbrücken.
He started as a consultant for the Swiss pharmaceutical industry and built up a team in GMP Operations. In 2013 he founded Entourage as a consulting company for the pharmaceutical industry with a focus on GMP operations, regulatory affairs and clinical development. Entourage is a management and personnel consulting company with a focus on pharmaceuticals, medical devices and healthcare. Based in Munich and Basel, the company recruits experts for the leading life science companies in the DACH region by placing scientific permanent employees and project-based consultants. Entourage currently employs around 90 people throughout the DACH region. He can be contacted at Moritz.haucke@theentourage.de.
 
Dominik Aumer, MBA, is an independent entrepreneur and founder of Entourage GmbH. He studied business administration at the University of Saarland and builds on more than 10 years of experience in strategic consulting and personnel development in the medical device technology area. He is CEO of Entourage GmbH and member of the advisory board of Entourage Pharma Consulting AG. He can be contacted at dominik.aumer@theentourage.de.
 
Simon D. Schulz, MSc, PhD, is a project consultant at Entourage GmbH and member of the task force at Entourage GmbH, providing quality compliance and regulatory consulting services in the medical device industry. A chemist, he is associate professor for experimental medicine at the University of Freiburg, Germany. He can be contacted at simon.schulz@theentourage.de.
 
Cite as: Hess RD, Wassmer H, Schmitt S et al. Drug shortages in Germany ‒ A critical appraisal. Regulatory Focus. May 2020. Regulatory Affairs Professionals Society.

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