Common and Typical GDP Violations
The wholesale distribution of medicinal products requires a Wholesale Distribution Authorisation (WDA). Within the European Union, these authorisations are issued by the national competent authority of the member state in which the wholesale distributor operates. The member states shall enter the certificates of good distribution practices which they issue in the EudraGMDP. This database is maintained and operated by the European Medicines Agency (EMA).1 If an inspection shows that the wholesaler's GDP compliance cannot be confirmed, a so-called GDP non-compliance report is issued.
The explanatory notes to the database state: "A certificate of Good Distribution Practice (GDP) is issued to a wholesale distributor by the national competent authority that carried out an inspection if the outcome of the inspection confirms that the wholesale distributor complies with Good Distribution Practice, as provided by European Union legislation. If the outcome of the inspection is that the wholesale distributor does not comply a statement of non-compliance may be entered into EudraGMDP. GDP certificates and statements of non-compliance may be issued to wholesale distributors of medicinal products and distributors of active substances."2
Documents issued by UK authorities up to and including 31 December 2020 remain available for consultation in EudraGMDP. However, as of 01 January 2021, they are no longer included or updated, with the exception of documents relating to sites in Northern Ireland.
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Number of Reports
The number of GDP non-compliance reports entered into the EudraGMDP database is rather small. As of mid-April 2022, a total of 26 documents were listed, 25 of which are from the period covered in this article - between 2014 and 2021.
The following table provides an overview of how the reports are spread over the various years.
|Year||Number of GDP noncompliance reports|
As can be seen from the table below, most GDP non-compliance reports were issued by German authorities in the period from 2014 to 2021. The table also shows that many countries have not yet entered any GDP non-compliance reports into the database.
|Country||Number of GDP non-compliance reports entered between 2014 and 2021|
Reasons for Issuing the Reports
The table printed below provides an overview of the deficiencies that led to the issuing of the 25 GDP non-compliance reports from 2014 to 2021. In each case, an attempt has been made to assign the deficiency in question to one of the requirements from the EU GDP Guidelines.3 Since the individual deficiencies are generally only described very briefly, certain imprecisions in the categorization cannot be excluded.
The total number of violations is much higher than the number of reports, as most reports list several independent aspects. Typically, therefore, it is not a single violation but rather a variety of deviations that led the respective authority to issue the GDP non-compliance report. However, the report itself often lists only the critical and major deficiencies, although there may have been other findings as well.
CHAPTER 1 — QUALITY MANAGEMENT
|1.2. Quality system|
|No adequate documentation for acting according to the procedures|| |
|Deviations from established procedures not documented or investigated|| |
|No GDP-compliant quality assurance system in place|| |
|No appropriate quality risk management established|| |
Inappropriate corrective and preventive actions (CAPA)
|It is not ensured that the product delivered maintains its quality and integrity and remains within the legal supply chain during storage and/or transportation|| |
|QA department understaffed|| |
|No change control system in place|| |
|Doubtful reliability of the CEO due to an ongoing criminal procedure|| |
|Other / general deficiencies (not further specified)|| |
|1.3. Management of outsourced activities|
|No sufficient control and verification of the outsourced activity|| |
|1.4. Management review and monitoring|
|No assessment of performance indicators that can be used to monitor the effectiveness of processes within the quality system|| |
CHAPTER 2 — PERSONNEL
|2.2. Responsible person|
|Services / availability of a responsible person not ensured|| |
|Responsible person does not fulfil his/her obligations|| |
|Doubtful reliability due to an ongoing criminal procedure|| |
|No regular GDP training performed / no training documentation available|| |
CHAPTER 3 — PREMISES AND EQUIPMENT
|Inadequate premises and storage facilities / storage facilities not qualified|| |
|No adequate access control system to prevent unauthorised access to the premises|| |
|Inappropriate cleaning|| |
|No pest control programme|| |
|No physical segregation of non-marketable medicinal products|| |
|3.2.1. Temperature and environment control|
|No or insufficient temperature and environment control|| |
|Temperature monitoring not performed by calibrated measuring instruments|| |
|Location of temperature measuring instruments not sufficient to meet the required purpose|| |
|3.3.1. Computerised systems|
|The computerised system has not been properly validated|| |
|3.3.2. Qualification and validation|
|Missing validation or qualification reports|| |
CHAPTER 4 — DOCUMENTATION
|Documentation not available or missing|| |
CHAPTER 5 — OPERATIONS
|No measures implemented to minimise the risk of falsified medicinal products entering the legal supply chain.|| |
|General deficiencies (not further specified)|| |
|5.2. Qualification of suppliers|
|Inappropriate qualification of suppliers|| |
|Failure to conduct due diligance before purchasing from a new supplier|| |
|5.3. Qualification of customers|
|No qualification carried out / no system in place / qualification inadequate|| |
|5.4. Receipt of medicinal products|
|Inadequate receipt control (for counterfeit drugs)|| |
|Insufficient documentation|| |
|General deficiencies|| |
|No temperature records available|| |
|General deficiencies (not further specified)|| |
|Documentation not available|| |
CHAPTER 6 — COMPLAINTS, RETURNS, SUSPECTED FALSIFIED MEDICINAL PRODUCTS AND MEDICINAL
|Inappropriate handling of complaints|| |
|6.3. Returned medicinal products|
|Inadequate handling of returned medicinal products|| |
|6.4. Falsified medicinal products|
|Trading in falsified medicinal products (not purchased from legal supply chain)|| |
|Missing connection to securepharm system|| |
|6.5. Medicinal product recalls|
|Effectiveness of the arrangements for product recalls not ensured|| |
|Responsibility not fulfilled|| |
CHAPTER 7 — OUTSOURCED ACTIVITIES
|7.2. Contract giver|
|Use of contracted entities without acceptable qualification|| |
|No audits carried out at contractor acceptor|| |
CHAPTER 8 — SELF-INSPECTIONS
|No regular self-inspections performed|| |
CHAPTER 9 — TRANSPORTATION
|No temperature records available / no temperature monitoring performed|| |
|Temperature deviations not adequately investigated|| |
|Incorrect and/or incomplete information given to inspectors / Failure to comply with the reporting requirements|| |
Many of the deficiencies documented in the GDP non-compliance reports are related to the duties of the responsible person.
According to chapter 2.2 of the EU GDP Guidelines, the wholesale distributor must designate a person as responsible person, which should fulfil his or her responsibilities personally and should be continuously contactable.
As can be seen from the overview table, in five cases the availability of a responsible person was not even ensured. In five other cases, a responsible person was available, but he or she did not fulfill his or her duties. In one case, there were doubts about the reliability of the person due to ongoing criminal proceedings.
The responsibilities of the responsible person include the organization and control of the wholesale operation. In addition to logistical activities, the responsible person also has a lot of other duties, such as4:
- Ensuring that initial and continuous training programmes are implemented and maintained;
- Approving any subcontracted activities which may impact on GDP;
- Ensuring that self-inspections are performed at appropriate regular intervals following a prearranged programme and necessary corrective measures are put in place;
- Approving any returns to saleable stock;
Thus, even most of the findings listed in the overview table can be linked, at least indirectly, to the fact that the responsible person in question did not perform his or her duties in compliance with the EU GDP Guidelines.
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One area of focus in this regard relates to falsified medicines. In addition to (intentional) trade in counterfeit drugs, insufficient checks and inadequate measures to minimize the risk of counterfeit medicines entering the legal supply chain were criticized on numerous times. The inadequate qualification of suppliers, which was mentioned in as many as nine GDP non-compliance reports, and the lack of due diligence mentioned in two cases should also be seen in this context. According to chapter 5.2 of the EU GDP Guidelines, appropriate qualification and approval of suppliers, should be performed prior to any procurement of medicinal products. Before entering into a new contractual relationship with a new supplier, a wholesaler should carry out due diligence checks. The purpose of this is, among other things, to minimize the risk of counterfeit medicines entering the legal supply chain.
Finally, the qualification of customers must also be mentioned. According to chapter 5.3 of the EU GDP Guidelines, wholesale distributors must ensure they supply medicinal products only to persons who are themselves in possession of a wholesale distribution authorisation or who are authorised or entitled to supply medicinal products to the public. In seven cases, companies did not comply with this requirement because either no qualification was carried out or the qualification was considered insufficient by the authority.
About the Author:
Dr. Markus Funk
... joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.
1 A free read only access to the EudraGMDP database is available via http://eudragmdp.ema.europa.eu/.
2http://eudragmdp.ema.europa.eu/inspections/selectLanguage.do; accessed 11 April, 2022.
3 Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use – 2013/C 343/01.
4 Cf. chapter 2.2 paragraph 5 numbers i to xii of the EU GDP Guidelines.