Extended QP responsibilities based on national legislation
According to directive 2001/83/EC each manufacturer has to have at his disposal at least one Qualified Person (QP). Within the directive and in the various chapters of EU GMP Part I and respective Annexes a variety of responsibilities are stated but only a limited number of tasks are assigned which must be personally executed by the QP. The responsibilities defined in the directive or the GMP Guide reflect all responsibilities and tasks fully harmonized across the European Union but the legal system for medicinal regulation allows that additional requirements are imposed on a national basis.
This survey intended to identify by which extent national laws of member states may or may not broaden the responsibilities and personal tasks of the QP. The membership of EQPA from all member states and beyond was expected to lead to more insight and to validate this area of concern. The results will be integrated into the Annex of the EQPA QPs Good Practice Guide as appropriate.
Responses have been collected from 89 survey participants - lower than expected - representing 20 EU member states with 76 responses, 2 EEA countries with 3 responses and 7 additional countries with 10 responses. While EU and EEA member states are expected to be highly aligned with EU directives and regulations more flexibility may be expected in other countries. Table 1 on the next page shows the countries from where we received responses.
The authors have insight into some of the national legal expectations and challenge some answers mainly from their own home country perspective. These countries include United Kingdom, Austria, and Germany. Applying such experience to the overall pattern of responses results in the following general impressions:
- The relatively low number of responses demonstrates a low level of interest or awareness of the topic. This may be driven by
- lacking appropriate training, or
- inconsistent enforcement through national inspections
- Comparison of responses from within the same member state is surprisingly often inconsistent
- For several member states no additional national requirements are known by the QPs
- Assuming that stricter responses with references to additional national responsibilities are well founded those who are not aware of such national legal expectations are likely to be at risk of executing their duties outside of compliance.
- Those legal national requirements the authors are aware of in their home countries are not consistently or comprehensively identified and reflected in the responses
As usual, interpretation of survey results is not always easy. Misinterpretations of the pattern of responses are possible. The authors therefore are looking for consistent patterns of responses or definite references on any requirements mentioned.
This survey specifically focused on requirements directly expressed in national law or ordinances. The accuracy of the answers may have been diluted by experiences during inspections and solutions implemented via the company´s internal quality system. In question 3 we asked for additional legal requirements. Based on the national background of the authors we offered a list of choices which was limited to requirements which are currently effectively expressed in the laws/ordinances of either Germany or Austria. As we can see in figure 1 the answers are not uniform across EU. More than 40 % of QPs are not aware of any additional national requirement they have to consider. Nearly 15 % of the QPs indicated that they are not sure, or they do not know of additional national requirements. One of the duties of QPs is to certify (or confirm) that all applicable laws including national laws have been followed for the batch in question. Not being sure of the legal requirements to be met obviously indicates a need for further investigation and training.
All the offered survey choices were confirmed by several QPs. Across participants from the same member state or country answers were often inconsistent. Although some QPs are sure, that they do not have to consider specific national requirements, often from the same country, other QPs are sure, that they have to consider one or more national requirements. These deviations are discussed in this essay. Each QP should investigate his own situation to fully understand his nationally defined duties.
The survey shows that some member states and other countries probably have no additional national requirements for QPs where all responses confirm this. Some countries may be represented by only one participant though. Table 1 attempts to differentiate countries by the pattern of responses received. Responses out of 10 countries marked in yellow do not indicate any additional national requirement. From 8 countries all responses confirm additional national requirements while the remaining 11 countries show mixed and therefore conflicting responses.
Berlin, Germany13/14 December 2023
Root Cause Analysis
Table 1 shows the responses by country and provides an overview of the patterns of responses
Figure 1: What QPs consider as additional nationally defined legal responsibilities
Table 2 details all answers given and which additional requirements are defined according to the awareness of at least some of the QPs in this country. Some responses may more reflect the perception during inspections and additional steps imposed by inspection observations rather than clearly expressed requirements in national law. Participants from countries with mixed patterns of answers are especially recommended to assess their local situation again. The authors hope that the overview of answers given help to identify gaps and opportunities more easily.
Twelve responses representing six member states indicate that they are not sure or do not know whether additional national requirements apply. Taking on the responsibilities of a QP without clarity on the legal expectation is precarious. Appropriate training should be considered to close this unfavourable gap. The results of this survey and this discussion of the results may also provide the information needed.
Table 3 correlates those countries with additional responsibilities by national law as identified at least once in responses from those countries. It shows also the share of confirming answers out of the total number of answers from those countries.
The survey included further more specific questions. The next two questions addressed potential additional batch related expectations based on national law.
A small share of 10 % of the responses confirmed additional national batch related expectations on certification for human medicinal products although the references given were EU GMP and therefore applicable also in other markets.
No additional requirements have been identified with the same question on veterinary medicinal products. With the new Veterinary Medicinal Products Regulation 2019/6 these national expectations should have ended.
Asking for additional responsibilities to be considered for Advanced Therapy Medicinal Products (ATMPs) reference to related regulations such as human tissues or blood regulations were noted in some of the responses.
6/7 February 2024
Combination Products - Live Online Training
For investigational medicinal products (IMPs) no additional tasks related. to certification exceeding the new guidelines of GMP for IMPs have been identified. Brexit was an issue for additional awareness both in the EU as well as in NI/GB. Such issues while existing should not be considered national as Brexit applies to all member states in the same way. National special solutions have of course been introduced in Great Britain to adopt to Brexit related new circumstances.
A few responses see potential additional national requirements for testing upon import on EU soil. Though, references made are covered by Annex 16 or the directive 2001/83/EC or the Regulation 2019/6 for veterinary products. Brexit caused issues for importation testing, which should not be different from member state to member state. For Northern Ireland some adaptations were needed on a local basis.
|Responsibility assigned to the QP|| |
|Denmark, Italy, Norway, |
Germany, Malta, Romania
|Author the release and certification SOP||12 out of total 30 responses from these countries|
|Belgium, France, Malta, Norway, |
Sweden, United Kingdom,
Switzerland, South Africa
|Sign Quality Agreements||19 out of total 58 responses from these countries|
|France, Ireland, Italy, Norway, |
Sweden, United Kingdom,
Germany, Israel, Malta,
|Perform the recall decision||19 out of total 43 responses from these countries|
|Austria, Denmark, Germany, |
Italy, Netherlands, Romania,
United Kingdom, South Africa,
Belgium, France, Ireland,
Malta, Norway, Sweden,
|Approve the Product Quality Review||27 out of total 72 responses from these countries|
|France, Italy, Netherlands, Romania, |
Germany, Malta, Norway,
|Approve Audit Plan||11 out of total 49 responses from these countries|
|Belgium, Ireland, Malta, Norway, |
Slovakia, United Kingdom,
Germany, Italy, Netherlands,
|Participate in audits||18 out of total 60 responses from these countries|
|Belgium, Germany, Malta, Norway, |
Israel, United Kingdom, France,
Denmark, Netherlands, Romania,
|Approve Audit reports||14 out of total 60 responses from these countries|
|Belgium, Germany, Italy, |
Netherlands, Romania, Israel,
Czech Republic, Ireland, Malta,
Norway, Sweden, Switzerland
|Approve Deviation Investigations||18 out of total 64 responses from these countries|
|Austria, Italy, Netherlands, Romania, |
Denmark, Malta, Norway, Sweden
|Approve the Validation Master Plan||11 out of total 32 responses from these countries|
|Austria, Germany, Malta, Norway, |
Denmark, Italy, Netherlands,
|Approve the Master Batch Record of the same site||10 out of total 46 responses from these countries|
|Denmark, Italy, Netherlands, |
Romania, Germany, Malta, Norway
|Approve the Master Batch Records of all sites involved in the supply chain||7 out of total 43 responses from these countries|
|Austria, Germany, Malta, Romania, |
Israel, United Kingdom, Denmark,
Italy, Norway, Sweden, Switzerland
|Approve Re-work and Re-processing||18 out of total 45 responses from these countries|
Table 3: Detailed number of responses in comparison to total number of responses from countries identified as imposing additional QP responsibilities
Figure 2: additional batch related elements to be considered for batch certification
According to a few responses from Great Britain (GB) there were national implications relating to safety features as a result of leaving EMVO, the EU serialization system, including transfer of serialized products through GB to other EU member states or Northern Ireland. These transitions and exceptions should not be considered national as transition periods and exceptions for smaller EU markets have always been defined by the European Commission. Some uncertainty or different national approaches are reflected in responses when asking about extended QP responsibilities under GDP. This is understandable as GDP is applicable also to manufacturers and not only to wholesalers. EU GDP regulations differentiate clearly the QP of the manufacturer and the responsible person of the wholesaler. Some QPs may have both roles or the point of handover of responsibility may not be clearly defined.
The last question as usual asked for areas missed by the survey. Some additional aspects of missing harmonization were added by the respondents. QPs are often assigned additional responsibilities where there is no harmonising EU legislation. This is the case for QPs in API manufacturing or for investigational medicinal products for veterinary use, which are required in some member states. Deviations from the standard rules were perceived for certification of Covid vaccines during the crisis and the role of the QP in falsification and reporting to the Authorities may be handled differently in member states.
Discussion and Conclusion
The survey provides an improved and arguably a clearer view on national approaches and expectations that QPs may be faced within one country based on national law rather than in all countries. The huge variety of answers though, indicates that many if not most of the QPs are not sure, which full set of requirements are defined at national level. This observation raises several areas of concern. QPs not aware of their duties likely risk not fulfilling their duties posing a severe risk to the QP. On the other hand, if such duties can obviously be neglected by many why do they exist, if indeed they do? Does the fulfilment of all such national duties increase the safety of the patient? This conclusion would be very interesting when in many member states no such additional national duties exist.
Differences between countries obviously exist. Some national laws may clearly describe additional personal responsibilities for QPs. Often the reported detailed expectations may in some cases reflect observations made by inspectors or requirements based on the organization´s Quality systems rather than literally defined by national laws. Those who see their own position not reflected in the answers of QPs operating in the same country may be motivated to re-assess their situation. Irrespective of whether we like it or not or would like to lobby for changes to the law QPs have to follow applicable current law. Not doing so is irresponsible.
This may lead to additional tasks, but it would be a significant relief of overwhelmed QPs if these tasks currently performed by the QP could be delegated as well. The pattern of answers, especially to question 3 have not met the expectations of the authors. For Germany only one out of the given 12 answers should apply (writing the release SOP). Eleven of the choices instead have been chosen from the cumulated German QPs. For the United Kingdom only one additional personal responsibility is known to the authors concerning the retention of documentation of batch certification. Oddly, no response received from UK highlighted this. For Austria 11 out of the 12 answers have been expected and only 4 have been confirmed by the cumulated Austrian QPs. No QP pointed to fiscal importations as an area of responsibilities. This missing accuracy and congruency of answers is at least astonishing.
These observations confirm that the clarity of requirements defined by national law and their enforcement by inspections is an area of concern and needs reflection by QPs. QPs may decide this is an area for additional training or otherwise assessment of the law. If a gap exists this should be closed as soon as possible.
Given the few responses received from several countries no proof is given for the additional responsibilities, which other colleagues from these countries should have known about. The QP has to certify that all laws including the national laws are met. Can this be reliably expected in light of the uncertainty reflected by the survey?
Another interesting view is the matter of comparability. By definition certifications and confirmations given by QPs are fully equivalent within EU independent of the member state the QP is located in. We assume that all QPs follow the European GMP, laws and regulations. If one QP in one country always personally has to perform all such national tasks before he can certify a batch, can the certification performed by a QP who did not have to fulfil these tasks or another pattern of tasks provide a fully comparable certification statement?
QPs should have a high interest in harmonization of responsibilities across EU and their implementation. Therefore, EQPA will continue to strive for such harmonization. From the perspective of EQPA no additional national responsibilities or duties should be necessary that exceed those harmonized at EU level. Surveys like this one provide the required transparency to identify the need for specific lobbying and help to form our argumentation. Also, the significant uncertainty reflected by QPs themselves is a good response and message. The colorful pattern of responses demonstrates, that national special solutions and interpretations are not effective. European references on responsibilities and duties are well understood by all QPs. Thanks to all who participated.
About the Author
Dr Urich Kissel
... is Chairman of the European QP Association. He was supported by David Cockburn and Georg Goestl, Board members of the European QP Association.