我们偶尔会接到一些很特别的咨询。客户手里的产品，很难直接套进一个标准的注册路径里。

它们不完全是全新的化学实体（NCE）或生物制品。也不是简单直接的仿制药。但它们又不太可能仅凭文献论证就走通一条路。

这些产品常常“卡在中间”，需要仔细评估，才能理出合适的法规策略。

哪些产品会面临这种情况？

过去几年，我们见过不少这类咨询：

• 针对特定疾病人群的特殊营养产品

• 主要靠已发表文献和长期临床使用经验来支持的产品

• 含有成熟活性成分、已在国际上广泛使用多年的产品

• 在海外已获批但从未在新加坡注册过的产品

• 已知活性成分的新复方，且不属于处方药范畴

• 在不同国家被归为不同类别的产品

在这些情况下，我们发现企业常常有几个误区。

常见误区

“这个产品已经在国外获批了，所以在新加坡也应该按同样的路径走。”

不一定。海外批准可以作为参考，但新加坡的法规要求是独立的，本地的监管期望还是得满足。

“原产国怎么分类，新加坡就怎么分类。”

不同国家对同一个产品的分类可能完全不一样。一个产品在别国被归为非处方药、保健品、医学食品甚至医疗器械，在新加坡可能完全不同。这就是为什么在投入大量资源准备文件前，先做分类评估很重要。

“必须要做新的临床试验。”

不一定。根据产品、适应症和现有证据的情况，已发表文献、公认的临床使用经验、海外的监管经验以及现有临床数据，都可能派上用场。但到底够不够，得一个一个产品具体看。

“现有文献能自动支持任何新适应症。”

光有文献可能不够。文献的质量、相关性、适用性和一致性，都是决定能不能支撑拟用适应症的关键因素。

NDA-2路径的真实要求

就算一个产品可能走NDA-2路径，也别以为监管要求会宽松很多。该交的东西一样不少：模块一的行政文件、模块二的综述和概述、模块三的质量信息，以及支持安全性和有效性的临床证据。

关键区别不在于“不需要证据”，而在于证据包怎么构建、怎么论证。对于成熟活性成分、临床用途已经被广泛认可的产品，用已发表文献和现有数据做科学讨论，可能就不用再做新的临床研究。但每个产品都得独立评估，没办法一概而论。

为什么早期评估很重要

根据我们的经验，项目一开始最有用的，就是先搞清楚产品分类对不对、现有证据包够不够支撑预期的法规策略。这通常涉及：产品分类评估、法规路径评价、临床证据差距分析、标签审查、海外监管状态评估，以及在准备文件前先把潜在问题找出来。

早期评估往往能帮企业避免不必要的法规延误，也能在投入大量资源之前，把数据要求搞清楚。

TRC如何提供支持

TRC帮公司评估产品分类、评价法规路径、审查证据包，在启动申报计划前找出文件中的差距。如果你手里的产品不太符合常规注册类别，早期的法规评估通常能帮你理清：NDA-2这条路能不能走，以及需要哪些支持文件才过得去。

One of the more interesting enquiries we occasionally receive involves products that do not fit neatly into a conventional registration pathway.

They are not entirely new chemical entities or biological products.

They are not straightforward generic medicines.

Yet they may not be suitable for a simple literature-based justification alone.

These products often sit somewhere in between and require careful assessment before an appropriate regulatory strategy can be established.

Over the years, we have encountered enquiries involving:

• Specialised nutritional products intended for disease-specific patient populations
• Products supported primarily by published literature and established clinical use
• Products containing well-established active ingredients with extensive post-marketing experience internationally
• Products approved overseas but not previously registered in Singapore
• New combinations of known active ingredients which are not prescription products
• Products that are classified differently across jurisdictions

In many of these situations, there are often misconceptions regarding the regulatory pathway.

Common Misconceptions

“The product is already approved overseas, therefore the same regulatory approach should apply in Singapore.”

Not necessarily.

While overseas approvals can provide valuable supporting information, Singapore regulatory requirements remain independent and local expectations must still be addressed.

“The product classification in the country of origin will be the same in Singapore.”

Product classification can differ significantly between jurisdictions. A product classified as a non-prescription medicine, health supplement, medical food, or even a medical device elsewhere may be classified differently in Singapore.

This is one of the reasons why an early classification assessment is often important before substantial resources are invested in dossier preparation.

“A new clinical trial is always required.”

Not always.

Depending on the product, indication, and available evidence package, published literature, established clinical use, overseas regulatory experience, and existing clinical data may contribute to the overall justification strategy.

However, the adequacy of the evidence package must be assessed on a case-by-case basis.

“Existing literature can automatically support any new indication.”

The existence of published literature alone may not be sufficient.

The quality, relevance, applicability, and consistency of the available evidence remain important considerations when determining whether the proposed indication can be adequately supported.

Understanding the Regulatory Requirements

Even where a product may potentially be considered under an NDA-2 pathway, companies should not assume that regulatory expectations are significantly reduced.

The submission may still require a comprehensive dossier package including:

• Module 1 administrative documentation
• Module 2 summaries and overviews
• Module 3 quality information
• Clinical evidence supporting safety and efficacy

The key difference is often not the absence of evidence requirements, but rather how the evidence package is constructed and justified.

For products with well-established active ingredients and recognised clinical use, scientific discussion supported by published literature and existing evidence may reduce the need for generating entirely new clinical studies. However, each product must be assessed individually.

Why Early Assessment Matters

In our experience, one of the most valuable activities at the beginning of a project is determining whether the product is appropriately classified and whether the available evidence package is sufficient to support the intended regulatory strategy.

This may involve:

• Product classification assessment
• Regulatory pathway evaluation
• Clinical evidence gap analysis
• Labelling review
• Assessment of overseas regulatory status
• Identification of potential deficiencies prior to dossier preparation

An early assessment often helps companies avoid unnecessary regulatory delays and better understand the data requirements before committing significant development resources.

How TRC Can Support

At TRC, we assist companies in assessing product classification, evaluating regulatory pathways, reviewing evidence packages, and identifying potential dossier gaps before submission planning begins.

For products that do not fit neatly into conventional registration categories, an early regulatory assessment can often provide greater clarity on whether an NDA-2 strategy may be appropriate and what supporting documentation may be required to support a successful submission.

没有什么比拥有一套整理完善、及时更新的产品注册档案更让法规人感到踏实了。

但现实往往不是这样。

我们接手过太多“循环再利用”的旧档案——经历了多年的生命周期变更、多次上市后修订、生产场地更新、供应商更替和法规要求的演变，信息逐渐碎片化，历史模块长期未更新，最终档案已无法真实反映产品当前的生产和质量状态。

在启动任何新申请或市场扩张之前，我们常常不得不先投入大量精力进行深度差距分析，将档案与产品现状重新对齐。这不可避免地拖延了整体进度，增加了审评问询的轮次，也制造了不必要的法规工作量。

对于总部的档案管理团队来说，这种状况是可以理解的。他们要同时应对新供应商引入、分析方法更新、生产工艺改进、法规要求变化、上市后承诺履行、安全性更新以及跨多个管辖区的持续变更。在众多优先事项的挤压下，档案维护很容易从主动管理变成被动应对。

TRC的团队常帮助公司进行针对性的生命周期档案审查，在法规提交、合作伙伴尽职调查或市场扩展活动之前，提前识别需要对齐的关键领域。

生命周期档案维护中的常见审查要点

模块一 — 行政与法规文件

行政文件应保持更新且随时可提交。

常见问题包括：授权信和声明函已过期、最新版说明书或包装图稿未替换嵌入档案、GMP证书未标注有效期或已失效、生产场地信息在各模块中不一致、原辅料授权文件和CEP未及时维护。

这些看似细小的行政问题，在审评过程中往往会造成不必要的沟通和澄清延误。

模块二 — 档案整体一致性

模块二通常是快速判断档案质量的最佳窗口。

质量综述、非临床综述和临床综述需要与模块三、四、五中的最新信息保持一致。我们常遇到的状况包括：生产描述已过时、质量标准与模块三不符、稳定性结论陈旧、临床定位已不再适用现有适应症、生命周期变更未完整整合。

维护良好的模块二能显著提升档案的可读性，减少下游的审评问询。

模块三 — 质量与生产工艺的生命周期管理

对于成熟药品而言，模块三通常是生命周期管理中最操作密集的领域。

关键审查要点包括：生产方角色与职责是否反映当前技术协议、是否引入了新的外包检测或生产场地、工艺验证报告是否更新、是否实施了新的分析控制及验证程序、年度稳定性承诺及持续稳定性数据是否已纳入、质量标准是否与现行方法对齐、批配方与拟议商业批量的匹配情况、药剂开发部分是否仍反映当前实践、现行批分析数据及杂质控制策略。

在许多老旧档案中，药剂开发部分往往是历史性描述，长期未根据实际工艺演变进行更新。

不同产品类型的生命周期考量

仿制药与成熟产品
对于成熟仿制药组合，生命周期管理更多是确保所有已实施的变更已完整反映在档案中。涉及生产工艺更新、质量标准修订、供应商变更、分析方法改进、稳定性周期延长、包装更新等，需要进行定期档案梳理以维持信息一致。

新化学实体（NCE）
对于NCE产品，生命周期维护不仅限于常规变更管理。法规团队还需评估临床定位演变、新增适应症、新剂量规格或剂型、风险管理活动更新及全球法规对齐策略。

生物类似药
生物类似药的生命周期管理更为复杂，因为在整个产品生命周期中，可比性始终是重点。即便是相对较小的生产变更，也可能需要审慎评估以确保与参照药的可比性论证持续成立。

细胞与基因治疗产品
对于ATMPs、细胞治疗和基因治疗产品，生命周期管理涉及高度动态的运营和法规环境。需持续关注起始物料控制策略、载体及病毒安全性更新、效价检测方法演变、冷链及物流确认，以及各区域快速变化的法规期望。

模块四 — 非临床生命周期更新

模块四在许多成熟产品中相对稳定，但以下情况下仍可能需要更新：新杂质产生、修订的毒理学评估报告、新增辅料安全性考量、额外的非临床论证数据。

模块五 — 临床及药物警戒维护

模块五的生命周期维护可能涉及：新增临床研究报告、适应症扩展支持、更新的文献综述、PSUR/PBRER维护、风险管理计划更新、以及与上市后安全性观察及承诺的持续对齐。

eCTD生命周期维护

对于采用eCTD格式维护的产品，定期技术性清理同样重要，包括超链接验证、书签完整性检查、生命周期操作准确性、序列一致性及区域结构对齐。技术层面的不一致可能在审评过程中造成可避免的审查障碍。

支持可持续的法规生命周期管理

档案维护或许操作繁琐，尤其对于跨多个市场管理的成熟产品组合。但前瞻性的生命周期管理能显著减少法规差距，提升提交准备度，并在合作伙伴尽职调查和市场扩展活动中更加从容。

TRC理解成熟药品、生物制品、生物类似药及先进治疗产品在生命周期档案维护中的复杂性。我们的法规生命周期管理支持服务，旨在帮助公司识别档案差距、梳理历史文件，并在产品持续全球演进的过程中，始终保持提交准备度。

There is no better feeling than having an organised and updated product dossier within a regulatory inventory.

Regulatory professionals will resonate with this immediately.

In reality, many companies eventually encounter what we often refer to as “recycled dossiers” — dossiers which have undergone years of lifecycle changes, manufacturing updates, process improvements, supplier transitions, and post-approval variations across multiple markets. Over time, information becomes fragmented, historical sections remain outdated, and internal documentation no longer fully reflects current operational practice.

Before any new submission or market expansion can proceed, significant gap assessments may be required to reconcile the dossier with the current state of the product.

This ultimately delays timelines, increases deficiency queries, and creates additional regulatory workload.

For central dossier management teams, this situation is understandable. Regulatory lifecycle management is complex. Teams are simultaneously managing:

• new suppliers,
• updated analytical methodologies,
• manufacturing process improvements,
• changing regulatory expectations,
• post-marketing commitments,
• safety updates,
• and ongoing variation implementation across multiple jurisdictions.

With competing priorities, dossier maintenance can gradually become reactive rather than proactive.

At TRC, we often support companies by performing targeted lifecycle dossier reviews to identify critical areas requiring alignment before regulatory submission, partner due diligence review, or market expansion activities.

Key Areas Commonly Reviewed During Lifecycle Dossier Maintenance

Module 1 — Administrative and Regulatory Documentation

Administrative documentation should remain current and submission-ready.

Common areas requiring verification include:

• validity of Letters of Authorisation and declaration letters,
• latest approved SmPC, PI, IFU, and packaging artwork,
• validity of GMP certificates and manufacturing licences,
• alignment of manufacturing site information across modules,
• maintenance of Drug Master Files and CEP documentation,
• regional administrative consistency.

In many mature dossiers, outdated administrative documents remain embedded within historical submission packages, creating unnecessary clarification rounds during review.

Module 2 — Overall Dossier Consistency

Module 2 often provides the fastest indication of the overall quality and maintenance status of a dossier.

Quality Overall Summaries, Nonclinical Overviews, and Clinical Overviews should remain aligned with the latest information presented in Modules 3, 4, and 5.

Common issues observed include:

• outdated manufacturing descriptions,
• specifications inconsistent with Module 3,
• obsolete stability conclusions,
• historical clinical positioning no longer aligned with current indications,
• incomplete integration of lifecycle changes.

A well-maintained Module 2 significantly improves dossier readability and reduces downstream regulatory queries.

Module 3 — Quality and Manufacturing Lifecycle Management

For mature pharmaceutical products, Module 3 maintenance becomes one of the most operationally intensive areas of lifecycle management.

Critical review areas may include:

• manufacturing roles and responsibilities reflecting current technical agreements,
• newly introduced outsourced testing or manufacturing sites,
• updated process validation reports,
• implementation of new analytical controls and validation procedures,
• annual stability commitments and ongoing stability data updates,
• alignment of specifications with current methodologies,
• consistency between batch formulae and proposed commercial batch sizes,
• continued validity of pharmaceutical development sections,
• current batch analysis data and impurity control strategies.

In many legacy dossiers, pharmaceutical development sections are historically written and no longer adequately reflect internal process evolution implemented over time.

Product-Specific Lifecycle Considerations

Generic and Mature Products

For mature generic portfolios, lifecycle management frequently involves ensuring that all implemented variations are consistently reflected throughout the dossier.

Over time, multiple post-approval changes may have been introduced involving:

• manufacturing process updates,
• specification revisions,
• supplier changes,
• analytical method improvements,
• stability extensions,
• packaging updates.

Without periodic dossier restructuring, inconsistencies may emerge between approved changes and the current dossier state maintained internally.

New Chemical Entities (NCEs)

For NCE products, lifecycle maintenance often extends beyond routine variation implementation.

Regulatory teams may need to evaluate:

• evolving clinical positioning,
• additional indications,
• new dosage strengths or formulations,
• updated risk management activities,
• global regulatory alignment strategies,
• incorporation of new post-marketing commitments.

As global development programmes mature, maintaining consistency across regional dossiers becomes increasingly important for efficient lifecycle expansion.

Biosimilars

Biosimilar lifecycle management introduces additional complexity due to the continued importance of comparability throughout the product lifecycle.

Common lifecycle review considerations may include:

• manufacturing process evolution,
• comparability exercise updates,
• analytical similarity reassessment,
• control strategy refinement,
• evolving reference product considerations,
• post-approval process optimisation,
• alignment between manufacturing changes and regulatory commitments across markets.

Even relatively small manufacturing changes may require careful assessment to ensure continued demonstration of biosimilarity.

Cell and Gene Therapy Products

For advanced therapy medicinal products (ATMPs), cell therapies, and gene therapy products, lifecycle management may involve highly dynamic operational and regulatory environments.

Areas commonly requiring ongoing review include:

• chain of identity and chain of custody documentation,
• starting material control strategies,
• vector and viral safety updates,
• evolving potency methodologies,
• comparability following manufacturing changes,
• long-term follow-up commitments,
• cold chain and logistics qualification,
• rapidly evolving regulatory expectations across regions.

Given the complexity of these products, maintaining an organised and continuously updated dossier structure becomes critical for sustainable lifecycle management.

Module 4 — Nonclinical Lifecycle Updates

While Module 4 may remain relatively stable for many mature products, updates may still be required where:

• new impurities emerge,
• revised toxicological assessments become available,
• new excipient safety considerations arise,
• additional nonclinical justification data is generated.

Module 5 — Clinical and Pharmacovigilance Maintenance

Lifecycle maintenance within Module 5 may involve:

• inclusion of new Clinical Study Reports (CSRs),
• support for indication expansion,
• incorporation of updated literature reviews,
• PSUR/PBRER maintenance,
• Risk Management Plan (RMP) updates,
• alignment with post-marketing safety observations and commitments.

As products mature commercially, pharmacovigilance activities often become increasingly important in supporting continued regulatory confidence.

eCTD Lifecycle Maintenance

For products maintained in eCTD format, periodic technical housekeeping is equally important.

This may include:

• hyperlink verification,
• bookmark integrity checks,
• lifecycle operator accuracy,
• sequence consistency,
• regional structure alignment.

Technical inconsistencies within eCTD submissions can create avoidable review complications during regulatory assessment.

Supporting Sustainable Regulatory Lifecycle Management

Dossier maintenance may be operationally demanding, particularly for mature portfolios managed across multiple markets. However, proactive lifecycle housekeeping significantly reduces regulatory gaps, improves submission readiness, and facilitates smoother partner due diligence and market expansion activities.

At TRC, we understand that lifecycle management is not a one-time exercise. As products continue to evolve commercially and technically, regulatory dossiers must continuously adapt alongside manufacturing updates, post-approval variations, safety commitments, analytical improvements, and changing regulatory expectations across different regions.

This becomes especially relevant for companies managing mature pharmaceutical products, biosimilars, advanced therapy products, or multi-market portfolios where internal regulatory resources are often balancing multiple competing priorities simultaneously.

Our regulatory lifecycle management support services are designed to assist companies in:

• identifying dossier gaps,
• restructuring historical documentation,
• reviewing lifecycle implementation consistency,
• maintaining submission readiness,
• and supporting ongoing regulatory maintenance activities as products continue to evolve globally.

For companies requiring longer-term operational support, TRC also offers flexible regulatory subscription support models tailored to ongoing dossier maintenance, lifecycle management activities, variation support, and regional regulatory coordination needs.

Good dossier practice may often go unnoticed internally — until the next submission, partner review, or market expansion opportunity arrives. Maintaining an organised and continuously aligned dossier today can significantly reduce regulatory burden tomorrow.

2026年1月16日，新加坡卫生科学局（HSA）推出了一项新的药品注册路径，专门针对“标准基本药物”（Standard Essential Medicines）。

这不是常规意义上的“简化路径”——审评标准并未降低。这条路径的真正价值在于：为那些没有新加坡参考药品（Reference Product）的仿制药，打开了注册的可能性。

过去，这类药物因为没有本地已注册的“对标”产品，连申请的机会都没有。现在，HSA允许企业凭充分的临床文献和本地使用历史作为证据，通过提交“意向书（Expression of Interest, EOI）”来启动申请流程。

一、哪些产品有资格？

这条路径不是对所有仿制药开放的，需要同时满足以下条件：

1. 安全性和有效性已被充分证实：产品必须在公认的科学文献中拥有良好的疗效与安全记录，例如被世界卫生组织（WHO）基本药物清单、英国国家处方集（BNF）、马丁代尔（Martindale）等权威参考文献收录。

2. 在新加坡有长期的本地临床使用历史：产品需要被列入新加坡卫生部（MOH）标准药物清单（Standard Drug List），或在公立医疗机构的药房与治疗委员会（P&T）清单中持续使用至少五年。

3. 没有对应的新加坡参考产品：这是这条路径最核心的准入条件。如果新加坡市场上已有同款原研药或参比制剂注册，则应通过传统仿制药路径（GDA）申请。

注意：HSA允许企业利用已有的本地临床使用经验作为安全性和有效性的证据。这意味着，如果产品已在本地医疗机构使用多年，这部分临床实践数据将成为注册申请的重要支撑。

二、关键前置步骤：提交“意向书”（EOI）

即使产品符合上述条件，也不能直接提交注册申请。

HSA要求企业必须在计划提交正式GDA申请的至少3个月前，先提交一份“意向书”（Expression of Interest）。

这份EOI需要阐明产品的基本信息、本地临床使用历史、以及为什么符合这条路径的准入条件。HSA审核EOI后，会决定是否允许企业进入正式的GDA申请阶段。只有在EOI获得HSA批准后，才能启动后续的注册工作。

这一步不是走过场。EOI的质量直接影响后续是否能顺利推进，需要认真准备。

三、这条路径需要重点关注什么？

对于手握成熟仿制药的企业来说，这条路径带来了新的市场准入机会，但并不意味着审评标准的降低。HSA对药品质量、安全性和有效性的要求，与其他注册路径是一样的，只是评价的方式不同。

在实际操作中，有几个关键点需要提前评估：

• 产品是否真正符合资格：对照HSA的准入标准逐一核查，确认产品是否确实在新加坡本地医疗系统中有不少于5年的连续使用历史，且被列入了MOH标准药物清单或公立医疗机构的P&T清单。

• 支持性文件是否充分：产品的安全性、有效性和质量文件是否与HSA的要求对齐。对于已经有多国上市历史的产品，现有申报文件（dossier）与新路径要求之间可能存在差距。

• EOI的准备工作：EOI的撰写需要清晰、严谨，能够说服HSA该产品确实符合本路径的准入标准。

• 后续注册策略：EOI获批后，正式的GDA申请需要完整的药学研究、非临床及临床数据支持，且所有文件必须符合CTD或ACTD格式要求。

四、TRC如何提供支持

如果企业考虑通过这条路径将产品推向新加坡市场，TRC可以在以下几个环节提供评估与申报支持：

• 产品资格评估：对照HSA的准入标准，审核产品是否具备申请资格，包括核实本地临床使用历史、文献支持程度等。

• 文件差距分析：审阅现有申报文件，识别与HSA要求之间的差距，提供具体补充建议。

• EOI准备与提交：协助整理和撰写意向书，确保提交内容符合HSA的审核标准。

• 正式GDA申报：在EOI获批后，提供端到端的注册申报支持，包括文件整理、提交、与HSA沟通审评问询等。

如果手上有这类产品，不确定能否走这条路径，欢迎进一步沟通。我们在新加坡做法规注册多年，清楚HSA的审评重点和实际操作要求。

How to set up a Quality Management System for a SME in medical field

It’s time of the year again where perhaps this question of setting up a Quality Management System has come up to your mind. Whether it is due to a new business direction or complying to upcoming regulations, it’s always good to start early. Let’s go through the 5 steps to do this quickly.

1. Understand what is required for the Quality Management System. A Quality Management System is a set of guidelines and operating procedures to ensure that the company meets its objectives to provide quality and efficient product and services. It can means having a masterfile to provide an overview of the company’s activities and a set of working SOPs/ Work Instructions (WIs) that are already in place.
2. Identify the objectives of the Quality Management System. Identify the key processes in your company’s activities that can impact on your product or services. Identify the key personnels as well as their roles and responsibilities in the Quality Management System.
3. Do a simple gap analysis exercise to improve upon what is missing and add on missing documentation.
4. Execute the Quality Management System for one to two months.
5. 5. Perform a internal audit to assess efficacy as well as area of improve or engage a third party internal auditor to provide feedback on the system.

 

Voila. If you are keen to learn more, please contact us !