Tackling Grandfather or Legacy Products: A Regulatory Perspective

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Amongst the ever-emerging trend of new generation drugs, there is a group that is not widely discussed yet still remains the gold standard of treatment — or even serves as the pharmacophore on which many modern drugs are built. Examples of grandfather products include aspirin, morphine, diphenhydramine, and propranolol — all introduced decades ago and still widely used today. Their pharmacophore structures have inspired the development of many modern drugs, demonstrating the enduring value of these legacy products. This term is exchanged quite regularly during conversations here and there but is often neglected when strategizing market entry. Today, we are here to touch on this group of special products.

What are Grandfather or Legacy Products?

In regulatory terms, grandfather products (also called legacy products) refer to products that were introduced to the market before modern regulatory frameworks were established. For chemical entity drugs, this usually means they were first approved decades ago under older requirements and have remained on the market with minimal updates to their dossiers.

Where do grandfather products often originate from?

Most grandfather or legacy products originate from established pharmaceutical markets such as the United States, Europe, and Japan, where products were approved under national regulations before harmonized ICH guidelines existed. Additionally, some products from regional manufacturers in ASEAN or other Asia-Pacific countries also fall into this category if they were registered locally before CTD implementation.

Such products may:

• Lack comprehensive ICH CTD-format dossiers, making it difficult to directly submit to regulatory authorities that require standardised formats
• Be registered under older country-specific formats with missing modules (e.g. no full Module 3 CMC data and incomplete Module 5 clinical data), resulting in significant rework before submission
• Have undergone manufacturing or formulation changes over time not fully captured in the current registration file, raising concerns on data consistency, bridging justifications, and regulatory acceptability

 

Common Issues with Legacy Product Dossiers

From my experience, clients often face these challenges with grandfather chemical entity products:

• Missing Module 3 data :Older products may only have a brief manufacturing summary without detailed process validation, impurity profiles, or stability data as per current ICH/ASEAN requirements. This leads to delays in submission preparation as sourcing and compiling such data can take months or require additional manufacturer support.
• Non-compliance with current guidelines:
  Specifications, analytical methods, and validation reports may not align with updated pharmacopeial or ICH standards. This could result in deficiency queries or rejection if no bridging justification is provided. – Specifications, analytical methods, and validation reports may not align with updated pharmacopeia or ICH standards.
• Outdated safety or clinical information : For most well-established grandfather products, additional clinical data is generally not required if the product retains its original formulation, indication, and dosage form, and has a long history of safe use. However, dossiers may still lack current risk management plans or pharmacovigilance documentation, which are standard expectations under modern regulatory frameworks. In some cases, if a product is being introduced in a new dosage form or combined with a novel formulation, regulators may request bridging data or justification to confirm its safety and efficacy in the proposed context.

How TRC Can Help

At TRC, we support clients to resolve these gaps for market entry or re-registration in Singapore. Here are realistic examples of solutions we have provided:

Case 1: CMC Gap Analysis and Strategic Planning

A client approached us to register a 1980s-origin chemical entity analgesic in Singapore. The original dossier had:

• No detailed process validation reports

• Only finished product specifications with limited analytical validation data

Our approach:

1. Conducted a Module 3 gap analysis against HSA’s current requirements
2. Identified critical missing data and advised on the feasibility of sourcing them from the manufacturer or via new testing
3. Developed a regulatory strategy to allow the client to decide whether to proceed with registration or prioritise alternative products in their portfolio

Case 2: Regulatory Intelligence Assessment for antibiotic 

A Southeast Asian client aimed to bring in a legacy antibiotic product registered regionally before ASEAN CTD implementation.

Our approach:

1. Conducted a regulatory intelligence assessment to clarify HSA expectations for legacy products
2. Identified potential data requirements (e.g. stability data under ASEAN climatic zone IVb conditions, updated impurity profile data)
3.  Prepared a clear requirements list for the client to initiate discussions with their manufacturer efficiently and to plan next steps for dossier preparation

Case 3: Specification and Analytical Review Support for CNS Product

A European manufacturer sought to register a CNS (central nervous system) drug but its finished product specifications were outdated.

1. Reviewed the current USP/EP standards for the active ingredient and finished product
2. Provided recommendations to align the specifications with current standards to mitigate the risk of questions being raised during screening and evaluation
3. Guided the client in preparing bridging justification documents to support acceptance of older analytical methods with supplementary validation where needed

Legacy or grandfather products hold strong market value, but their outdated dossiers often pose barriers to registration under modern frameworks.

Performing a regulatory intelligence exercise early — to understand current requirements and feasible pathways — is critical. Starting a gap analysis as the first step ensures that data gaps can be proactively addressed, reducing time to market entry.

At TRC, we specialise in guiding clients through these complexities to achieve successful registration outcomes in Singapore. Contact us if you need support in revitalising your legacy products for new market opportunities.

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