European Qualified Person Association - Publications/Question
and Answer Documents
Questions and Answers QP Forum 2013:
Q: How can we manage brokers’ registration across Member States?
A: This is a role for each local authority, manufacturers should ensure that their SOPs for procurement of materials from Brokers states that the registration status of the broker should be checked /verified before placing an order.
Q: What is EMA doing to ensure a consistent approach to GDP inspections across the EU (e.g. frequency, scope)?
A: As I understand there has been training of the inspectors at member states, there will be a level of monitoring and readjustments by EMA to ensure consistency of approach. However, I anticipate this to take couple of years, we need to wait and see. Feedback from companies involved in inspection will be valuable and I will try to gather information for the next QP Forum.
Q: What exactly is a GDP certificate? Will this be introduced in all Member States?
A: We are not sure if this is something every member state is going to issue after inspection.
Q: Is it mandatory to have a dedicated area for suspected falsified medicinal products?
A: Unfortunately the new EU GDP section 3.2 parg. 4 (premises), states any falsified medicinal products, expired, recalled and rejected found in the supply chain should be immediately physically segregated and stored in a dedicated area away from other medicinal products. As I understand there is no option for electronic segregation of falsified medicines.
Q: Does the Product Specification File (PSF) necessarily have to be completed before manufacturing and testing? Or is it regarded to be sufficient if it is completed/ filled out at the stage of batch release?
A: According to Annex 13, sec. 9 “the Product Specification File (PSF) should include, or refer to, the following documents:
Specifications and analytical methods for starting materials, packaging materials;
(Specifications and analytical methods for) Intermediate, bulk and finished product;
In-process testing and methods;”
… and all other documents listed in Annex 13, sec. 9
Those documents are typically maintained as controlled documents (“updated as development of the product proceeds, ensuring appropriate traceability to the previous versions”) and have as such to be completed prior to manufacturing and testing, e.g. specifications and analytical methods for bulk product to be completed prior to analytical testing of the bulk product.
Further need of completion of the PSF prior to manufacturing, testing and final batch release, respectively, depends on how the PSF is defined and organized in the individual company.
An overview on different PSF approaches was given during the IMP Pre-conference of the QP Forum 2012 (presentation Dr. A. Stijnen, see USB stick).
Assuming that the PSF in your company is defined as an additional list of documents referencing single controlled documents* the completion of this list prior to final batch release is deemed to be sufficient (“The information should form the basis for assessment of the suitability for certification and release of a particular batch by the QP…”).
*pre-requisite: single controlled documents have been completed at appropriate points in time for the respective manufacturing / testing steps.
(Italics = citations Annex 13, sec. 9)
Q: So many CEPs are withdrawn after inspections. This is very critical for industry. Why are CEPs issued before inspection?
A: CEPs are mainly used to demonstrate whether the quality (impurity profile) of a product is suitably controlled by the Ph. Eur. monograph it refers to. It is not intended to be a proof of GMP compliance. The EDQM follows the rules in place for official inspections of API manufacturers in the EU: inspections are not carried out on a systematic basis but on a risk based selection of sites considered “at risk”.
In EU, the responsibility to verify GMP compliance of API manufacturers is on the shoulders of the manufacturers of medicinal products, and not on CEPs.
Q: When IMPs are important from outside EU; how could I set up a working relationship as a contract QP when it comes to liability and insurance?
As a contract QP you are a “normal” contracting party (i.e. just like any other service provider for the company but with the specific legal responsibilities and risks of a QP) and therefore no employee of the company. That means that you are not covered by any of the insurance programs which companies usually provide for their employees (e.g. D&O insurance). As a result, you should mention that fact – and the related legal risks – during your contract negotiations with the company.
Ideally, there should be an indemnification clause in the service contract providing for that ‘the company indemnifies the contract QP from any and all third party claims related to the services which the contract QP may perform under the service contract’. If your current contract does not contain such provision, you should ask the company to sign an amendment with aforesaid clause.
You can also ask the company to get yourself explicitly included in its D&O insurance contract (some insurers may actually be ready to do so because of the specific situation of the contract QP). From my point of view, this inclusion could be the first part of the contractual provision, followed by the indemnification clause mentioned above.
Q: How do you perform batch record review of batches produced in China, when they are not bilingual or translated?
How about the following options:
Only in audits
Translation of one example
Full translation of every batch
A: Firstly there must be a Technical Agreement and a recent (within the last 3 years) audit of the company. If the company is supplying finished drug product into the EU which needs a QP certification a translation of one batch record as an example and a summary of each batch would be required together with a CoA. It is important that the QP can understand the process and whether there was any excursions/CAPA’s /changes etc. and what they were and how they were concluded. If this was a new company to the QP, and especially if supplying parenteral drugs, I would initially want an audit at least every 12months until the relationship was fully established.
If the company was supplying API’s then the Technical Agreement and Audit requirements and ability to understand any changes/excursions would still apply. I would also want to see a copy of the process flow document together with all the critical process parameters and be able to identify these comply on a batch to batch basis together with a CoA.
The companies would also need to comply with all aspects of 2011/62/EU to the satisfaction of the QP and be accompanied by a written confirmation from the competent authority of the exporting third country which … confirms that the standards of good manufacturing practice and control of the plant are equivalent to those in the EU, (unless a waiver has been granted).
Q: Does the manufacture and purchase of raw materials represent an activity governed by Chapter 7?
A: In principle, Chapter 7 covers all outsourced activities. Therefore, the general requirements for supplier selection, approval and performance management apply equally to raw materials as to other outsourced activities. There may not be a need for Quality/Technical Agreements with the supplier; this will depend on the nature of the arrangement between the parties. For example, if the purchaser contracts the supplier to manufacture raw materials for them, then the arrangements would need to be covered by a Quality/Technical Agreement. However, if the purchaser simply buys raw materials from the supplier a QTA would not be required.
Q: Does the company which imports a medicinal product into the EU have to hold a Manufacturing Authorisation? Or can the product be imported on the basis of a Manufacturing Authorisation of a company in another EU country?
A: The importer of a medicinal product from outside the EU/EEA is required to hold a Manufacturer’s Importation Authorisation to cover such importation. An exemption to this applies if the product is being imported solely for re-exportation outside the EU/EEA. The ownership of the product will determine the party that needs to hold the MIA.
Q: After revision of Annex 16, will all batches of a finished product manufactured and packed in a 3rd country require sampling and full release testing within the EU?
A: Drug Products release testing if the batch was manufacturer in a 3rd country and testing is not exempted under the provisions of an MRA always have to be performed on EU soil according to directive 2001/83/EC. The current draft text of Annex 16 is very specific on sampling as well, such as that sampling has to be performed “on each occasion” after importation. Purpose of this explicit requirement is on the one hand side to control the supply conditions and be sure, that samples reflect supply conditions. On the other hand this requirement obviously should ensure that the sample is taken from the product shipped in order to avoid falsification. Applying this requirement would mean, that the product needs to be sampled and tested on each shipment on bulk drug product or finished drug product whatever is imported. – The QP association commented that this requirement should be modified
3.4.6 Sampling of imported products … taken after arrival in the EEA
• Sampling should follow a risk based approach. This would be in line with the upcoming revision of chapter 6, section 6.12., e.g. the sampling in the country of origin should be an option
• Clarification for IMPs, that full testing is not required upon importation (2003/94, Art. 11(2))
Q: If an audit required by Annex 16 is performed by corporate QA or a global QA function of the same company but part of different legal entity (e.g. from US), will I need a contract or is an SOP sufficient?
A: European understanding on different legal entities even within the same larger company has to be considered as independent to each other in terms of GMP. According to Chapter 7 EU GMP all services contracted out should be covered by a contract. If such a service is provided to the QP by a global function it should be covered by a contract. Topics to be considered are provisions of influence on sequence, audit agenda, audit reports availability, auditor rating, and possibilities to accompany the audit as an auditor.
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