Investigational medicinal products Flashcards

Question

Follow up: ar. Yes, it is a blinded study. Why are you bothered if this statement is missing in some packs?

Answer 1

Why It Matters: 1. Risk of Unblinding: • If the missing statement only affects either active or placebo, it may introduce unintended visual differences — potentially unblinding the investigator or patient. 2. Risk of Misuse / Breach of Protocol: • A pack without this statement may not be recognised as an IMP, increasing the risk it is used outside the trial setting or stored improperly. • This could lead to a protocol deviation or participant exclusion, which affects both patient safety and trial data integrity. 3. Regulatory Compliance: • Labelling non-compliance with Annex 13 is a serious GMP issue and must be investigated fully before QP release. Immediate Action: “I would speak with the packaging operator to determine whether this issue could have affected other units or batches, and whether it was a known issue or potentially systemic. I would ensure a full deviation and root cause investigation is underway before making any batch certification decisions.”

Answer 2

As a QP, I cannot rely solely on operator assurance. GMP requires evidence-based verification. I would personally review the batch, perform a 100% check if required, or statistically justified sampling based on risk — depending on process robustness and quality systems.”

Answer 3

If I can demonstrate through 100% inspection that all packed units are correct, and the issue is confirmed to be limited to the dummy/example pack in the BPR, then I would consider batch certification. I appreciate that all 200 packs have been visually inspected and appear compliant. However, as a QP, before making a final decision to certify the batch, I must ensure that the pack shown in the BPR with missing information was truly an isolated example-pack issue — and not representative of any product that could reach a trial subject.” ⸻ Next Steps Before Release: 1. Check Retention and Reference Samples: • These are independent samples and should reflect the labelled product as released. • If they are compliant, it adds strong assurance that the labelling process functioned correctly. 2. Review the Label Reconciliation Record: • Ensure no overages or label wastage that could indicate a possible label mix-up or print issue. 3. Interview the Operator: • Confirm the source of the BPR example pack — was it from live production or mock-up? 4. Complete the Deviation Investigation: • Document all findings. • Ensure root cause is understood and justified. ⸻ Conditional Certification Statement: “If, after checking all packs, retention samples, and reference samples, and reviewing full documentation and deviation outcome, I have confidence that: • The defect is limited to a documentation/example issue, • The GMP process was otherwise in control, • And patient safety is not compromised, then I may proceed with batch certification — provided CAPA is in place to prevent recurrence.”*

Answer 4

This suggests the issue may be limited to an operator error when preparing the example pack or a documentation issue. However, I would still need to understand the root cause — was the dummy pack made with live labels? Why did this error occur? Was there a mix-up risk?”

Answer 5

*“Possible causes include: • Use of obsolete or rejected label stock for the dummy pack. • Human error — incomplete label applied for example only. • Lack of control over the creation of example/dummy packs — no defined procedure or checks.”*

Answer 6

*“My CAPA would include: • Update SOP to define the process for example pack preparation — only use controlled labels with appropriate checks. • Prevent use of rejected or obsolete labels for any GMP documentation purposes. • Operator re-training on labelling controls and documentation accuracy. • Consider system-based controls — e.g., barcoding, label verification software upgrade to prevent use of unapproved label templates.”*

Answer 7

*“Software control is a good long-term solution for managing approved label templates — but human error and process discipline remain critical. I would also consider: • Strengthening procedural controls. • QA verification step during example pack preparation. • Review of line clearance procedures to prevent unapproved label stock presence in packaging areas.”*

Answer 8

*“Until CAPA is fully implemented, I would mandate: • 100% visual inspection of all packs before release. • QA oversight of example pack preparation. • Independent verification step of label content before documentation is completed. • Operator and QA re-training on the criticality of labelling controls in IMP packaging.”*

Answer 9

1. Non-authorised IMP (highest risk) — New chemical entities. 2. Authorised IMP but new indication (not in SmPC). 3. Authorised IMP but new conditions of use (new route/population). 4. Authorised IMP used within SmPC (lowest risk).

Answer 10

• Check CTA if shelf-life extension is pre-approved. • If not, raise a substantial amendment for MHRA and REC approval. • Execute change control. • Prepare approved labels (Annex 13 guidance). • Ensure QP oversight: • Approve procedure/protocol. • Check segregated relabelling area. • Ensure reconciliation and no unblinding risk. • Relabelling should not obscure original information (Annex 13). • Re-release is not always required but QP oversight is essential. • if it is conducted in MIA/IMP site, recall and IMP/QP certification required.

Answer 11

A. Extending the shelf life of an IMP is considered a substantial amendment and involves multiple regulatory and GMP-compliant steps. The process is as follows: 1. Regulatory Notification (Substantial Amendment): The shelf life extension must be notified to MHRA Clinical Trials via a substantial amendment to the CTA. If the original IMPD includes a predefined protocol allowing shelf-life extension when new data becomes available, it may not need a new amendment. Otherwise, approval from MHRA must be obtained before use of the IMP with an extended shelf life. 2. Update to Product Specification File (PSF): The Product Specification File (PSF) must be updated to reflect the new shelf life. This ensures that manufacturing sites and certifying QPs are operating against the correct specification. 3. GMP-Compliant Relabelling Process: If IMPs have already been manufactured and require relabelling: a. Stock Not Yet Shipped: Should ideally be returned to the MIA(IMP) holder site for relabelling in a GMP-approved environment. A new QP certification is required for this stock after relabelling. b. Stock Already at Clinical Trial Sites: Relabelling can be performed at the site (hospital/clinic) if: Conducted by or under the supervision of a pharmacist or trained healthcare professional Performed according to Annex 13 and a site SOP Documented and reconciled (e.g., line clearance, label reconciliation) Reviewed as part of trial documentation QP certification is NOT required again for relabelled stock at clinical sites if all of the above GMP requirements are fulfilled. 4. Handling Frozen or Difficult-to-Label Products: Use of IMPs beyond their labelled expiry is generally not acceptable under EU GMP unless: Provision is critical to patient care, and MHRA Clinical Trials approval is obtained in advance. If relabelling is not feasible due to the product being frozen, the sponsor should explore all GMP-compliant alternatives before seeking exemption. Cumulative time out of storage for relabelling should be tracked and assessed against stability data. 5. Labelling Expectations (Annex 13): An additional label must state: New expiry date Repeat the batch number and trial reference Superimposition over the original expiry date is allowed, but not over the batch number. Must be done in a partitioned area, with full documentation, SOPs, 100% reconciliation, and second-person verification. 6. QP Oversight: The QP who certified the batch should be made aware of relabelling activities. They are not required to re-certify if relabelling is done at a clinical site by qualified personnel. However, the QP must be satisfied that a robust GMP process is in place (e.g., through documentation review or record sampling). Summary Points: Shelf life extension = substantial amendment to MHRA. PSF must be updated. Relabelling requires GMP controls; QP re-certification only needed if relabelled at MIA(IMP) site. Frozen or hard-to-label stock must not be used beyond expiry without prior MHRA approval. Annex 13 principles must always apply for any relabelling.

Answer 12

o Initially felt like a trick question. After asking clarifying questions, I realised they wanted to test my understanding of expiry management in blinded studies. I discussed QP oversight, updated PSF, protocol amendments, and relabelling requirements. Clarifying Questions Asked by the Candidate: 1. What is the product? (Clarified to be an IMP — a blinded pack of active and placebo.) 2. What is the current shelf life and proposed extension? 3. What is the justification for the shelf life extension? Is it based on stability data? 4. Who is responsible for relabelling the packs — is it done at the clinical trial unit? 5. How many packs are affected? (Answered: Only 50 packs.) ________________________________________ Key Considerations and Model Structure of the Candidate’s Answer: 1. Regulatory and QP Oversight * IMP shelf life extension requires: o Supporting stability data. o Approval via change control and possibly amendment to the CTA if it’s a substantial change. o QP oversight of the extension process and relabelling. 2. Review of Clinical Trial Documents * Referred to: o CTA o Protocol o IMPD/PSF * Ensured alignment with trial requirements and randomisation integrity. 3. Labelling Considerations * New label must include: o Updated expiry date. o Same batch number or repack batch number as appropriate. * Referred to Annex 13 and GCP requirements for relabelling of blinded IMPs. 4. Site Capability and Risk Control * Asked whether the clinical trial unit staff are: o Trained in relabelling procedures. o Operating under approved SOPs. * Confirmed label reconciliation and accountability to prevent unblinding or mix-ups. 5. Documentation and Evidence * Requested: o Photographic evidence of all relabelled packs. o A repackaging/relabel protocol. o QA or QP approval of the process and final check of the relabelled product. ________________________________________ Model Answer (Structured Summary): “For a blinded IMP requiring shelf life extension, I would first verify the justification via stability data and ensure that any change control has been appropriately assessed. If it’s a substantial amendment, I would check that the CTA has been updated and approved. I would confirm that the updated expiry is applied consistently across both active and placebo arms to preserve blinding. I’d review the relabelling procedure, ensure staff are trained, and confirm reconciliation is managed to prevent mix-ups. The QP must approve the relabelling protocol, and I’d request photographic evidence of the updated labels on all 50 packs. If the relabelling is delegated to a clinical trial unit, I would ensure the process is documented, controlled, and compliant with Annex 13 and GCP expectations. Once satisfied, I would document my assessment in the QP certification record and confirm that the updated packs are fit for release and use within the clinical trial.”

Answer 13

The Human Medicines Regulations 2012 applies to therapeutic doses. In this legislation there are some exemptions from the need for a manufacturing licence such as the 'Section 10' exemption which can be invoked here. There is no such exemption for the manufacture of IMPs. So, the manufacture of even one dose for immediate use requires an MIA(IMP) authorisation and Qualified Person (QP) certification.

Answer 14

It would be expected that the analysis would be performed in a GMP-compliant laboratory. Testing in support of certification and release is considered part of manufacturing and therefore compliance with GMP is expected. For an IMP, the certifying QP may rely on the results of analysis from a non-EU laboratory and not repeat testing on import to the EU/UK, however they must assure themselves that the laboratory is compliant with EU GMP as part of the process of supply chain assurance and issuance of the QP Declaration for import. This is described in the sections relating to release of batches within EU GMP Annex 13.

Answer 15

Yes. The analytical requirements should be agreed with MHRA Clinical Trials via the clinical trial application (CTA). If an activity defined as manufacture takes place (see above) then the resultant IMPs should be tested to confirm that the specification submitted in the CTA is met. There may be exceptions for certain types of products, e.g. ATIMPs or radiolabelled IMPs where testing may not be performed prior to release due to very short shelf life, however the associated rationale should be documented and agreed by MHRA Clinical Trials in advance.

Answer 16

All sites involved in manufacturing steps starting with the conversion of the API into the dosage form and including primary and secondary packing and also any contract laboratories involved with release or stability testing. A guidance template for the information that should be included on the QP Declaration is provided in Eudralex Vol 10 Chapter III. Note: Import of finished IMPs that have been QP certified in an EEA country into Great Britain requires an oversight process under the supervision of a UK MIA(IMP) holder (see Q15b), however this does not require a UK QP Declaration.

Answer 17

No. The starting point for a QP declaration of EU GMP should be an audit conducted by or on behalf of the importing company. Any departure from this should be justified and documented and will be subject to scrutiny during an MHRA inspection. It may be possible to use the fact of a regulatory inspection by an EU Competent Authority as part of this justification, but these are general inspections which may not address the specific technical or GMP issues associated with your product. It may not even have covered the same factory or part of the factory. A regulatory inspection cannot be used unconditionally to remove the need for your own audit. The audit does not need to be done by the QP, however the QP needs to be satisfied that it has been done correctly by an appropriately trained individual as the QP will be taking final responsibility.

Answer 18

Although there is a Mutual Recognition Agreement (MRA) with Switzerland, it remains a third country therefore the IMP would need to be imported by an MIA(IMP) holder. As such, a QP Declaration of EU GMP compliance would need to be included as part of the CTA for each site outside the EU and the IMP would need to be certified by a QP upon import prior to release for use in the clinical trial.

Answer 19

Since the UK’s exit from the EU, and from January 2022, import of finished IMPs into Great Britain from EEA countries requires oversight by a UK MIA(IMP) holder. Additional certification by a UK QP is not required, however the UK MIA(IMP) holder responsible for the import oversight process needs to be listed in the UK CTA along with the site of final certification in the EEA. The import oversight activity needs to be specifically authorised in the UK MIA(IMP) and an application or variation to an existing licence should be submitted and approved prior to undertaking this activity. Further details on the requirements for this process can be found at the following link: https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries.

Answer 20

Once a trial has stopped, the product ceases to be an IMP and becomes a medicinal product. If it is a licenced medicinal product then it can be purchased and supplied as normal from the authorised supply chain. However, more often than not, the ex-IMP will not be licenced. Material already existing physically as an IMP in the UK can be retrospectively notified to the MHRA Import Notification System (INS) as an importation of unlicensed medicines according to MHRA Guidance Note 14. This regularises the stock as an unlicensed medicine and the packs can be supplied as such, should MHRA not object to it. The clinical trial particulars should be removed from the product particulars (labelling and product information) ahead of supply taking place. Any stock not currently in the UK must be notified to INS ahead of the importation taking place. The importer of an unlicensed medicinal product (a “special”) into the UK must hold; (a) a Wholesale Dealer’s Licence (WDA (H)) if the product is to be imported from an EEA member state i.e. the EU plus Norway, Iceland and Liechtenstein, or (b) a Manufacturer’s “Specials” Licence if the product is to be imported from a third country i.e. a non-EEA country. The holder of the Wholesale Dealer’s Licence or Manufacturer’s “Specials” Licence, must comply with certain obligations in relation to the import of an unlicensed medicinal product, which are set out in Schedule 4 of the Human Medicines Regulations 2012. These are explained and summarised in MHRA Guidance note 14.

Answer 21

There is no requirement for APIs used in IMPs to comply with EU GMP Part II in full, but there remains a responsibility for IMP manufacturers to assure themselves that the API is of an appropriate quality. Section 19 of Part II of the GMP Guide describes the expectations. The EMA has also published a Q&A concerning the GMP status of APIs used in IMPs. However, for Biological Products and Advanced Therapy Investigational Medicinal Products (ATIMP), there is a requirement for EU GMP Part I / Part IV to apply across all manufacturing steps as applicable, including from cell banks and vectors onwards, as detailed in EU GMP Annex 2 and in the PIC/S GMP Guide Annex 2A for manufacture of ATMPs for Human use for example. This is due to the ways in which Biological and Advanced Therapy medicinal products are manufactured and controlled, and the greater significance of the first steps in the manufacture of these products. As such all sites in third countries should be listed in the associated QP declaration for import as part of the submission for UK CTAs.

Answer 22

As such products are not IMPs, then the general requirements relating to medicinal products come into force, in particular the need for a Marketing Authorisation under the Human Medicines Regulations 2012. Where a medicinal product is not the subject of a valid Marketing Authorisation, the process for the supply of an unlicensed product provides a means of actually getting the NIMP into the UK for use in a clinical trial. The framework described in Guidance Note 14 is seen as an appropriate means of giving the legal method for the sponsor to actually obtain the NIMP, otherwise there would be no legal basis for supply. Further information on the importation of unlicensed medicines is available on the MHRA website: Supply of unlicensed medicinal products.

Answer 23

Firstly, MHRA Clinical Trials would need to be informed via a variation to the CTA. Extension of shelf life represents a substantial amendment, unless you have previous agreement within the approved IMP Dossier to extend the shelf life when more stability information becomes available. Secondly, the Product Specification File (PSF) would need to undergo a controlled change such that manufacturing sites and the QPs can take appropriate action such as updating labelling instructions, certification criteria etc. Thirdly, if advantage of the longer shelf life is to be taken for IMPs already manufactured, these IMPs will need to be relabelled. This relabelling will need to be conducted, checked and documented in accordance with EU GMP Annex 13 (see also the following question).

Answer 24

No. Although this would be preferable, it is recognised that this shipping backwards and forwards could cause more GMP problems than it solves. It is permissible in these circumstances for the relabelling to be done at the clinical site. The certifying QP should certainly be aware of this and be involved in setting up the required GMP systems. The relabelling should be done by appropriately trained staff, documented, and the records stored in the original trial file. Any stock not already supplied to clinical sites should be relabelled prior to shipping. Note that the EU GMP Annex 13 deals specifically with this issue. It states: “If it becomes necessary to change the expiry date, an additional label should be affixed to the investigational medicinal product. This additional label should state the new expiry date and repeat the batch number and clinical trial reference number. It may be superimposed on the old expiry date, but, for quality control reasons, not on the original batch number. The re-labelling operation should be performed by appropriately trained staff in accordance with good manufacturing practice principles and specific standard operating procedures and should be checked by a second person. This additional labelling should be properly documented in the batch records. To avoid mistakes the additional labelling activity should be carried out in an area that is partitioned or separated from other activities. A line clearance at the start and end of activity should be carried out and label reconciliation performed. Any discrepancies observed during reconciliation should be investigated and accounted for before release. The re-labelling operation may be performed by authorised personnel at a hospital, health centre or clinic.”

Answer 25

This approach is usually not acceptable, as this is not compliant with EU GMP or Annex 13 requirements, except where provision of IMP is critical to the ongoing care of trial participants and has been agreed by MHRA Clinical Trials in advance of implementation. It is expected that relabelling processes should be fully explored before seeking approval to bypass relabelling activities. It is likely that additional mechanisms will be required to manage the continued use of incorrectly labelled products whilst correctly labelled stock is made available. Any additional handling or cumulative time out of storage for the relabelling should also be considered in line with the available stability data and this should be appropriately documented within the associated records.

Answer 26

A new certification after relabelling is required for stock which has not been shipped to an investigator site. For product held at the trial site, QP certification is not required if the relabelling activity is carried out by, or under the supervision of a pharmacist, or other healthcare professional, with appropriate documented evidence in accordance with EU GMP Annex 13.

Answer 27

Confirmation that a transitional IMP QPs has been assessed as being suitable and eligible to act as a QP at a given site can be verified by referring to list of authorised personnel within the appropriate UK MIA(IMP) licence. Eligibility certificates for transitional IMP QPs were not issued by MHRA, however if a TQP has been previously named on a UK MIA(IMP) they will continue to be recognised as eligible in this capacity. On receipt of an application to name a TQP on an MIA(IMP), the individual’s suitability will be assessed based on experience of both the authorised dosage forms and the company’s systems. Where an application to name a TQP on an MIA(IMP) is received, it is expected that this only applies to those already named on a previous MIA(IMP) licences. Any QP not yet known to the MHRA via inclusion on an MIA(IMP) will be expected to have undergone the applicable assessment via the Joint Professional Bodies on behalf of the MHRA. The MHRA are no longer reassessing TQPs in line with the requirements of the EU Clinical Trials Regulation 536/2014 following the UK exit from the EU. This is a change from the approach indicated prior to leaving the EU.

Answer 28

This 'post certification labelling' can be used for the following and is expected to be performed prior to despatch in the distribution area at the MIA(IMP) holder site; or where justified and controlled then immediately prior to administration to a subject or patient: application of an identifier to ensure that a reconstituted IMP in its final container is administered to the correct subject application of expiry date labelling (or revised expiry date labelling) (see also Q20) application of an investigator name application of a protocol number. It should, in the first instance, be done at a site with an MIA(IMP) unless the risk to the quality of the product is unacceptably elevated by any required transportation back to this site. The level of assurance of product quality should not be less than if this labelling were performed prior to QP certification. It should also be noted that there is no expectation for hospital pharmacy or investigator sites involved in the application of labels as part of the final dispensing process to return packs to a licensed facility for this process. NOTE: Such labelling should not effectively incorporate allocation of doses against a randomisation code. It is important that allocation takes place before this to ensure adequate QA scrutiny and QP confirmation and to ensure that staff applying such post certification labels are not accidentally unblinded. GMP expectations for 'post certification labelling' are: finished IMP doses, certified by a QP, should exist prior to the labelling the activity should be planned and described in the CT protocol relative responsibilities should be described in a technical agreement where appropriate the process should be described in an SOP personnel doing the labelling should be appropriately trained and retrained at intervals labels should be stored securely with arrangements in place to ensure that records for removal and usage are kept. Labels should be transported in a secure way from the label store to the location for use the activity should be carried out in an area which is partitioned or separated from other activities. It should also preferably be done in a quieter environment a line clearance at the start and end of the activity should be carried out and label reconciliation performed to 100%. An investigation should be carried out if this is not the case. This should be verified by a second person the activity should be recorded in a batch record or equivalent document which is subject to independent review the certifying QP should be aware of the post certification process and be satisfied that the elements described above are in place. Although further QP certification is not necessary, some oversight is expected, and some assurance should be gained (e.g. by sampling of records) to confirm that the process is being carried out correctly. If conducted at an investigator site the sponsor is responsible for ensuring that the activity is carried out in accordance with GMP, and the advice of the QP should be sought in this regard. the process should be covered by normal quality system elements such as change control and non-conformance management.

Answer 29

Medication pooling is the production of IMPs which may be used in a number of clinical trials and which are left in a "generic" state until after QP certification. This would usually be by leaving a space for the protocol number to be added at the point of dispensing, or where multiple protocol numbers are on the label with the others being deleted at the point of dispensing. Only after certification is it decided which protocol the particular IMPs are destined for, this is when it is being dispensed to the patient. This is acceptable provided that the QP certification is against all of the possible clinical trials which may use the IMP, the protocol number is added to the IMP doses prior to release to the trial, and the GMP points outlined in Q23 (above) are considered.

Answer 30

Non investigational medicinal products (NIMPs) are not IMPs and so the legislative requirements of The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004/1031] (as amended) do not apply to such products. There is therefore no requirement to source such products from a site holding an MIA(IMP) or for QP certification of the product. There is an expectation for the Sponsor to ensure that NIMPs are of the necessary quality for human use. Further guidance on sourcing NIMPs is included in Eudralex Volume 10 Clinical Trials Notice to Applicants.

Answer 31

As for licensed products, there is no such discretion available to a certifying QP. However, if a batch is manufactured and does not meet the authorised specification then a substantial amendment to alter the specification may be submitted to MHRA Clinical Trials provided it is deemed that safety, quality and efficacy are not compromised. If required, an expedited review may be requested via the Clinical Trials Helpline. Administration of an Out of Specification (OOS) ATIMP may be acceptable in exceptional circumstances without or prior to a Substantial Amendment; however, these must be discussed with MHRA Clinical Trials with regards to impact to the trial prior to administration.

Investigational medicinal products Flashcards

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