Q: If you want to qualify a wholesaler that will provide me with commercial products for the use in clinical trials, as a comparator or for the manufacture of IMPs, what controls are expected to ensure that the wholesaler doesn’t provide me with falsified products? What if the wholesaler is not willing to disclose the supply chain?
A: a) The wholesaler should be qualified by an audit (e.g. check facilities, availability of licenses, e.g. MIA for importation of third country comparators, supply chains for comparator sourcing, tools; please do also refer to the presentation of Mr. Paul Hargreaves, MHRA at QP Forum 2016).
A quality assurance agreement should be in place to agree on the sourcing supply chains, regular check for recalls by the wholesaler, rapid communication line, etc.
b) In this case it is recommended not to use the wholesaler.
General remark: Within the TransCelerate initiative a comparator network has been established. More information is available on the TransCelerate website.
Q: If more than one third party manufacturer is listed [in the dossier], do we need to keep them all “active” to start production immediately if needed?
A: For EU Health Authorities the expectations are clear on having all registered parties qualified and prepared for their intended manufacturing activity/ies as well as having all active parties within a supply chain being registered.
Q: What is the QP responsibility when it comes to audits performed by the API manufacturer of their suppliers? Should our auditor look at the audit programme of the API manufacturer? Can we demand to see the respective audit reports?
A: Directive 2001/83/EC in correspondingly chapter 5 and Annex 16 all define the supply chain starting form starting materials for API manufacturing down to the point of certification. Correspondingly all involved parties should be subject of GMP and audits and subject to QP GMP compliance assessment. Audit planning and audits execution as well as the handling of observations and deviations from GMP on any party within this supply chain including any suppliers should be a routine subject during audits.
Q: If we have audited our API supplier more than three years ago, would a remote (paper based) audit be sufficient?
A: Within your Quality system strong risk assessments procedures should support your approaches. Dependent on your risk assessment a longer period may be acceptable to support the needs of the QPs assurance of GMP at your API supplier. Any issuance of a QP declaration should be supported by such risk assessments, if no audit report younger than 3 years is available. – It is upon the discretion of the QP, whether he is satisfied to assess and confirm GMP compliance on such basis.
Q: An MAH has a technical agreement in place with a CMO for the manufacture of medicinal products. MAH has audited CMO and has delegated the responsibility to audit the API supplier to the CMO. The CMO does also manufacture APIs for some of our products. Is it acceptable for the QP of the MAH to create/ sign the QP Declaration on the basis of audits performed by the CMO, which in some cases are self inspection reports?
A: An API manufacturer usually does not have a QP and such API manufacturing activities should not be part of the same manufacturing license of a drug product manufacturer where the QP is situated, even if both activities are executed at the same company/site. From the perspective of the QP it should be ensured, that QP declaration should refer to audits performed by personnel not belonging to the API manufacturing organization. As such personnel from the drug product manufacturing organization or an independent party (refer to Annex 16) should have performed such audits. Additional explanation may be given in the respective field of the template.
Q: Is there a time period defined for prospective validation? How much time would be allowed to complete a prospective validation?
A: No definition in EU-GMP requirements about any time-frame.
Q: Can we transfer a product from one warehouse to another warehouse before the product is certified for release?
A: Annex 16 chap. 4.1: Until a batch is certified, it should remain at the site of manufacture or be shipped under quarantine to another site which has been approved for that purpose by the relevant Competent Authority.
Q: Data Integrity: what do you expect to see in a company? SOP/ Policy on Data Integrity, computerised systems, processes? Anything else?
A: If requirements from Annex 11 (computerized systems) for electronic data and EU-GMP Guideline Part 1 chap. 1 (documentation) for paper based documents are fulfilled in conjunction with "good documentation practice" there need no additional documents to be created to assure or proof data integrity to EU-authorities.
Q: Scale-up batches: can I certify them for release and sale?
A: Annex 15 chap. 5.8, which is on validation for commercial products/processes: Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified or specified in other sections of EudraLex, Volume 4.
Only for submission batches other batch sizes may be possible acc. EMA-Guideline on process validation for regulatory submission (separate guidelines for medicinal products and biotech-products). Batches can only be commercialized, if they fulfill all Annex 15 requirements.
Q: Concurrent validation: the first batch passes, the second batch fails. Do I need to recall batch No. one?
A: That is to be discussed with the competent authority, because there is no detailed requirement exactly for this case. Annex 16 chap. 1.7.12 says, that batches can only be certified if process is in a validated state. Therefor the requirements for certification are retrospective not fulfilled for the first batch. Definitely your validation master plan or validation plan should predefine how to deal with the situation of failure in concurrent validation.
Generally, concurrent validation pre-sets a detailed product- and process-knowledge, which from my point of view is not existing, if this happens. That's why, concurrent validation is the wrong validation-approach for such a product.
Your approach on such a situation should be synchronized with your competent authority to be on the safe site.
Q: After a successful accelerated stability study, the long term stability study fails. What is expected to do with the batches manufactured between accelerated study and long term results?
A: Annex 16 chap. 1.7.14: Any regulatory post-marketing commitments relating to manufacture or testing of the product have been addressed. On-going stability data continues to support certification.
Following from this, certification requirements are not fulfilled. Batches can only stay on market as long as on-going stability data show stability over shelf-life.
Q: Serialisation of multi country packs: Reimbursement codes are included in the matrix, making the matrix code unique for a country. How can we deal with multi country packs?
A: As I understand the system, a unique reimbursement code will be included in the matrix, once a pack is assigned to a country, this code will be cross referenced to the country’s reimbursement system. If a pack is reassigned to another country, then the reimbursement code will be cross referenced to the new location. Please note that the matrix can be cross referenced to any country it is destined to, there will be no physical reimbursement label on the unit, therefore it is possible to reference the number. This is very different to the current ways of working the new process has been designed to cater for such events.
Q: Correct wording: what is the difference between “Certification” and “transfer to saleable stock”? Can an MAH perform batch release only based on batch certification performed by an external QP?
A: The process of batch release includes the following steps
The checking of the manufacture and testing of the batch in accordance with defined release procedures.
The certification of the finished product batch performed by a Qualified Person, signifying that the batch is in compliance with EU GMP and the requirements of its marketing authorisation (MA)
This step is called “Quality Release”
Once the QP has signed the register, the batch can be transferred in a third step to the saleable stock – either by assigning a release status in an ERP system or by affixing “release labels”.
This is the final step in the process which effectively releases the batch for sale or export. This could be done by the QP as an integral part of certification or it could be done afterwards by another person. If this is delegated to another person, this has to be covered by a SOP or contract.
Q: Annex 16, 2.2 requires: “audit report should address general GMP requirements, …, all relevant production and quality control procedures related to the supplied product…”. To what extent should this be done? Is an audit of a contracted manufacturer expected to last 2, 3, …10 days? Are one or more auditors required?
A. The points to be covered in an audit may be derived by the EMA Q&A that is dealing with the particulars that have to be reported in an audit report of an API manufacturing site. The same or even more is requested to be documented in case of the audit of a contract manufacturer for finished products.
Usually two auditors are better than one and the audit should last at least 2 full days for an initial audit.
Later for re-qualification audits this may be reduced to one day.
Q: Where do you see the QA department/ Quality Unit? I have the impression that the QP needs to be involved in everything. Does QA/QU have no responsibility?
A: Discussing the manifold activities the QP is involved in should not indicate the QP is responsible for everything.
EU GMP part I, chapters 1, 2, 5, 6, and 8 are describing numerous responsibilities of other key personnel at a pharmaceutical manufacturer – e.g. Head of Production, Head of Quality Control, Qualified Person for Pharmacovigilance.
The revised Annex describes in detail in part 1.7. what activities may be delegated to these key personnel and how the QP can rely on these activities and the Pharmaceutical Quality System.
According to the EU GMP Guideline, Part I, Quality Assurance is a system rather than a department.
Q: Elemental Impurities: Will it be necessary to submit variations to the national competent authority, following the risk assessment? What about those cases where results are above and below the threshold?
A: No variation has to be filed if the risk assessment and the supporting tests clearly indicate that no further controls, or replacement or change of quality of starting or packaging materials used, or change of the manufacturing process are needed.
If any of these points is needed a variation has to be filed.
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