Health Products Registration
Biologics in Singapore: What Makes the Dossier Different?
1. Drug Substance: More Than Just Chemistry (Module 3.2.S)
Biologics are made using living systems, which means the drug substance section (Module 3.2.S) is much more complex than in small molecule applications. HSA expects:
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Detailed information on cell bank systems, including Master and Working Cell Banks (MCB/WCB)
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Description of the expression system and host cell line
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Clear flowcharts of the manufacturing process with critical control points identified
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Robust validation of viral clearance steps
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Risk assessment of raw materials, especially if animal- or human-derived
A well-structured CMC package here is essential for a smooth review.
2. Comparability and Characterisation: Not Optional
One of the most common causes of regulatory delays in biologics submissions is insufficient comparability data. This applies to both innovator biologics (post-change) and biosimilars.
HSA will look closely at:
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Physicochemical characterisation: including glycosylation profiles, size variants, aggregates
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Biological activity assays: to demonstrate that the biosimilar or updated product maintains expected functionality
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Comparative studies across Modules 3, 4, and 5 — not just one section in isolation
If you’re referencing a non-local comparator product, a strong scientific and regulatory justification is critical.
3.Stability Studies: Real-Time, Real-World
Biologics are temperature-sensitive and prone to degradation, making stability studies a critical part of the dossier. Although biologics are excluded from the ASEAN Stability Guidelines and not required to be tested under Zone IVb conditions (30°C/75% RH), HSA still expects robust stability data under ICH-recommended conditions.
For Module 3.2.P.8, HSA typically expects:
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Real-time, real-temperature stability data under the proposed storage conditions (e.g., 2–8°C), using ICH Q5C guidance as reference
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Data from multiple commercial-scale batches to support consistency in shelf-life across manufacturing lots
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Shipping validation studies, including stress testing or temperature excursion data, to ensure product integrity during transport
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A well-justified shelf-life, based on real-time data, not solely on extrapolation from accelerated studies
Even though Zone IVb is not applicable to biologics, your stability strategy must still demonstrate that the product remains safe, pure, and potent throughout its lifecycle — including under real-world transport and storage conditions.
Incomplete stability data is one of the most common flags at the screening stage.
4.Clinical and Nonclinical Data: Focus on Immunogenicity
In Modules 4 and 5, HSA’s review focuses on whether the clinical and nonclinical data:
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Clearly support the biologic’s safety, efficacy, and immunogenicity profile
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Include bridging data or scientific justification if the biosimilar comparator is not registered in Singapore
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Are derived from ICH-compliant studies, even if conducted overseas, as local Singapore data is not required by default
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Include robust immunogenicity assessments, especially for biologics intended for chronic use or repeated dosing
While HSA does not require studies in Singaporean patients, it expects that the clinical data be applicable to the intended population, and any major differences in demographics or clinical practice should be addressed through scientific justification.
Even for rare diseases or products supported by limited clinical data, a well-reasoned explanation is still expected.
5. Quality Overall Summary (QOS): More Than a Summary
The QOS (Module 2.3) in Singapore plays a central role in the reviewer’s assessment. It’s not just a summary — it’s a narrative of your product’s journey, from manufacturing to safety to clinical utility.
A good QOS should:
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Clearly connect CMC, nonclinical, and clinical data
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Provide justifications for control strategies and batch selection
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Reference tables and annexes logically
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Be tailored to HSA’s review style — concise, structured, and scientific
Cut-and-paste summaries from EU or US applications often don’t work well in Singapore.
6.Regulatory Strategy: Think Local Early
While HSA accepts ICH-aligned submissions, it expects sponsors to demonstrate a clear understanding of the local regulatory context.
Key points to consider:
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Reference product: If a biosimilar comparator is not registered in Singapore, provide bridging data or a scientific justification referencing global approvals and literature
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Post-approval commitments: Be prepared for ongoing requirements, such as continued stability studies or local pharmacovigilance plans, especially for newly marketed biologics
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Clear comparability strategy: HSA places importance on how changes to manufacturing or biosimilarity are justified. Submissions should include a transparent, risk-based comparability plan that aligns with ICH Q5E principles
Even for biologics already approved by major agencies (e.g., FDA, EMA), you may need to bridge data or adapt your justifications to address specific HSA queries or the Singapore healthcare context.
7. Common Pitfalls to Avoid
Based on experience supporting biologics submissions in Singapore, here are common areas that often lead to screening queries or delays during HSA review:
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Quality Overall Summary (QOS) not clearly presenting key quality attributes or addressing issues HSA typically prioritizes (e.g., comparability, control strategy, or stability justification)
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Comparability data that is insufficient, unclear, or does not adequately support product consistency or biosimilarity
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Stability protocols that overlook ICH Q5C guidance or fail to provide adequate real-time, real-temperature data — biologics are not subject to ASEAN Zone IVb requirements, but must still demonstrate product integrity
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Reference product justification missing or weak for biosimilars, especially if the comparator is not registered in Singapore
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Analytical method validation or bridging justifications not sufficiently detailed in Module 3, particularly when methods are adapted across sites or jurisdictions
Addressing these areas early can help reduce avoidable screening issues and improve overall dossier quality.
Starting with a gap analysis is highly recommended if you’re adapting a dossier from another region.
How TRC Can Support You
At TRC, we help companies prepare and localise their biologics submissions for the Singapore market. Our services include:
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CTD format and content gap analysis tailored to HSA expectations
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Submission preparation and planning, including guidance on required documents and formatting
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Support with regulatory strategy, such as identifying reference product considerations or bridging needs
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End-to-end coordination through the evaluation process, including screening query management and communication with HSA
We work closely with clients and their technical teams to ensure submissions are well-aligned with Singapore’s regulatory requirements — without duplicating scientific or manufacturing work already in place.
Biologics are powerful therapies, but the regulatory path in Singapore is not straightforward. Each module of the CTD needs careful attention — not just to meet international standards, but to reflect what HSA expects locally.
Whether you’re a small biotech or an established pharma company, having a clear local regulatory strategy can significantly shorten your path to approval.
Feel free to reach out if you’d like to discuss your biologics submission plans. We are happy to support.
Disclaimer: This blog is written based on the author’s current understanding, regulatory experience, and publicly available information. It is intended for general informational purposes only and does not constitute regulatory advice. For official requirements, please refer to the latest guidelines issued by the Health Sciences Authority (HSA) .
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