Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2 (Appendix 5) Quality data required for the approval review of changing a strain in the vaccine for which the manufacturing process is well established — PMDA Early Consideration Summary

In Plain Language

This document describes quality data for applications to change the strain in a SARS-CoV-2 vaccine whose manufacturing process is well established. It separates applications into an expedited review process and a standard review process, based on whether the strain can be changed using an established process without unintended quality changes. For the expedited route, the document describes a focused set of data, with several provisions that may allow less information at application when specified conditions are met. The standard route is for cases where the process needs changes beyond minor manufacturing-parameter changes, or where unintended changes in a quality attribute are observed. The distinction matters because the standard route includes comparability evaluation and more stability data, while the expedited route is intended for a vaccine that can be prepared and reviewed on a faster timetable.

What This Guidance Covers

The document addresses the quality information for an approval application to change the strain of a SARS-CoV-2 vaccine in Japan when the vaccine’s manufacturing process is well established. It sets out what quality data are described for the expedited and standard review processes and discusses whether a good manufacturing practice (GMP) inspection application is needed.

The document is written with messenger RNA (mRNA) vaccines and recombinant protein vaccines in mind. For other types of SARS-CoV-2 vaccines, it may be used as a reference, but prior consultation with the Pharmaceuticals and Medical Devices Agency (PMDA) is required. The document also identifies situations where its outlined approach is not intended to stand alone: vaccines undergoing a strain change for the first time, or cases where there are concerns about the impact of a strain change on quality or safety. For those situations, it points readers to two other named PMDA documents: Appendix 1 on evaluation of vaccines against variants and Appendix 4 on immunogenicity-based evaluation of variant vaccines modified from parent vaccines and booster vaccines with new active ingredients.

Its scope is therefore narrower than a general account of vaccine development or of all evidence relevant to a vaccine approval. Its focus here is the quality data for strain-change applications under the described circumstances.

Why It Matters

The background explains that SARS-CoV-2 variant strains continue to emerge and cause outbreaks, and that reinfection and sequelae of COVID-19 (referred to in the document as “Long COVID”) remain relevant concerns. It notes a public-health demand for an ongoing supply of effective vaccines against epidemic strains. At the same time, regulatory authorities had reached a consensus on a platform approach for updating vaccine composition, including the coding sequence or strain, to align with a new variant. As described in the document, that approach accepts submission of necessary quality and non-clinical study data at application, with other quality information and real-world data on immunogenicity, efficacy and safety collected after approval.

For a strain-change approach to work, the manufacturing process must be sufficiently robust: the effects of changing the strain on vaccine quality need to be evaluated, and manufacturing processes, specifications and analytical procedures need to be established for the change. The document responds by describing quality-data expectations according to whether an application is suitable for expedited or standard review.

The document says its concepts were developed based on scientific knowledge and international trends as of April 2024, and may change as those develop. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication, which may change as scientific knowledge develops.

Key Recommendations

1. Choose the review route according to the process and quality impact. The expedited route is described for a vaccine already approved in Japan when strain changes have been accepted in a previous application, and when the vaccine’s quality and safety are likely not to be affected by the strain change and immunogenicity can be predicted through non-clinical trials. The document assumes a robust manufacturing process is established even when the strain changes.

   The document says that if the established manufacturing process needs to change because of the new strain, excluding minor changes of manufacturing parameters, or if unintended changes in quality attributes are observed, the applicant should apply through the standard procedure. In such cases, comparability of the drug substance, drug product or their intermediates before and after the changes will need evaluation, making it difficult to obtain the necessary development data and complete procedures within the expected rapid review period. The application would normally be submitted after the necessary results for approval review have been obtained.

2. For expedited review, prepare for strain selection and supply in advance. The document envisions an applicant able to manufacture a prototype candidate vaccine using the established process before the strain for that year is selected, and to have initiated non-clinical pharmacology studies to show adequate immunogenicity against the prevalent strain. After selection, the applicant should be able to start supplying within 3-5 months. If such a vaccine is available, the document says the applicant should submit an approval application with the expedited review process.

3. Provide new-strain material information for either review route. For both expedited and standard review, submit characterization and specification data for the template DNA, cell bank and viral seed for the new strain.

4. Provide characterization and batch-analysis data, with the quantity depending on the route. Both routes list characterization data for at least 1 batch. For expedited review, characterization of the post-change product—its structure and other characteristics, and impurities—should be compared with the complete characterization data for the pre-change product, except for properties not affected by the strain change. If there is concern about an effect on quality attributes, such as a different trend in post-change characterization, data for at least three batches may be required. For standard review, compare post-change characterization with the full pre-change characterization, excluding properties not affected by the change; where characterization is expected to vary from lot to lot, data from multiple lots may be required.

   For batch analyses, the expedited route calls for, in principle, at least 3 batches at manufacturing scale. For mRNA vaccines, data from at least one manufacturing-scale batch can be acceptable if prior knowledge from the product before the strain change can explain production consistency before and after the change. The standard route calls for at least 3 manufacturing-scale batches. These data are intended to confirm consistency of production before and after the strain change.

5. Provide stability information appropriate to the route. For expedited review, the document describes, in principle, a post-approval stability protocol for at least one batch whose manufacture and storage are representative of manufacturing-scale production. One batch is acceptable on the assumption that results from long-term stability studies of at least three batches at initial approval and at least three batches at approval of a previous strain change raise no concern about stability effects from lot to lot or before and after the strain change. The pre-change product’s shelf life can be applied to the post-change product.

   For standard review, provide a minimum of 6 months’ stability data from at least 3 batches whose manufacture and storage are representative of manufacturing-scale production. Batches at manufacturing scale are acceptable. If no difference in stability is observed before and after the strain change, the pre-change shelf life can be applied to the post-change product.

6. Address GMP inspection and changes to analytical procedures or specifications. A GMP inspection application is not required for expedited review under the table. If a GMP inspection is deemed necessary, the applicant should submit through the standard review process. For standard review, a GMP inspection application is, in principle, required. When validated analytical procedure parameters, reagents or reference materials change along with the strain change, revalidation of the analytical procedure is required. If specification acceptance criteria change, documents explaining the rationale for those criteria are required.

7. Consider all manufacturing sites. If there are multiple manufacturing sites, data are required for each site. However, if comparability of products between sites can be ensured after the strain change, approval can be obtained with data from one manufacturing site; the marketing authorization holder can verify data from the remaining sites.

Practical Implications

Interpretation: The route choice has consequences for both the evidence package and the timing of an application. A development team considering expedited review would need to assess early whether it can use its established process, whether the strain change is expected to affect quality or safety, and whether the specified non-clinical prediction of immunogenicity is available. It would also need a plan for prototype manufacture and study initiation before the annual strain is selected, in keeping with the document’s scenario for a rapid strain update.

Interpretation: Quality teams can use the document’s categories—materials, characterization, batch analyses, stability and inspection—to organize the application evidence. Comparisons with the pre-change product are central to the characterization discussion, but the document attaches conditions to how much information may be appropriate. For example, the expedited route’s lower stability submission at application depends on the stated history of stability data and the absence of concern about lot-to-lot or pre-/post-change effects; it is not presented as an unconditional reduction for every strain change.

For analytical and manufacturing teams, a strain change may affect more than the vaccine sequence or strain itself. The document specifically calls attention to changes in validated analytical procedure parameters, reagents or reference materials, and to changes in specification acceptance criteria. Regulatory teams coordinating several manufacturing sites should also establish whether the post-change comparability between sites can be ensured, since that affects whether data from every site are required at application or can be verified by the marketing authorization holder.

These are practical interpretations of the data categories and conditions in the document, not additional PMDA requirements. The document does not give a universal timetable for every product or application; its 3-5 month supply scenario is framed around the envisioned expedited strain-change setting.

Technical Details

The document’s review-route distinction can be read as a sequence of decisions. First, consider whether the vaccine and prior strain-change history fit the expedited-route description. Then assess whether the process remains established and whether the quality and safety impact is expected to be limited. If process changes beyond minor manufacturing-parameter changes are needed, or unintended quality-attribute changes are observed, the document points to standard review and comparability evaluation.

“Characterization” in this context concerns elucidating structure and other product characteristics, including impurities. The comparison is with the product before the strain change, leaving out properties not affected by the change. The document distinguishes the expedited route’s “complete characterization data” and the standard route’s “full characterization data” for this comparison; it does not provide a separate numerical formula for those terms.

The principal quantitative differences in the table are the stated batch counts and stability durations: characterization is listed for at least 1 batch in either route; for batch analyses, standard review calls for at least 3 manufacturing-scale batches and expedited review calls for at least 3 in principle, with the stated exception for mRNA vaccines; and standard review includes a minimum of 6 months of stability data from at least 3 representative batches. The expedited route’s stability provision instead describes a post-approval protocol for at least one representative batch, with the conditions and prior stability history noted above. These figures should be read together with the document’s qualifications, not in isolation.

The document also makes a distinction between submitting data and later verification when several manufacturing sites are involved. It states that data are required for each site, but where comparability between sites can be ensured after the strain change, approval can be obtained using data from one site, with the marketing authorization holder verifying the remaining-site data.

Who Should Read It

This document is relevant to regulatory affairs professionals preparing Japanese approval applications for SARS-CoV-2 vaccine strain changes; quality and analytical scientists planning characterization, batch testing and stability work; manufacturing and process-development teams assessing whether an established process can accommodate a new strain; and statisticians or data reviewers who help organize and interpret batch and stability evidence. It is also useful to clinical development and non-clinical teams involved in the document’s description of predicting immunogenicity and preparing for strain selection. For vaccine types other than mRNA and recombinant protein, or for first-time strain changes and quality or safety concerns, the scope limitations and consultation note are particularly relevant.

Official PMDA Source

• Official title: Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2 (Appendix 5) Quality data required for the approval review of changing a strain in the vaccine for which the manufacturing process is well established (Early consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency; Office of Vaccines and Blood products
• Date on the cover: May 29, 2024
• Official PMDA PDF: Read the PMDA document (PDF)
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document for the full text; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ.

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