The distribution of medicinal products in Bulgaria is regulated by the Law on Medicines in Human Medicine (2007) and Regulation 39/13.09.2007 on the principles and requirements of Good Distribution Practice. Relevant EU documents are also applicable. According to the official registry of Bulgarian Drug Agency, there are 263 valid authorizations issed for wholesaling activities for companies with facilities within the territory of the country (Figure 1). Previous publications, Stoimenova et al. (2013), reported 202 authorizations in 2012 which is substantial increase. In addition, there 10 registrations of wholesalers authorized by another competent authority in EU (Cyprus, Czech Republic, Hungary, Netherlands, Romania and United Kingdom) and operating in Bulgaria with no local facilities. 31 out of 263 distributors are dealing with medicinal products containing narcotic substances and only 9 are selling radiopharmaceuticals (Table 1). 49 authorizations for wholesaling of medicinal products have been suspended in Bulgaria for the period 2009–2018 and were not included in the Table 1 (Figure 2).

Figure 1. 

Number of authorizations issued 2007–2018.

Table 1.Download as CSV 

Wholesalers in Bulgaria.

Total No of wholesalers	No of wholesalers distributing narcotics	No of wholesalers distributing radiopharmaceuticals	No of wholesalers distributing immunology/ plasma-derived products
263	31	9	80

Figure 2. 

No of suspended wholesale authorizations 2009–2018.

During 2017, inspections were performed in 48 distributors. A wide range of business models are represented, e.g. full line, short line, third party logistics, marketing authorisation holders, and exporters. One inspection was follow-up inspection related to previously found major deficiencies. During the inspections, 17 non-conformities (NCs) have been documented (Table 2). The NCs were identified in 3 wholesalers and 6 deficiencies were classified as major. No critical deficiencies were found. Recommendations were given to 5 companies related to quality management system as these were lacking Quality mannuals and some documents related to the management of the system, ensuring setting quality goals and continuous improvement & preventive culture.

Table 2.Download as CSV 

Observed deficiencies during inspections in 2017.

	Computerized systems	Temperature mapping &monitoring
Major NCs	2	4
	DDD	Incoming control	Storage	Picking
Other NCs	5	3	2	1

Some examples of major non-conformities documented in 2017 are:

• Temperature mapping exercises had not been adequately conducted, to establish the suitability of the storage areas or to determine the placement of the thermometers in the areas that experience the extremes of temperature fluctuations;
• Unproper monitoring of temperature and humidity for the ambient storage;
• Sofware for stock management not available and failure to prove exisitance of reliable system for recall of medicinal products;

According to the World Health Organization GDP for pharmaceutical products (2010), new temperature-controlled storage areas must be temperature-mapped as part of a fully documented verification process, before the installation is commissioned and handed over by the installer. This is also reflected in GDP requirements under p. 3.2.1 Temparture and environment control which requires initial temperature mapping exercise to be carried out on the storage area before use, under representative conditions. The temperature monitoring equipment should be located according to the results of the mapping exercise, ensuring that monitoring devices are positioned in the areas that experience the extremes of fluctuations. Untill this has been done, its is not safe to store temperature-sensitive medicinal products in such areas. 4 of the companies failed to prove that the mapping exercise was done accordingly.

Computerized systems are required by p. 3.3.1 of the Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01). Moreover, these systems before brought into use, it should be demonstrated, through appropriate validation or verification studies, that they can achieve the desired results accurately, consistently and reproducibly.

Some examples of other non-conformities documented in 2017 are:

• Documentation not compliant with GDP – lack of standard operation procedures (SOPs) for some activities such as incoming control of medicinal products, storage and picking of goods or substantial part of pocessess not described well;
• Lack of Disinfection, disinsection and deratization (DDD) program – reference to GDP: Premises and Equipment.

Previous publication of Stoimenova et al. (2013) shared results from audits against ISO 9001 requirements of wholesalers in Bulgaria. ISO 9001 certification is not obligatory but in 2004 it was set as a requirement for distributors supplying hospitals. Unlike the inspections which seeks to confirm the compliance with the legislation, auditing is an independent, objective assurance and consulting activity designed to add value and improve an organizations’ operations. It helps an organization to accomplish its objectives by bringing a systematic, disciplined approach to evaluate and improve the effectiveness of risk management, control and the governance process. This different approach ensures the different nature of the inspections vs. audits which based on the sample approach might lead to different deficiencies found. The number of NCs found by the certification companies as per Bruinink and Bishara (2018) correspond to the number we observed in the inspection reports. The major NCs found during the audits in period 2002–2012 concerned the storage and transportation of temperature-sensitive medicinal products. Lack of temperature mapping was also an issue during the period 2002–2005 as well as deficiencies related to the monitoring of temperature and humidity in the ambient storage areas. No deficiencies regarding the computerized systems were documented according to the publication, which could be related to the fact that the new EU requirements for GDP were not in force when the audits reviewed have been performed. No new similar data is available in order to ensure adequate comparison of findings. The type of other NCs found during the inspections in 2017 were not detected as deficiencies during the audits in the period 2002–2012.

There is a limited number of publications concerning deficiencies raised during GDP inspections across the EU countries. We found results from inspections performed in Malta, Netherlands and United Kingdom (UK) and reported by Brown (2017a); Bruinink and Bishara (2018a) and Farrugia et al. (2018a) (Table 3).

Table 3.Download as CSV 

Results from GDP inspections Bulgaria, Malta, Netherlands and United Kingdom.

Country	Period	No of companies	NCs found	Nature
Bulgaria	2017	48	Critical-0; Major-6; Other -11.	Major : Computerized systems, Temperature mapping & monitoring. Other: Documentation, Premises and Equipment.
Malta	2013–2018	78	Critical-10; Major-132; Other -633.	Critical : Premises and Equipment, Storage, Documentation, Training and Falsified Medicine. Major: all sections of the EU GDP guidelines. Other: Quality System, Other personnel and Training.
Netherlands	2016	35	Critical-not discussed; Major-56; Other-not discussed.	Critical: Major: temperature management & mapping, quality management, risk management, transportation, Responsible Person, qualification of suppliers and customers. Other:
United Kingdom	2016	1428 inspected, 148 selected for the report.	Critical- not included into the report; Major (for the sample) -209; Other- not included into the report.	Critical : N.A. Major: Quality system, Transportation, Responsible person, Supplier qualification, Equipment, Documentation, Temperature control, Storage and customer qualification. Other: N.A.

According to Brown (2017b), in 2016 1428 distributors were inspected against the GDP requirements in the UK, and nearly 10% of them (148 companies) were sampled for the purpose of analysis of the inspection findings. Critical deficiencies were excluded from the published analysis as they generally cover broader sections of the GDP guidelines and are assessed individually due to the seriousness of the issues. Other deficiencies due to their high number were not included in the published results. Top cited major deficiencies against GDP requirements, found during inspections in United Kingdom in 2016 were those related to the quality system (22%); transportation (13%); responsible person (12%); supplier qualification (10%); equipment, documentation and temperature control (each 9%); storage and customer qualification (each 5%).

In Malta, as reported by Farrugia et al. (2018b), during a period of 6 years 78 companies were inspected aganst the GDP requirements. The number of deficiencies documented were quite a lot: 10 critical, 132 major and 633 other non-conformities. The nature of the deficiencies is shown on Table. Major deficiencies have been assigned to nearly all sections of the EU GDP guidelines. It was found that 44% (n = 34) of wholesale dealers were assigned one or more major findings in Malta.

The results of the 35 GDP inspections in 2016 in Netherlands according to Bruinink and Bishara (2018b) showed 56 major findings. These are in the areas of temperature management in storage areas: temperature mapping and control, quality management issues, transportation issues, Responsible and qualification of suppliers and customers.

The deficiencies found in the wholesalers, inspected in Bulgaria during 2017 are related to equipment, documentation and storage which are represented by 9%, respectively 5% in the findings raised by MHRA in United Kingdom. The nature of major findings in Bulgaria match with those one detected in 2016 during the GDP inspections in Netherlands.

No single NCs was raised by the Bulgarian Drug Agency against the responsible person requirements or transportation unlike the findings in UK/Malta. Bulgarian inspectors did not raise any critical deficiencies in 2017. The percentage of the wholesalers with major deficiencies recorded is significantly lower in Bulgaria in comparison with the other countries (i.e. 6.25% vs. 44% in Malta and 56 major NCs were recorded for 35 inspections in Netherlands vs. 6 major NCs recorded for 48 inspections in Bulgaria). Regarding the quality system, only recommendations were documented during the inspections in Bulgaria.