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European Qualified Person Association - Publications/Question
and Answer Documents
Role of the Qualified Person in the Supply Chain
Q: What are the most critical elements of the supply chain requiring QP involvement?
A: First of all QPs must define the relevant supply chain, for many companies this starts from procurement of the raw materials (e.g. APIs, excipients, packaging components etc.), ending when the product reaches the customer. The QP then needs to identify what input is required at each stage, then either personally provide that input or delegate the activity to another person or department within the company and ensure to stay informed.
Q: Where does the responsibility of the QP end? When the product is handed over to wholesaler/RP?
A: Normally once the product is delivered to the customer it is assumed that the customer will take responsibility for the product from the point of receipt. If the product is supplied to a wholesaler, it very much depends on who owns the product, if the wholesaler has purchased the goods, then they should take responsibility. However, if the product at the wholesalers belongs to the QP’s company, then the QP continues to have the responsibility for the goods whilst at the wholesaler. The responsibility for the product at each stage of its life cycle should be clearly defined in the internal procedures, and where external parties involved (e.g. wholesalers) in the Technical (Quality) Agreement between the company and the wholesaler. It is possible for the QP to delegate this responsibility to the RP at the wholesaler, but this must be clearly defined (including the limitation which may apply) in the technical agreement. Please note that the QP retains the responsibility for recall of the products in the market place as well as ensuring that any product complaints have been fully investigated and appropriate corrective actions have been taken.
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.
The Qualified Person and Contract Manufacturing
Q: In case of an existing quality agreement, is it sufficient to rely on the certification of other QPs or should there be a review of for example batch records and deviations for the final batch certification?
A: In theory it is sufficient to rely on the certification of other QPs if the final certifying QP has knowledge of the other QPs and of the quality systems within which each of them is operating. In practice the final QP should be aware of any matter that might affect his/her decision to certify the batch (for example deviations or OOS results/investigations) and hence should review documentation from time-to-time, particularly if contract manufacturers and contract QPs are involved in the process.
Q: Is it allowed that a Quality Assurance function of the contract manufacturer can perform the audit of the contract manufacturer on behalf of the QP of the contract giver?
A: The audit must be performed by a qualified auditor who has no conflict of interest in the company being audited. This would mean that the contract manufacturer could not audit himself. But it would be quite acceptable to have an independent third-party auditor carry out the audit on behalf of the QP. It does not have to be carried out by the QP in person.
Q: PQR: A contract manufacturer is responsible for final batch certification but is not the MA-holder. Does the MA-holder have to have a copy of the PQR?
A: The answer is given in the full text of the EU Guidelines to Good Manufacturing Practice Part I, Chapter 1: “The manufacturer and, where different, marketing authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection. (…)
Where the marketing authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the product quality review.”
The marketing authorisation holder is a key player and must have a copy of the PQR. How else could he be able to evaluate the result of this review?
Q: A contract manufacturer’s QP certifies a finished product, confirming the compliance with GMP. The QP of the MA-holder makes the final batch certification, confirming compliance with the MA. If the MA-holder is outside the EU, must the contract manufacturer’s QP confirm compliance with the MA?
A: Yes. Irrespective of the final release of the batch by some “QP” function outside the European Union it is the clear requirement of Article 51 of Directive 2001/83 that the QP releasing the batch in the EU has to ensure that
1. (a) “in the case of medicinal products manufactured within the Member States concerned, that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization;”
Usually the Technical or Quality Agreement contains an annex, describing the requirements of the marketing authorisation like manufacturing process, test methods and specifications. This is signed by both parties. Any changes and variations then have to be handled via a change control system. This ensures that the QP of the contract manufacturer always has the appropriate information.
Q: A contract manufacturer’s QP certifies a finished product, confirming the compliance with GMP. The MA-holder provides artwork and labelling. What assurance should the QP of the contract manufacturer take as a minimum about compliance of artwork/ labelling with the MA?
A: There must be a Technical or Quality Agreement describing the requirements of the marketing authorisation like manufacturing process, test method and specifications. In case the contract manufacturer also performs secondary packaging, all relevant information of the packaging and labelling applying at the time of signature of the agreement must be included. This is signed by both parties. Any changes and variations have to be handled via a change control system. This ensures that the QP of the contract manufacturer always has the appropriate information.
Q: How do you perform batch record review of batches produced in China, when they are not bilingual or translated?
A: There must be a Technical Agreement and a recent audit of the company. If the company is supplying a 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 will 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 12 months until the relationship was fully established.
If the company is supplying APIs, the Technical Agreement and audit requirements and ability to understand any changes/excursions will 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).
APIs and other Starting Materials
Q: Raw material for API production: are on-site audits required for all suppliers?
A: No; however a risk based supplier quality audit programme should be established. It is important to perform a risk analysis to determine whether a supplier needs to be audited.
Q: A batch of an API has been released before all testing and final approval was completed. How do I handle this in the certification of the final product?
A: Within the EU shipment of unapproved API is not be acceptable under EU law. For shipments outside of the EU the local laws would have to be checked. It would be necessary to check what is stated in the API producer’s SOP with reference to shipping unapproved material and whether that contravened any regulatory laws. The quality agreement between the API producer, the contract manufacturer and the MA holder should also be looked at to see if there is any reference to the movement of unapproved material being acceptable. It is not good practice to ship unapproved materials and as such this should have been picked up by the quality person releasing the API. Further, a deviation should have been raised and a full investigation carried out as to the root-cause. In addition the contract manufacturer should have quarantined this material on receipt and also raised a deviation to find out what went wrong. If this was a one-off incident and not a fundamental break down of the API’s manufacturers and/or the contract manufacturers Quality System, then as long as the API was formally approved, you should reference the deviation report and as long as everything else was in order, certify the final drug product. However, if this incident was part of a systematic failure of the Quality System would recommend not to certify the drug product as the potential for other GMP non-conformances would be too great. The follow-up to the deviation could involve an audit of the API producer initiated by the MA holder.
Q: How far down the manufacturing supply chain (finished API – intermediate – starting materials) has the QP to place consideration when preparing a GMP API declaration?
A: Based on a risk-assessment of the process the QP must evaluate the critical materials or critical steps. The QP can base his decisions on statements of authorised persons within a QA-System.
Q: API-supplier audit: If a big company is purchasing the API in bulk and then repackaging it and doing the QC testing and release, do I as the final QP need to audit the bulk manufacturer?
A: It is the responsibility of the QP for the MAH to assure that each step in the supply chain from the starting material onwards has been manufactured in accordance with GMP. In this example it would be necessary for the final QP to either audit, or have an approved auditor carry out an audit of the bulk manufacturer. This would be in addition to having a Quality Agreement in place between the bulk manufacturer and the drug product producer.
Q: Is a QP responsible to release an API?
A: No. The EU Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Part II Basic Requirements for Active Substances used as Starting Materials does not contain a reference to a Qualified Person. It is the Quality Unit that has this responsibility.
But the QP is required to confirm in an EU marketing application that the API has been manufactured in accordance with Part 2 of EU GMP. It is important to emphasise that it is the QP who is certifying the final drug product and who has to give the assurance that the API has been made in accordance with the relevant GMPs. Hence the QP must have access to appropriate documentation including supplier audits (not necessarily by the QP themselves) together with a Quality Contract (Agreement) signed by both parties, to assure her-/himself that the API does comply with the valid standards.
However, some Member States may have differing national regulations that might require QPs for certain APIs, e.g. in Germany those APIs derived from a human, animal, microbiological source, and manufactured by biotech methods.
Q: How are APIs covered under the MRA? Do APIs from non-MRA states have to be retested?
A: An API has to be re-tested on receipt no matter where it comes from. In this case the MRA is irrelevant. Testing can only be reduced or eliminated (but the ID still must be done) until the supplier has been fully qualified and has provided materials over a period of time with no issues. An on-site audit of the supplier would also have to be undertaken to ensure the supplier is meeting the required standards.
Q: What is the minimum requirement/ expectation for supplier qualification of excipients? Are on-site audits required?
A: The minimum requirement is that starting materials (including excipients and others) and packaging materials are only purchased from approved suppliers.
There is no regulatory requirement for on-site audits for excipient suppliers, this is only mandatory for APIs that are manufactured under GMPs. Nevertheless, own audits or qualified third party audits or joint audits should be considered as a part of the qualification programme for suppliers and distributors of excipients besides quality and delivery history, full analysis and performance based tests.
Q: Does the manufacture and purchase of raw materials represent an activity governed by Chapter 7 of the EU GMP Guide?
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 (QTA) 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: The notice to applicants requires the submission of a declaration signed by the Qualified Person (QP) that the active substance used is manufactured in accordance with GMP. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration?
A: Full compliance with GMP for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products, the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business.
Alternative sources should normally be sought, but in exceptional circumstances the manufacturing authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation.
The declaration provided by the QP should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach, which can be used as a basis for discussion on related amendments to guidelines in the future.
(source: EMA Q&A)
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