Restructured the page so it is easier for users to read. Added dates to show when flexibilities were added. We have also added in new information on clinical investigations for devices, relaxation of risk minimisation measures and flexibility in reporting requirement for ICSRs. Clarified what information the MHRA needs from manufacturers and wholesalers about when they use flexibilities, and in what circumstances this information should be sent to us.
This is in the 'Inspections and good practice' section. Added a new section on Pharmacovigilance. Published updates to: Medical Devices section on the derogation process and the Medicines regulations section on QP declarations. Added information in the 'Medicines regulation' section on further flexibility around labelling, the limit for replies to questions on Type IB variations and the extension of the day national phase for DCP CMS.
Added new information about medical devices regulation. Check what you need to do. Book your coronavirus vaccination and booster dose on the NHS website. To help us improve GOV. It will take only 2 minutes to fill in. Cookies on GOV. UK We use some essential cookies to make this website work. Accept additional cookies Reject additional cookies View cookies.
Hide this message. Home Clinical trials and investigations. Contents Making use of regulatory flexibilities Clinical trials Marketing authorisations Pharmacovigilance Inspections and good practice Blood components for transfusion Medical devices. Print this page. Making use of regulatory flexibilities Please bear in mind that flexibilities do not displace or diminish any other obligations applicable to the relevant products. Clinical trials Scientific advice and reviews published 1 April We are providing expedited scientific advice, and rapid reviews of clinical trials applications to support manufacturers and researchers on potential treatments for COVID Please send notification of requests to expedite to MHRA in advance of submission: For variations: variationqueries mhra.
NA mhra. Separate guidelines are available for products containing chemically-defined active ingredients and for those containing biologically- or biotechnologically-derived active ingredients. However, despite the availability of these guidelines, a number of common deficiencies relating to the Quality section of the dossier have been identified. The name of the drug product, marketing authorisation number or its equivalent, marketing authorisation holder and the country that granted the marketing authorisation should be given.
Section 2. Copies of spectra should be provided. Section S. This guideline further requires that if the manufacturing process of a biological has changed during development, comparability data will be required to ensure that the changes have not had an adverse impact on clinical characteristics of the product see section S. Characterisation data are frequently either missing from the dossier entirely, are deemed to be inadequate or insufficient interpretation of the data has been provided.
In each of these circumstances, a GNA point will be raised and the applicant asked to provide additional data or further interpretation. Sections 2. These data are required in order that the applicant demonstrates that the analytical methods are suitable for their intended purpose and that confidence can be held in the batch release and stability data.
For phase I trials, it is sufficient to confirm the suitability of the analytical methods used and provide the acceptance limits and parameters for performing validation of the analytical methods in tabulated form. However, if analytical validation has already been carried out, a tabulated summary of the results should be provided. It should be noted that there is no requirement for the inclusion of a full validation report and this should not be provided.
CTA applications should be supported by summaries of data rather than full reports. Batch analysis data for each company listed in the IMPD as a proposed site of manufacture for drug substance and for drug product should be provided. In this context, a company is regarded as a legal entity. It may be possible to provide data for batches that have been produced at a different scale or using a modified method; in such circumstances the IMP dossier should include a justification that these batches are representative of the clinical trial material.
In the same way, a substantial amendment supported by batch analysis data will have to be submitted and approved prior to the inclusion of manufacturing sites which represent a new company legal entity. For biological and biotechnological products, batch analysis data will be required for each site of clinical manufacture and, for early phase trials that are often characterised by a limited number of batches, results for relevant non-clinical batches should also be provided.
Further details can be found in sections S. Failure to include batch analysis data for all manufacturing sites listed in the IMPD will result in a GNA point being raised, requesting the provision of these data. In particular, limits for impurities should be justified based on safety and toxicity data. Dissolving or dispersing the IMP in a diluent immediately prior to administration or diluting with a vehicle for administration commonly water for injection, saline, glucose — perhaps in an IV bag would most likely be considered reconstitution activities.
Measuring or weighing out quantities of several materials to be combined in a defined sequence or with a specified mixing time that perhaps includes some in-process testing to confirm details such as concentration or pH, sterile filtration into another container and integrity testing of the filters prior to making a release decision would all be considered manufacture, must therefore be conducted at a facility that holds an MIA IMP and must be certified by a Qualified Person prior to release to the Sponsor for use in a clinical trial.
Scenarios are considered on a case by case basis — if in doubt ask us via the CTU helpline details provided below. For example if the IMP reconstitution requires added protection while diluting into an IV bag this may need to be performed in a clean area such as a laminar air flow cabinet.
Preparation of the IMP to be subsequently stored for use at a later date would not be considered reconstitution. If you have any further queries relating to clinical trials, please continue to send these to the Clinical Trial Helpline. It is also permissible without an MIA IMP to label them after reconstitution with an identifier to ensure that the dose goes to the correct subject.
See also Q23 for further information. This would fall within the scope of manufacture. Any operation such as weighing out, adding other materials, or combining IMPs is not considered to be for the purposes of administration and so would require appropriate authorisation under a MIA IMP. This situation is potentially complicated and should be considered on a case by case basis by the MHRA. The Human Medicines Regulations 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. 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. Yes, 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, 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.
Paragraph 8 in Part 2, Schedule 7 of the Clinical Trial Regulations requires the manufacturing authorisation holder to keep samples of each batch of formulated products readily available for examination.
There should be enough finished packs for testing in duplicate. As IMPs are often small packing runs from one bulk batch, Annex 19 accepts a justification for retaining the required sample quantity of the bulk batch and separate samples of packaging components used on each packing run.
The sample of the bulk batch should be in the final primary pack in order to be representative of the materials going on to be used. The requirements are detailed in Annex 13; paragraphs 36 and Samples of IMPs used in EEA clinical trials should be stored within the EEA or an MRA country unless suitably justified and defined in a technical agreement between the sponsor, importer and third country manufacturer cost of the IMP would not be considered an acceptable justification.
There is no requirement for QP certification. IMPs are not 'Specials'. When granted a QP certification against that clinical trial authorisation is required. Section 37 of the UK Clinical Trials Legislation contains a specific exemption which is relevant here. This provides an exemption from the need for a hospital or health centre to hold a MIA IMP authorisation to assemble an IMP in a hospital or health centre, when the 'assembly' is carried out by a doctor or pharmacist, or under the supervision of a pharmacist.
The exemption applies only if the product is to be used exclusively in that hospital or health centre or any other that is a trial site for the same clinical trial in which the product is to be used. This exemption does not apply to anyone else such as separate organisations which happen to be situated within a hospital or to companies which have a contract to supply hospitals or health centres.
Capsules are specifically excluded from the definition of a container in the Clinical Trials Regulations SI An organisation cannot act as a contract batch certification site only. The sponsors of a clinical trial may wish to keep the final QP certification step of IMP manufacture in house as they carry ultimate responsibility for the trial.
Otherwise, any contract organisation such as yours must be involved with some manufacturing or importation of an IMP if they wish to carry out batch certification.
In this respect, the legislation differs from that for medicinal products. Note that the storage and distribution of a licensed medicinal product must remain in the licensed distribution chain until it is supplied to the Sponsor for use in a trial. Note that the Clinical Trial Regulations define an investigational medicinal product including a licenced medicinal product as being:. However, it may be that the radiopharmaceutical used in a clinical trial may not be an IMP. Comment by Concepcion Rubalcava posted on on 06 September Comment by Claudio Lorck posted on on 08 December My comment is actually a question to chapters 1.
This would mean that additionally to the written agreement between the QPs as requested in 1. Is my understanding correct? Thanks for commenting, Claudio. Comment by Sara Berry posted on on 15 December Thank you for your query. Ultimately it is the responsibility of the final certifying QP to satisfy themselves that the information on which they base their certification decision is appropriately supported and justifiable to the Competent Authorities as required.
Comment by Siegfried Schmitt posted on on 04 July I have a question regarding the segregation of duties. Would it be acceptable for a QP to be in the role of the head of the production department? Would this constitute a conflict of interest? Comment by Sara Berry posted on on 05 July This would be an unusual scenario and would need to be discussed and assessed on a case by case basis therefore we would encourage any organisation considering this arrangement to contact the MHRA via gmpinspectorate mhra.
Read our guidelines. How do the requirements for sampling and testing of imports, detailed in section 1. Do all the 21 points detailed in Annex 16 section 1.
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