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:
- Requires blood regulations to incorporate EMEA requirements
- Requires a plasma master file
- Establishes inspections and licensing by competent national authority
- Establishes exchange of information with EU, USA, PIC/S
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:
- FDA inspectors are considered more flexible in the types of corrective actions that they will allow to bring a center into compliance. Their inspections are generally unannounced.
- European inspectors are more “prescriptive” in the correction of perceived deficiencies. But EU prides itself on “uniform” interpretations. Their inspections, for logistics reasons, are always announced.
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:
- Two copies of the Site Master File and attachments
- Copies of current organizational chart and floor plans
- SOPs and Quality Manual easily accessible
- Job descriptions
- Current Annual Report
- Short supply agreements and specifications
- Copies of contracts with external service providers (e.g. test labs, pest control)
- Any look-backs necessary
- Plasma storage freezer records (at least six months back)
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:
- Ensure all relevant staff is present for the initial inspection meeting
- Ensure that a knowledgeable QA staff member is available to accompany inspectors at all times
- Develop a back-up plan for management and a list of key personnel and authorized substitutes and make them available to the inspectors
- Set up a comfortable room for inspectors to work in during the visit. Provide water and coffee, as well as lunch.
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
Manufacture of proteins which are labile in plasma
Manufacture of proteins which are not labile in plasma
Plasmapheresis or Whole Blood
Time to freezing
≤ 24 hrs
≤ 72 hrs
-200C to -150C (should be -20 degrees to -15 degrees) at one or more occasions.One time >-15OC (should be the degree symbol in all cases) but never > -5OC
Total time exceeding -20OC: 72 hrs
Other Pharmacopoeia recommendations include:
- Recommend testing for Parvovirus B19 for anti-D immunoglobulin for production of solvent/detergent-treated plasma
- Recommends NAT for HIV, HBV and HCV for plasma used for fractionation
- Accepts testing performed in large pools (up to 1,000 samples). All must be discarded if pools test positive
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.
The EMEA Guideline issued January 20, 2005 describes data that must be included in the PMF. This Guideline defines prevalence and incidence, as well as:
- Seropositives and NAT-only positives
- Prospective, first time, repeat and regular donors
- First-time tested and repeat-tested donors (critical issue for standards for source plasma)
- Reporting number of positives and rates/100,000
- Antibodies to HIV 1/2, HIV NAT only
- Antibodies to HCV, HCV NAT only
- HBsAg, HBV NAT only if tested
- Separate data for First time and Repeat (source plasma will have to report data for “applicant donors”)
- Data reported to PMF holders (fractionators)
- Fractionators define criteria for epidemiological assessment, corrective actions, three-year trends and estimation of residual risk
- Sent to Competent Authority and EMEA
- Effective July 2005, extension to 2007
What Makes an EU Inspection?
EU inspectors evaluate sites on six different points: identification, hygiene, workflow, bio-waste, documentation, and validation. Depending upon the report on these factors, a plasma center may have to reconfigure its site to pass the inspection.
A picture ID is required when a volunteer registers for plasma donation. The donor will have to re-identify himself prior to the screening or interview process and again before venipuncture. This is known as “active” identification.
EU inspectors require that sites minimize the cross-contamination risk. Proof of adequate pest control must be shown and there can be no pictures, posters, or an personal items allowed in manufacturing areas. All surfaces must be readily cleanable and gloves must be worn when plasma products are handled.
Workflow functions should be physically separated. Products and materials should follow a continuous, well-defined path. Access to workflow areas must be restricted to authorized personnel.
All bio-waste must be handled in such a way as to avoid potential contamination. Viral marker positive units must be stored under lock and key. Bio-waste is a restricted access material with its own disposal area.
All contracts and records must be complete and include signatures. SOPs must be specific. Backups for key personnel must be in writing; documented designees for all key personnel must be listed.
All validation records must be complete and all criteria must be specified in the plan. Before inspectors arrive, be sure all the instruments used in validation have been validated.
Make a Good Impression
Remember that you never get a second chance to make a first impression. EU inspectors are sharp and expect to be treated with respect. Don’t assume that because your site is in the United States, it is worthy of passing inspection; Americans can learn a lot from European inspectors about preparing excellent plasma centers.
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.
Becky See is the Director Quality Source by Blood Systems. She is a certified quality auditor from ASQ and an AABB assessor and has more than 20 years’ experience in quality assurance.
Becky is in demand as a conference speaker and has served on many committees of Americas Blood Centers, AABB, American Society of Clinical Laboratory Science, and other state organizations.
She can be reached at (480) 323-6580.