Karl Ennis

To help ensure drug product quality and safety, health authorities in many countries have implemented, or are considering implementing, quality control (QC) testing requirements for pharmaceuticals, biological/biotechnology, and/or vaccine products entering their countries-also referred to as import testing. A survey was conducted within the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) to analyze data on import testing, other categories of re-testing (e.g., post-marketing surveillance), and applied waiver types. The findings suggest that import testing does not add significant quality or safety benefits to patients, provided that the products are uninterruptedly controlled according to the globally harmonized manufacturing, distribution, and storage standards (GMP, GDP, GSP). In fact, it was observed that import testing could potentially increase risks to the patient by causing delay in the supply chain and other complexities.

	Historically, re-testing requirements may have been necessary to prevent the distribution of unsafe or non-conforming drug product; however, laws, regulations, and regulatory oversight have changed significantly. Today, pharmaceutical, vaccine, and the biotechnology industries have developed and implemented robust quality systems and control of the supply chain to ensure the identity, safety, purity, and potency of its drug products throughout their manufacture and international distribution channels. The requirement of import testing is, therefore, regarded to be redundant (1, 2). This perspective has been evidenced by data presented herein, analyzing quantitative figures on import testing collected from multinational pharmaceutical companies.


	The presented data were received from six multinational pharmaceutical companies-Amgen, AstraZeneca, Bayer, F. Hoffmann-La Roche, Johnson & Johnson, and Pfizer-associated with IFPMA, unless otherwise specified. In total, 184 data sets of information on 149 countries, collected from September to November 2014, were analyzed. Data were collected from the six companies on:

		number of out-of-specification (OOS) investigations and batch rejections

		the costs associated with the testing and related costs, such as warehousing or blocked capital.

Categories of re-testing in the country of destination. 

Apart from re-testing associated with the import of pharmaceutical products, other testing categories were reported. Re-testing may be performed by companies themselves, contractors, and/or governmental laboratories in each country. The different categories of local re-testing reported and their impact are described subsequently:

		QC testing (full or partial local re-testing against approved specifications) for medicines as part of the importation process.

		Performed in governmental laboratories or under the responsibility of the manufacturers/importers.

		Causes prolonged storage of the goods in warehouse upon import.

		Increases complexity in chain of custody/supply chain.

		Can lead to delayed supply of medicine to the patient or product stock-out.

		or small markets, the amount of required samples can be a significant portion of the total importation.

(a) Testing in conjunction with initial registration

		Regarded as part of the initial “validation” by law in some countries.

		Often implemented to establish innovative test methods/techniques in a country.

		Can result in a significant delay to availability of new innovative medicines to patients.

(b) Testing in conjunction with post-approval changes and/or license renewal

		Results in administrative and financial (high sample costs) burdens.

		Does not usually impact supply during the commercial phase.

		Represents an independent control of medicines on the market.

		Opportunity to detect counterfeit/falsified medicine (3) or unauthorized imports. These data may also help to understand these threats and to define appropriate measures.

		No delay in access of medicines to patients.

		An accepted practice to monitor the quality of marketed medicines.

Data on requirements from 129 countries (the European Union market was counted as one country) were collected and assessed. 

provides an overview of the countries with such requirements by categorizing them in terms of the extent of testing. 

outlines the testing requirements by country. The countries are subsumed by regions: Asia Pacific, Eastern Europe, Western Europe, Commonwealth of Independent States (CIS), Middle East, Africa, North America, Central America and the Caribbean (CAC), and South America.

Testing requirements by country. Status as of November 2014.
	Who performs the testing: Governmental laboratory (Gov), Companies laboratory (Comp), Company could use certified laboratory (Gov/Comp).
	Requested testing for product categories: Active Pharmaceutical Ingredients (API), API biological/biotech (API/B), Drug Product (DP), Drug Product Sterile (DP/S), Combination Product/Medical Device (Comb), Vaccine (Vac), Others (O).

	
	EDQM is European Directorate for the Quality of Medicines & HealthCare; EEA is European Economic Area; EFTA is European Free Trade Association; MOU is Memorandum of Understanding; MRA is Mutual Recognition Agreement; N/A is not applicable; N/I is no information available; OMCL is Official Medicines Control Laboratories; Reg. is registration testing at governmental laboratories; Surv. is surveillance testing at governmental laboratories.

	Multiplication of tests along the global supply chain. Multinational manufacturers manage global product supply chains. One drug product batch may be dispatched to several countries (i.e., batch splitting) after country-/region-specific packaging. Accordingly, the same batch may undergo several re-tests. 

 provides examples for a recombinant interferon and a chemical product.

	A special situation exists in Chile, where two local sets of re-tests are required for the import of biological products (4). In addition to the partial re-test under the responsibility of the importer/manufacturer, the products are subject to testing at governmental laboratories, referred to as “series control.”

 The local re-testing process takes significant time. Information from 29 operations in 18 different countries was received. The average supply-chain delay is summarized in 

 and ranges from two to 19 weeks. The maximum absolute delay was reported as 22 weeks (such as biologics testing in China). It is noted that re-testing can be further prolonged in case of OOS investigations or other delays (e.g., if required materials/reagents are temporarily not available due to import procedures).

 The survey collected annual data on the number of re-tests (full or partial), OOS investigations, and batch rejections. Six companies reported a total of 18,616 re-tests performed per year. Of these, one re-test resulted in a batch rejection. The overall figures are shown in 

 The following costs (per year) were queried in the survey: (a) costs of local QC analytics (e.g., for testing, samples, contract laboratories) and (b) loss by blocked capital due to longer storage duration of the inventory (e.g., warehoused at customs). The responses were aggregated in subsets according to the reported cost figures, as follows:

Nine in-country operations reported both figures (a + b). Countries reported are Argentina (1 operation), China (1 operation), EU (3 operations), Israel (1 operation), Mexico (2 operations), and South Korea (1 operation). The resulting annual costs associated with import testing accumulate to €57,716,457, calculated from costs of local QC analytics (€20,044,198) and blocked capital (€37,672,259).

Thirteen in-country operations reported just one of the requested figures (a or b). The total reported annual costs from all 22 in-country operations (including Subset 1) add up to €88,305,744.

A second survey within the European Federation of Pharmaceutical Industries and Associations (EFPIA), conducted January to February 2015, was performed focusing on material subjected to import testing in the EU after import from the United States. Fifteen multinational pharmaceutical companies reported 8495 product batches for 2014 (5). Considering €2950 as the average cost per re-test (see below), the costs add up to €25,060,250.

Costs per re-test were deduced from the data sets, where in-country operations reported the number of re-tests and costs (at least the costs of local QC analytics). Twenty two in-country operations reported 17,164 re-tests and an associated costs of €50,633,485. The resulting average costs per re-test are €2950.

 Companies provided details of additional resources required for local re-testing even if the testing is not performed under their responsibility. To support re-testing at the government laboratories, costs arise, for example for:

		analytical method implementation (including training activities)

		equipment (e.g., chromatographic columns) and devices (e.g., method-specific apparatus)

		critical reagents and reference standards (including qualification)

		importation and customs requirements for these materials.

	These additional costs are typically not monitored and may not be reflected in the reported figures accordingly.

 Global re-testing requirements were presented in 

. Responding companies also reported that local regulations permit waivers from local re-testing, where different approaches were identified:

		formation of an union (e.g., EU member states)

		mutual recognition agreement (MRA) (e.g., EU-Switzerland, Australia-Canada)

		Agreements on Conformity Assessment and Acceptance of Industrial Products (ACAA), which is a specific type of MRA based on the alignment of the legislative system and infrastructure of the country concerned with those of the EU (e.g., EU-Israel)

		for specific product categories (e.g., chemical products, Egypt or orphan drugs/indications, South Korea)

		for products filed under a simplified procedure (e.g., Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries [CADREAC] in Turkey)

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