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Pharmaceutical Manufacturing and Packing Sourcer

IMP Importation

Advanced therapy medicinal products (ATMPs) – new IMPs for the context of this article – are regulated as per other more traditional medicinal products entering into EU clinical trials.However, there are certain issues that are encountered which would not occur with the more traditional small molecule IMPs.

The QP must confirm that the IMP has been manufactured in accordance with Good Manufacturing Practice (GMP) guidelines, as specified in 2003/94/EC (principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use).The QP must also confirm that the IMP complies with the relevant clinical trial authorisations (CTA) issued by member states within the EU, and that the IMP complies with the Product Specification File (PSF).The PSF is a reference file containing, or referring to files containing, all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an IMP.

There are four main topics that will be expanded upon within this article:
  1. The IMP QP certification process
  2. IMP importation for export to non-EU trial sites
  3. Regulatory issues for combination IMP kits (an IMP combined with a medical device)
  4. The future for IMPs and their impact on the QP The IMP QP Certification Process
The IMP QP certification process is covered in three separate stages:
  • Bulk IMPs which are imported from a third country which require further packaging and assembly
  • Finished IMPs which are imported requiring no further processing
  • Non-EU comparators with the method of selection if EU comparators are not available
The bulk IMP QP certification process often starts with a teleconference with the client to allow for introductions to occur.This allows the QP to gain an understanding of the aims of the clinical trial and the critical stages of the IMP manufacturing process. Following completion of the teleconference, it can be confirmed that it is possible to assist the client with the IMP importation process and the accounts department can draft a master services agreement (MSA) for all companies involved to sign.

A Technical Agreement (TA) will be drafted to outline the quality requirements for the work undertaken and clearly defining roles and responsibilities. A main component of the TA will be the identification of audit requirements associated with the IMP being imported which, once established, will be completed by adequately trained personnel. Once all audits have been completed and closed, the QP must submit a QP declaration to the sponsor for the IMP, which has been imported from the third country, for inclusion in the sponsor’s clinical trial application.

While the sponsor is awaiting regulatory approval for their clinical trial, a PSF will be set up which contains many documents (as detailed earlier) such as the Investigational Medicinal Product Dossier (IMPD), a TA, a clinical trial protocol and eventually the CTA from the EU member states where the clinical trial is being conducted.The QP will then review bulk batch records associated with the IMP manufacturing process up until the point of receipt. Following completion of these main points, a QP will issue a bulk IMP QP certificate for the intermediate product received, which is usually awaiting secondary packaging and kit assembly.

Audits

When importing IMPs from the third country, audits are an essential prerequisite as detailed within 2001/20/EC and the EU GMP guidelines for IMPs (EudraLex,Volume 4, Annex 13). Sites requiring audit must be identified, including the sites of manufacture, packaging and testing. As discussed previously, the audit requirements must be detailed clearly in a suitable TA or another controlled document.

When importing new IMPs, the drug substance manufacturer may require a QP assessment which is different to more traditional IMPs. Most regulatory authorities within the EU consider certain drug substance manufacture to be so close to the finished drug product that the drug substance manufacturer must be audited to confirm that they are operating within compliance of EU GMP.This is different for small molecule IMPs imported from the third country; for these, the API manufacturer does not require audits to confirm EU GMP compliance.However, the quality of the API should be known and deemed acceptable in this situation.Often, risk assessment techniques can be employed to justify whether audits are required;however, if there is doubt as to whether a critical site is EU GMP compliant, an audit will be required.

One final element that must not be overlooked prior to performing the audit is communication.There must be clear communication with the sites being audited to confirm the audit agenda and to confirm that the audit team will be assessing the site for compliance to EU GMP standards.The certifying QP must ensure that any auditors utilised for third country GMP inspections are experienced in the dosage form for which they are auditing.

Recent MHRA inspections reveal that MHRA auditors are keen to establish how the auditors are selected and how their experience and skillset can justify suitability for performing such critical audits to assess equivalence with EU GMP. QPs must be aware of the corporate auditors operating within their organisations to ensure that the auditors are familiar with the dosage form and critically EU GMP.When establishing the audit agenda, the auditor must ensure that key personnel, facilities and documents are available on the day of the audit and that any language barriers are identified.

Non-Compliance

Post audit completion, any noncompliances that exist must be clearly communicated to the auditee with critical and major non-compliances treated as priority.The audit report is submitted to the sponsor for relevant parties to agree corrective actions to address any non-compliances.There may be a need to re-audit a site to verify the effectiveness of corrective actions, however this depends on critical nature of the non-compliances observed.

Following closure of all audit reports associated with the IMP being imported, the QP will issue a QP declaration to the sponsor for inclusion in the CTA. Although very rare, in some cases critical non-compliances that are attributed to big pharmaceutical and small biotech companies alike are found.When these situations arise, a lot of pressure is placed on the auditor, the certifying QP and the contract manufacturing organisation (CMO), especially if the critical noncompliance has been detected with the IMP already manufactured, which can happen if the sponsor commences work with the CMO relatively late into their project.

Obviously, however, the primary concern with any non-compliance is that patient safety and product quality must not be affected.Working as a CMO, the client has to pay for the audits that are conducted, therefore, any audits have to be justified to the client, and when issues are identified QA, project management and operational teams work very closely with the sponsor to resolve the issues.

Although rare, the following are examples of some serious noncompliances observed during new IMP site audits in the third country:
  • An issue was observed whereby a non-sterile filter had been used in the final filtration stage of an aseptically prepared product. The IMP batches had already been manufactured; therefore, QPs were not able to certify the batches as compliant to EU GMP and the batches were rejected.Working closely with the sponsor to agree corrective actions,we re-audited the relevant manufacturing site and the QP-certified new batches of IMP
  • During an audit of a Phase 1 IMP manufacturing unit, it was detected that no media fill data was available to support the aseptic manufacturing process; on this occasion the manufacturing site was not approved for IMP manufacture and media fill validation data is currently being awaited from this site
  • The last example relates to an issue detected whereby there was insufficient environmental monitoring observed in a sterile area for non-viable particulates. The site audited was not operating in compliance with EU GMP Annex 1. Corrective actions were agreed with the site which involved implementing additional environmental monitoring which was duly performed with subsequent IMP batches manufactured QP-certified for use in EU clinical trials Audits allow supply companies to gain confidence in the manufacturing processes as import testing is not routinely conducted, unless it is a mandatory requirement in some EU member states. Import testing would be difficult for new IMPs whereby analytical methods are not fully validated and method transfer would be extremely difficult.
Batch Records

Once the audits are complete, QPs would review batch records for each individual batch of IMP imported. Audits ensure that non-EU sites are GMP-compliant, batch record review ensures that each batch manufactured has been checked to ensure it is compliant to EU GMP, the CTA and the PSF.

 The QP can review drug substance batch records, drug product batch records, environmental summary reports and certificates of analysis (CofAs) for all starting materials and finished product. It is also very important that the QP reviews any out of specification and deviation reports associated with the batch under review. Common issues observed by QPs include:
  • Language complications with complex batch documents requiring translation into English in order to allow for review to commence by the QP
  • Document size; some batch documents are extremely large and require thorough review by the QA and the QP
  • Complexity of operations being performed
  • Differing interpretations of OOS and deviations with the resolution of issues often difficult when you are faced with different timezones
The QP review process involves splitting the QP review into bulk QP review and then final QP certification upon completion of secondary packing. EudraLex Volume 4, GMP Guidelines, Annex 13 stipulates that batch record review is required where possible, however, if translation of batch records into English is particularly difficult due to complexity, then audits and summaries of out of specifications, deviations and CofAs for all processes and final release could justify omitting a formal batch record review.

Storage

Often new IMPs require very cold storage conditions. It is important to work closely with the sponsor to ensure that any processing conditions are not going to affect product quality adversely. When removing any IMP from usual storage temperature conditions, a record should be made to ensure cumulative exposures can be calculated. It is possible to secondary package IMPs on pre-conditioned gel packs at 2 to 8ºC if the IMP is a cold chain product, or IMPs can be packaged on dry ice to maintain frozen temperatures as much as possible.However, limited stability data might dictate that the secondary packaging occurs in a freezer room. Whichever option is chosen, the process must be controlled, clearly documented and should not have an adverse impact on product quality.

Upon completion of secondary packaging activities, the QP will certify the IMP for use in clinical trials after checking packaging batch records, the PSF and the CTA. Final QP certification allows for IMP to be shipped to clinical trial sites; however, the QP must be satisfied that suitable controlled systems are in place for storage and distribution to the trial site. If work is undertaken at multiple EU manufacturing sites then the QP certification from other EU sites can be utilised, providing that a clear TA has been drafted that outlines QP responsibilities between all sites involved in the supply chain.

Finished IMPs Received

When finished IMPs are imported from the third country that are final packaged then our QPs would also have to review the packaging operations performed in the third country to verify that they are compliant to EU GMP and that the finished kits are compliant with the PSF and the CTA.The packaging site in the third country will have been audited to confirm they are operating in compliance with EU GMP.

Occasionally issues have been observed with finished IMP imported, whereby the IMP labelling does not strictly comply with Annex 13. This can be difficult for the QP, especially when the CTA has been approved by an EU regulatory authority. On these occasions we would risk assess the variance and if the risk is acceptable we would inform the sponsor of our findings with the risk assessment filed in the PSF. If the trial is blinded, components and finished kits should be checked to ensure that between the different treatment arms the blind is maintained; the blind check should be documented.

Unique Issues with New IMPs

Retained samples can be an issue for new IMPs, such that if you comply with the regulations, reference and retention samples could account for 20 per cent of the total batch size. On these occasions it is worthwhile discussing the issue with the relevant competent authority as some new IMPs may be a single batch per patient, so what would be the approach here with regards to reference and retention samples?

New IMPs often require storage at very low temperatures – some as low as -140ºC – therefore robust product processing, storage and shipping systems must be in place in order to minimise the risk of affecting product quality.

Secondary clinical trial labelling is not possible on vials already frozen down to -140ºC so it is vital that the complete IMP supply process is evaluated as early as possible to ensure that once the new IMP has been filled into its primary container it is labelled with the appropriate labelling prior to the IMP being frozen down to temperature. It is helpful here to send clients Annex 13 compliant labels for use prior to the IMP being frozen down; obviously the label adhesive used should be suitable for the intended storage temperatures and this should be qualified where possible. New IMP batch sizes are sometimes very small, which increases the number of QP certifications required. Some new IMPs could require one QP certification per patient so obviously this has time implications for a study.

Awareness is also needed during importation of other regulatory requirements. For example, in the UK, if cellbased products are imported for storage only, and not linked to a clinical trial, then the importer may need a human tissue authority (HTA) licence. Also for animal origin products a DEFRA licence may be required in the UK. Finally when supplying new IMPs that are cellbased, a complete registry is required to enable traceback to the original cell donor if adverse events are recorded during a clinical trial or post-marketing authorisation.

The Future for New IMPs and Impact on the QP

So what does the future hold for the QP and new IMPs trialled in the EU? Review of some of the issues associated with new IMPs reveals that manufacture and packaging will be required for clinical trial use, with some new IMPs being required at trial sites within 48 hours of completion of manufacturing and packaging.This would result in the IMP being used in patient treatment prior to completion of analytical testing. This type of manufacturing will require the utmost confidence in the quality management system at the sites of manufacture, perhaps with a requirement for the QP to be based at the non-EU site during the manufacturing process. One question that we could ask is that with some of the new IMPs being developed today, are we pushing the QPs towards having a requirement for a medical background and education? The role of the QP will undoubtedly get more difficult when challenged with certifying new IMPs, which are pushing the boundaries in terms of technological and medicinal development. Ultimately however, the QP must satisfy themselves and the regulatory authorities that they have appropriate skills and knowledge for the IMP being certified to ensure the patient is protected and the product is manufactured to appropriate EU GMP standards. Indeed, life doesn’t get any easier for the QP!


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Tristram Evans is QA Manager for Biotec Services International Ltd. After graduating in Chemistry from the University of Wales, Cardiff, Tristram joined Penn Pharmaceuticals as a Quality Control Analyst. This was followed by the position of Quality Assurance Auditor at Norgine, where he gained a wealth of experience performing audits to ensure GMP compliance. Tristram subsequently joined Biotec in 2007 as the Quality Assurance Manager. Email: tristram.evans@biotec-uk.com
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