Preparing for Assessment by the European Union (EU)
By Becky SeeDiscusses how a U.S. blood center should prepare for an EU inspection.
A safe and adequate blood supply is essential to the practice of modern medicine. New advances, particularly in the area of automation, have enhanced both safety and blood availability on an international scale. Sovereign countries formerly looked to their own citizens for their blood plasma needs; today, plasma is an international commodity and as such, its collection centers are assessed by European and American inspectors.
U.S. blood centers may be assessed by EU inspectors if they send recovered plasma to European manufacturing facilities. Recovered plasma is not an FDA-licensed product, so there are no rigid restrictions on its shipment. However, U.S. plasma manufacturers must meet national and European standards in order to sell plasma-derived products in Europe.
The U.S. is a major supplier of plasma products; it provides 60 percent of the world’s needs for plasma, both recovered and source. The U.S. collected 2.4 million liters of recovered plasma in 2003, with an estimated value of $90 million a year. Being a major player in the plasma market means the U.S. merits assessment by the EU.
Blood centers that sell plasma in global markets must conform to standards and requirements beyond those in the U.S. Recovered plasma is not an FDA-licensed product per se, although the FDA expects all licensees to audit the facilities and processes of contractors and suppliers, including blood centers. The inspection is to ensure that firms manufacture biological products that are safe, pure, potent, and have the quality that they represent and that they manufacture these products according to Current Good Manufacturing Practices (CGMP) for Blood and Blood Components regulations and applicable standards.
Currently, there are no mutual recognition agreements for inspections between FDA and the European Agency for the Evaluation of Medicinal Products (EMEA). EMEA intends that U.S. sites be inspected every two years but so far, U.S. facilities had been unaware of the organization’s standards. Several blood centers that underwent EU inspections were cited for violations that could have been avoided if they’d had a better idea of EU priorities and expectations.
On one hand, U.S. standards are very clear for blood centers operating within the U.S. The Code of Federal Regulations (CFRs) have the force of law. FDA Guidances only have the force of law if a blood center integrates them into its standard operating procedures after implementation.
Blood centers operating in Europe are governed by the Pharmaceutical Inspection Convention: Guide to Inspections of Source Plasma Establishments and Plasma Warehouses (PIC/S Guide) and the European Pharmacopoeia Monograph 0853 -- Human Plasma for Fractionation. The Monograph provides legally binding standards for the composition and preparation of substances used in the manufacture of medicines. They also operate under Eudalex Vol. 4 Pharmaceutical Legislation, Good Manufacturing Practices and World Health Organization (WHO) recommendations.
When a standards comparison is drawn between a European country and the United States, it is clear that the two have different expectations for inspections. Take a look at Austria, which operates under the Austrian Medical Products Import Act. The Act:
Each Austrian blood collection establishment must have a quality system in place. This includes a designated quality assurance person in charge who is named on the organizational chart, a hemovigilance system and a reporting system.
A European site inspection ensures that SOPs, personnel and training documents comply with European standards and terms of manufacturer-specific contracts. These inspectors will look for “state-of-the-art facilities.” EU inspectors look upon a facility as a supplier of plasma for fractionation, which they consider “pharmaceutical grade raw material.” As such, they expect conditions at blood centers to match conditions at their processing plants.
An FDA inspector will ensure that facilities, equipment, and SOPs, personnel and training documents comply with regulations and guidances. FDA inspectors take a systems focus, looking at QA; donor eligibility; product collections, processing and testing; quarantine; and storage facilities. FDA inspectors look upon a facility as a provider of blood products, which are considered drugs under the Food, Drug and Cosmetic Act.
There are two major differences between FDA inspectors and European inspectors:
The main areas of concern for European inspectors are documentation, training, cleanliness, workflow/organization, and proper plasma handling procedures, with an emphasis on cleanliness. They also scrutinize contracts with external service providers, control and release of starting materials, quality management and mobile collections.
When a U.S. center receives notice of an impending European inspection, there are a number of steps which need to be taken to ensure a successful visit.
First, the following documents must be readily accessible:
Next, take a look at the organization chart. For a European inspection, the position of QA director in an organizational chart should be between the CEO and operational departments. The intention is to show that QA has direct authority and access to all operational departments.
When inspection day arrives:
Efforts Toward Harmonization
The U.S./EU inspection situation may not always be this challenging; there are efforts among countries for harmonization. European efforts to harmonize regulations started in the early ’90s using voluntary standards created by international organizations, even if they were not members of the EU. Countries like the U.S. and Australia joined these organizations as observers.
Until harmonization arrives, U.S. plasma centers should be aware of the standards, partially incorporated into EU directives, by which they will be judged.
Recommendations of European Pharmacopoeia Plasma for Fractionation
Other Pharmacopoeia recommendations include:
The Plasma Master File (PMF) is of significance to EU inspectors. Each center under inspection must provide PMF data, including information about testing (serological and NAT), bags, storage and transportation. The EMEA, upon approval of the PMF, issues a certificate that ensures product acceptance.
What Makes an EU Inspection?
Make a Good Impression
Know the regulations before the inspectors arrive but don’t flaunt your knowledge. Ask for advice if you need it. Forego “casual dress” during the inspection and dress for success. Europeans value etiquette, so mind your manners. Better to err on the side of formality than be too laid-back, making a less-than-positive impact.
She can be reached at (480) 323-6580.