The Hidden Operational Cost Contained In Every Small Molecule Portfolio

By Megha Sinha, founder and CEO, Kamet Consulting Group

Small molecule drugs still account for the majority of the world’s most widely used medicines, and behind each of them lies a manufacturing and regulatory engine that never stops. Once approval is secured, the operational work of managing that product — across dozens of markets, through continuous manufacturing changes, supplier switches, site consolidations, and labeling updates — becomes a permanent, compounding burden that most organizations are under-equipped to handle.

A large pharmaceutical company assesses roughly 6,000 post-approval changes every year.¹ Around 3,300 of those require regulatory submissions — and because each must be filed separately across multiple markets, that figure expands to an estimated 90,000 country-level filings across more than 140 health authorities worldwide.² Where a single mature oral solid product may be registered in 80 to 120 countries, the scale of this operational burden is considerable. A manufacturing site transfer for one such product can generate hundreds of individual regulatory submissions, each with its own timeline, documentation requirements, and grace period rules. It can take three to five years to achieve full global approval for a single change, and most of this is managed through spreadsheets, email, and weekly status calls.

Since the regulatory pathways for CMC modifications are generally well established in traditional pharma, and associated evidence packages are relatively standardized, the defining characteristic of life cycle change management here is not so much complexity per change, but rather the sheer volume and simultaneity of changes running in parallel. A large company will not be managing one site transfer or one supplier switch at a time, for instance. It must manage dozens of overlapping programs, many affecting the same products in the same markets at the same time. In most organizations, each of those programs is tracked by a different team, in a different spreadsheet, unsupported by an aggregate view of how those various activities interact.

The Pressure Is Intensifying From Several Directions At Once

The U.S. BIOSECURE Act, now signed into law, is forcing companies to reevaluate API and CDMO relationships, with every supplier switch triggering a new wave of post-approval submissions across every registered market. Tariffs and the broader reshoring agenda are adding further impetus to manufacturing site moves, each of which generates three to five separate submission categories per country for a globally registered small molecule product. The patent cliff — with more than $200 billion in branded small molecule revenue at risk through 2030 — is driving portfolio rationalization decisions that produce waves of product discontinuations, market withdrawals, and marketing authorization holder (MAH) transfers, all requiring regulatory execution at scale. And the workforce that has historically absorbed this complexity is thinning, as experienced regulatory operations professionals retire, taking with them institutional knowledge about which markets allow parallel filings, which implementation grace periods are strict, and which submission bundling strategies actually work in practice.

The Real Cost Is Hiding In Plain Sight

One of the most consistent and costly failures in small molecule life cycle management is the decision to initiate a change before anyone has calculated whether it is actually worth doing. Manufacturing will identify a cost-saving opportunity — a supplier switch, a process optimization, a secondary packaging site consolidation — and the projected savings can look compelling. But the full execution cost of a post-approval change for a globally registered small molecule product is rarely visible to the team proposing it. Regulatory fees across 50 or more countries, artwork updates, dual production runs to maintain supply across markets with different approval timelines, stock write-offs for packaging that cannot be redirected, translation and notarization costs, and two to three years of experienced resource time all need to be accounted for. In many cases, the total cost of implementing the change approaches or exceeds the savings it was supposed to generate.

Because planning is fragmented across regulatory, supply chain, quality, and manufacturing functions, there is rarely a single point at which anyone calculates the full picture. The change is initiated as a technical or compliance exercise (what do we need to do to make this happen?) rather than as a business decision (should we do this at all, and if so, in which markets?). For small molecule companies managing large, multi-country portfolios, the opportunity to make smarter decisions — evaluating the cost of maintaining registrations against the commercial value of doing so and bundling related changes to consolidate submissions — is significant and almost entirely unrealized.

The consequences of poor execution are everywhere. I have seen a large-scale API site transfer across more than 50 markets where a single missed grace period deadline — in a market where no product may be sold from the old site once the deadline passes — created a supply gap lasting weeks, with revenue at risk in the millions. The root cause was not a regulatory failure; the submission had been approved on time. It was a coordination failure between the supply chain team planning the manufacturing cutover and the regulatory team tracking grace period trigger dates. They were working from different timelines, and nobody identified the gap until it was too late to build buffer stock.

In another case, a company executing a post-merger rebrand discovered midway through that its artwork pipeline was not aligned with the regulatory submission waves. Artwork was produced for markets that had not yet received approval, while approved markets were left waiting for updated packaging. The result was a four-month delay to market entry in several countries, unplanned dual production runs, and around $200,000 in packaging write-offs. For a small molecule product registered in 80-plus markets, the coordination surface area for exactly this kind of failure is enormous.

Actionable Steps For COOs And CQOs

There are three priorities that can begin generating results quickly, without a multiyear transformation program.

The first is establishing a genuine total-cost-of-change view before any change is initiated. This involves building a cross-functional cost model that captures regulatory fees, execution costs, dual-run costs, and resource time alongside the projected manufacturing savings — and making that model a standard part of the change initiation process. For large portfolios, this alone can prevent significant wasted expenditure on changes that were never financially justified.

The second is systematic bundling. Small molecule regulatory teams know that submissions can be grouped to reduce filing costs and simplify country-level approval tracking, but in most companies, this is done opportunistically (through informal conversations) rather than systematically. Building a structured view of which changes across the portfolio overlap in country scope and timing, and actively sequencing submissions to consolidate where possible, can materially reduce both cost and execution complexity.

The third is treating institutional knowledge as infrastructure. Too often the expertise of regulatory operations professionals, who know the grace period rules, the parallel-filing restrictions, the notarization timelines for specific markets, is not being captured in systems. When those individuals leave, the knowledge leaves with them. Encoding that expertise in structured form, so that it can be applied consistently and automatically to every change in the pipeline, is the most durable investment a small molecule organization can make in its post-approval operations.

The industry is in an era where AI can take care of so much of this (encoding practitioner knowledge, computing cross-functional dependencies, and flagging risks before they materialize), giving organizations an aggregate view across concurrent change programs they have never had before — including the ability to identify where the total cost of implementation is likely to exceed projected savings. In reality, the probability of AI delivering real near-term operational return in small molecule life cycle change management is significantly higher than in most of the areas currently attracting the most attention, yet this opportunity remains almost entirely untapped.

For CQOs and COOs in small molecule organizations, the call for transformation is growing louder. The volume of post-approval changes is rising, experienced people are moving on, and the manual approaches that have worked until now are no longer adequate for what is coming. The companies that get ahead of this — building structured regulatory intelligence, connecting planning to execution across functions, and treating life cycle change management as a strategic operational capability — will spend less, execute faster, and protect supply continuity more reliably than those that do not.

References

1. Harris R. et al., “An Evaluation of Postapproval CMC Change Timelines,” ISPE’s Pharmaceutical Engineering journal, September/October 2023. Available at: https://ispe.org/pharmaceutical-engineering/september-october-2023/evaluation-postapproval-cmc-change-timelines
2. Vinther A. et al., “Approaches to Design an Efficient, Predictable Global Post-approval Change Management System,” Therapeutic Innovation & Regulatory Science, 2024. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11043098/

About The Author:

Megha Sinha is founder and CEO of Kamet Consulting Group, which advises global pharmaceutical and life sciences companies on regulatory operations, quality, and large-scale transformation. With more than 17 years’ experience across the industry, including senior leadership roles at global consulting firm PwC, Sinha has worked with many of the world’s largest pharma organizations, solving their most complex regulatory, supply chain, and life cycle management challenges.