Implications for APIs in the European Falsified Medicines Directive

German/E+/Getty ImagesEnsuring the quality of the pharmaceutical supply chain is of utmost importance to the pharmaceutical industry. The European Falsified Medicines Directive (FMD), which was adopted in July 2011, contains measures, which became effective in July 2013, requiring that all active substances manufactured outside the European Union (EU) be accompanied by a written confirmation from the regulatory authority of the exporting country. These statements are to be issued per manufacturing site and per active substance to ensure that standards of good manufacturing practice (GMP) equivalent to those in force in the EU are upheld. To gain insight on these provisions, two key industry groups, the Active Pharmaceuticals Ingredient Committee (APIC) and the European Fine Chemicals Group (EFCG), both sector groups of the European Chemical Industry Council (CEFIC), offered their perspectives on the strengths and weaknesses of the FMD.

The European Falsified Medicines Directive (FMD) seeks to prevent falsified medicines entering the legal supply chain in the European Union (EU). The directive was adopted in July 2011, and EU member states began applying provisions in January 2013. The purpose of the directive is to harmonize and strengthen safety and control measures across Europe in four main areas: safety features of medicines, the supply chain and good distribution practices (GDPs), active substances and excipients, and Internet sales (1-3).

From July 2, 2013, all active substances manufactured outside of the EU and imported into the EU must be accompanied by a written confirmation from the competent authority of the exporting country that confirms that the standards of good manufacturing practice (GMP) and control of the manufacturing plant are equivalent to those in the EU (4). These requirements constitute one of the main areas of change of the new FMD to provide a clear legal basis for the concept of international cooperation on active substances, which is based on sharing responsibilities with local regulators (4). The written confirmation is required per manufacturing site and per active substance and should provide the following assurances:

• Standards of GMP applicable at the plant are at least equivalent to those in force in the EU.
• The plant is subject to regular and strict controls and effective enforcement of GMP, including inspections.
• Information on findings relating to noncompliance is supplied by the exporting third country without delay to the authorities in the importing country in the EU.

The duration of validity of the written confirmation is established by the exporting non-EU country (4). As noted by the European Medicines Agency (EMA), these new requirements reinforce the need for pharmaceutical companies to ensure that the active substance manufacturers they are working with are registered with their respective local authorities and subject to adequate regulatory oversight (4).

Additionally, the directive specifies that exporting countries with a regulatory framework equivalent to that of the EU will not need to issue written confirmations subject to approval.

Following a request from a non-EU country, the European Commission (EC), together with GMP experts from member states and with the support of the EMA, will assess the regulatory framework of the requesters, and if the assessment is positive, the county will be listed as an “equivalent country” (4). As of July 2, 2013, four countries have been listed by the EC: Australia, Japan, Switzerland, and the United States. An equivalence assessment is ongoing for Brazil. Israel and Singapore have requested to be listed as an “equivalent country” (4).

To avoid the risk of shortages of medicines if the required written confirmation cannot be obtained, the FMD provides for a waiver from the written confirmation in exceptional circumstances. The waiver can be used where an inspection by an authority of the European Economic Area has been carried out with a positive outcome and the issue of a GMP certificate (4).

The FMD also puts into place measures on the distribution side of the pharmaceutical supply chain. It includes new responsibilities for wholesalers and a definition of brokering activities as well as new responsibilities for brokers. The EMA’s revised guideline on GDP, which was published in February 2013, includes specific provisions for brokering activities (1-3, 5). Reflecting the inclusion of GDP into European provisions, the EudraGMDP database also now includes information on GDP. EudraGMDP is a modification of the EudraGMP database, which was launched in April 2007 to facilitate the exchange of information on compliance and noncompliance with GMP among the regulatory authorities within the European medicines network. The new database, now called EudraGMDP, was a deliverable of the FMD. It is gradually being updated by medicines regulatory authorities in EU member states with distribution-related information and will be maintained on an ongoing basis (1, 5). The additional information will include: wholesale distribution authorizations; GDP certificates; statements of noncompliance with GDP; and registrations of manufacturers, importers (including information on their suppliers), and distributors of active substances (1, 5).

Although the FMD took steps to fortify the supply chain as it relates to APIs coming into the EU, there is concern that the FMD falls short in adequately strengthening the inspection process for APIs imported in the EU. To gain a perspective on these issues, Pharmaceutical Technology discussed the FMD as it relates to API supply with representatives from the Active Pharmaceutical Ingredient Committee (APIC) and the European Fine Chemicals Group (EFCG), both sector groups of the European Chemical Industry Council (CEFIC), the trade association representing 29,000 large, medium and small chemical companies in Europe. APIC represents approximately 65 fine chemical companies, contract manufacturers, and pharmaceutical companies. EFCG represents approximately 40 small, medium, and large fine-chemical companies including four national and European industry associations: APIC; ASCHIMFARMA--the Italian Association of Manufacturers of Active Ingredients and Intermediates; CPA--Italy’s Chemical Pharmaceutical Generic Association; and SICOS, which represents French fine and biochemical producers (6-8).

FMD sparks concerns

PharmTech: Do you think the measures contained in the FMD are sufficient to ensure the quality of pharmaceutical ingredients coming into the EU or are there other measures that need to be taken?

APIC and EFCG: No, the FMD does not sufficiently ensure the quality of APIs entering the EU. We have been very close to this topic since the FMD concept was born, and we remain concerned that, despite its objectives, it fails to fully meet the needs of EU patients with respect to product quality. Its effectiveness is still too dependent on industry’s supply chain self-evaluation and open to corrupt practices. Other measures that are needed include:

• Stricter enforcement of existing laws by all member state regulatory authorities, plus tough sanctions to punish the violators
• A consistent approach of member states when transposing the FMD into national law throughout the EU

• A change in the existing laws to include mandatory inspections by competent authorities of all API manufacturers with the industry paying for extra regulatory resources if needed similar to the Generic Drug User Fee Act (GDUFA) in the United States

• APIs contained in imported finished and semifinished drug products, mixtures of API with excipient(s) and semifinished (crude, moist) APIs should be included in the scope of the FMD.

The EC should have rigorously tested its assumption that there are 15,000-20,000 API manufacturers selling APIs into Europe before they decided not to propose the mandatory inspection of all API producers. In fact, the Heads of Medicines Agencies survey of medicine manufacturers in Europe, published on Mar. 27, 2013, showed that the top 18 third-country manufacturers/exporters of APIs to Europe had only 1479 manufacturing sites (9). It is, however, never too late for the EC to re-consider mandatory inspections to better protect EU citizens and patients.

Inspection process

PharmTech: One concern raised by the FMD is the adequacy of enforcement measures, particularly the inspection process with the new directive lacking a provision requiring mandatory inspections of API producers in third countries (i.e., countries outside the EU). From an industry perspective, what are the advantages/disadvantages of the current inspection process of API producers in third countries? In what areas can the process be improved and at what level/jurisdiction should it be made?

APIC and EFCG: The advantage of the current inspection process eases the continuity of supply of APIs from third countries for EU patients and, hence, avoids major product shortages. The disadvantage is the continued risk of substandard APIs/products entering the EU due to a lack of adequate enforcement and tough sanctions to punish individuals and companies. We suggest the following process improvements:

• Ideally, change the FMD to provide for mandatory inspections by EU authorities of API producers in third countries with industry helping to pay, or
• Achieve the same end result by providing for mandatory inspections of third-country API producers by European authorities together with other country authorities applying the same EU GMP standards to share the inspection responsibility via mutual recognition agreements (e.g., US, Australia, and Japan)

• Inspectors should be trained to detect falsification or fraud, for example, facade constructions, ghost plants, and falsified official papers.

GDP guidelines

PharmTech: Earlier this year, the EU finalized a guideline on GDP for medicinal products in the EU. Although it addresses the distribution of medicinal products from an end-market perspective, the intent of the guideline is to further ensure the quality of medicines coming into the EU. From an industry perspective, what are the implications for suppliers of APIs and other pharmaceutical ingredients?

APIC and EFCG: The industry must ensure transparency of sources and intermediaries (brokers and traders) and a register of evidence of compliance at each step along the entire supply chain from raw-material suppliers to the final medicine. Additionally, the EC published in February 2013 a draft guideline on the principles of Good Distribution Practices for Active Substances as part of the implementation of the FMD. Although this guideline only lays down the “principles” of GDP, it will be a step in the right direction.

Supply-chain security

PharmTech: From an industry perspective, as regulatory and industry groups seek ways to fortify the pharmaceutical supply chain in an increasingly global environment, what are the implications in the outsourcing relationship, either from the perspective of a sponsor company (i.e., pharmaceutical company) or contract manufacturer/supplier?

APIC and EFCG: The sponsor company needs a contractor that it can trust to meet appropriate GMP standards in terms of product quality, quality culture, regulatory compliance with the laws of the country of product destination, and delivery at a price they are prepared to pay. Roles and responsibilities with respect to manufacture and distribution, including sub-contracting or use of third party distributors, should be clearly defined and understood by both parties. The contractor should be aware of the relevant regulations and should be able to comply with them. They must not fail their sponsor by delivering sub-standard products.

Initiatives from APIC and EFCG

PharmTech: Can you outline key recent activities of APIC and EFCG in 2012 and 2013 in response to the EU FMD implementation and other measures that affect API supply into the EU?

APIC and EFCG: APIC and EFCG have been very active opposite the EC during the implementation of the FMD. We have written letters and made face-to-face representations to the EC’s Directorate-General for Health and Consumers (DG SANCO) to point out the continuing risks to EU patients (we are all patients) and to the EU API manufacturing base (our members). The latter suffer unfair competition mainly from Asian API manufacturers, many of whose facilities fall well short of the EU-required GMP standard (ICH Q7) (10).

We have challenged the “loopholes” that remain within the FMD, which unless rigorously enforced by the various national regulatory authorities, will not prevent substandard APIs from continuing to enter the EU market, either as bulk API (requiring written confirmations) or through formulated products (where there is no separate check on APIs). We are pleased to note via DG SANCO that the national authorities in China and India have severely limited the number of sites for whom written confirmations are permitted. APIC and EFCG will continue to press for mutual recognition agreements with other countries (e.g., US, Japan, and Australia) that operate to the same GMP standards to help level the global playing field.

References

1. P. Van Arnum, Pharm. Technol. 37 (7) 62-63 (2013).

2. EMA, “Falsified Medicines,” www.emaeuropa.eu/ema/index.jsp, accessed July 16, 2013.

3. EC Directive 2011/62/EU, Falsified Medicines Directive (Brussels, July 2011).

4. EMA, “Falsified Medicines Directive: Imported Active Substances Need Written Confirmation to Guarantee GMP Standards,” Press Release (July 2, 2013).

5. EMA, “Key Deliverable of Falsified Medicines Directive Achieved,” Press Release (Apr. 8, 2013).

6. CEFIC, “About CEFIC,” www.cefic.org, accessed July 16, 2013

7. APIC, “Objectives,” www.apic.cefic.org, accessed July 16, 2013.

8. EFCG, “Membership,” www.efcg.cefic.org, accessed July 16, 2013.

9. European Commission website, Mar 27, 2013, http://ec.europa.eu/health/files/committee/70meeting/pharm622.pdf, accessed July 27, 2013.

10. ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Step 4 version (2000), http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf, accessed July 22, 2013.