Weichang Zhou helped transform China-based WuXi Biologics into one of the top three global biologics CDMOs. He then joined antibody-drug conjugate (ADC) company MediLink Therapeutics at a time when ADCs are leading the charge in driving Chinese innovation onto the global stage. «When I returned from the US over a decade ago, global new drugs were entering China; today, the reverse is happening — it is our high-quality Chinese ADCs, bispecifics, and trispecifics that are going global», says Zhou.

In its Decision-Makers DeepTALK column, PharmCube sits down for an in-depth conversation with Zhou, discussing the challenges and trends in CMC (Chemistry, Manufacturing and Controls) development within China’s ADC sector to present an industry veteran’s deep insights into the global competitive landscape of Chinese ADCs.

Aiming for Global Commercialisation from the Start

PharmCube: From a CMC perspective, what are the fundamental technical bottlenecks that have long hindered ADCs in terms of homogeneity, stability, and scale-up? Currently, most ADC drugs are lyophilised formulations; is a large-scale shift towards liquid formulations possible in the future? How will breaking through these bottlenecks impact commercialisation?

Weichang Zhou: The fundamental bottleneck lies in the fact that an ADC is a highly complex multi-component system. The key is the linker — it must remain stable in blood circulation without releasing the toxin prematurely, yet release it effectively within the tumour microenvironment (TME). Balancing stability with timely release is a perennial challenge. Combined with conjugation methods, DAR (drug-to-antibody ratio) control, and scale-up, this presents a massive engineering hurdle.

Early ADC products had clear deficiencies in these dimensions, such as poor product homogeneity, which directly caused significant issues for dosage and quality control. Last year, Enhertu (trastuzumab deruxtecan) achieved global sales of nearly USD 5 billion. Its success in overtaking competitors was largely due to major process improvements in achieving a uniform DAR=8 conjugation and the selection of a new potent toxin; this translated directly into clinical and commercial advantages.

These bottlenecks have been difficult to overcome for two reasons. Firstly, the optimisation of each ADC component is an arduous task requiring years of expertise. Secondly, these optimisations cannot rely solely on scientific design; they require a vast amount of practical experience to facilitate trial-and-error and iteration. Chinese companies possess an engineer dividend — the capability to systematically verify every possible combination. This is a structural advantage.

Regarding stability challenges in CMC, the early stages of the field saw lyophilised formulations dominate the market. The main requirement for shifting to liquid formulations, or even high-concentration subcutaneous injections, is precisely that the linker and conjugation technology must be stable enough to control toxin release in both solution and blood. MediLink’s TMALIN platform has a natural advantage here due to its hydrophilic linker and superior product stability; we have already achieved liquid formulations for some products. This means ADC administration is expected to increasingly resemble that of mature antibody drugs.

Simultaneously, the ADC field is evolving rapidly: designs such as bispecific and dual-payload ADCs have already demonstrated clinical value. As molecules become more complex, CMC challenges increase exponentially. In the past, excelling in five out of ten factors was enough to establish an advantage; now, one must meet standards across the board. Whoever can systematically solve these problems will have the opportunity to capture market opportunities that leap from the tens of billions to the hundred-billion-USD level.

PharmCube: To prioritise clinical speed, many biotechs often make trade-offs in CMC during the early stages. How does the nature of the CMC challenge change when a project advances to Phase III clinical trials and the PPQ (Process Performance Qualification) stage? What strategic steps have you taken at MediLink at this critical juncture?

Weichang Zhou: Making trade-offs for speed in the early stages is understandable, but one must clearly judge which gaps can be filled later and which will become permanent liabilities. Once a project enters Phase III and the PPQ stage, CMC shifts from background support to the decisive force determining whether a marketing application can be successfully filed. We have seen many cases where clinical data was excellent, but CMC fell behind, resulting in a failure to gain approval; or instances where both were handled well but the pace was too slow, allowing others to seize the market first.

The team at MediLink actually possessed solid capabilities for early-stage clinical samples, with no significant obstacles in moving from Phase I to Phase II. However, advancing to Phase III and PPQ represents a completely different level of challenge. We are preparing to submit the New Drug Application (NDA) for our first product this year and hope for approval next year. Founded at the end of 2020, obtaining approval by 2027 would be extremely fast for an ADC biotech — contingent, of course, on CMC not failing at any point.

Since joining MediLink, the team has invested heavily in completing PPQ. Last year, MediLink also successfully obtained its B-type license for Marketing Authorisation Holders (MAHs) and built a quality system and team capabilities that meet MAH requirements. This is a significant achievement for the entire team.

At this stage, managing risk across several dimensions is paramount. The first is CDMO management. MediLink does not have its own industrialisation base, so late-stage production must be entrusted to CDMOs. Every CDMO has a different philosophy and business model; one cannot simply sign a contract and wait for results — the team must be sent to the front line. We might have over a dozen people tracking a key project simultaneously, with weekly meetings between project groups during critical phases. During PPQ, we are together almost every day, with senior management maintaining regular alignment.

The second is on-site inspections by regulatory authorities. This is the final exam, as there are no re-sits in drug development; you must pass on the first attempt. My philosophy is that for any audit, domestic or international, if you only prepare to a 60% standard, weak points will inevitably be exposed during spot checks. Therefore, one must aim for 100%. Some domestic companies may find this philosophy difficult to accept, preferring to take shortcuts or cut corners. However, if problems do arise, the cost is ultimately far greater.

The third is supply chain security. Once a product is approved, stable supply to patients must be guaranteed, whilst also adapting to the China’s pricing environment and controlling costs. We have already begun constructing our own industrialisation base because the company is going global and the pipeline is expanding; we are no longer a single-product company. Having our own base does not mean abandoning CDMOs; rather, it is to more reliably ensure supply chain security while maintaining flexibility and speed. This has been a key strategic move I have driven since joining.

PharmCube: Regulatory communication is a crucial component of CMC. What are your views on the breakthroughs in China’s segmented production policies? Are there still challenges at the practical level?

Weichang Zhou: The progress made by domestic regulators has been significant. A few years ago, segmented production for ADCs was completely impossible to implement in China; however, pilot programmes began in 2024, and it is now under normalised management. This is necessitated by the nature of ADC products: the toxin is a chemical component while the antibody is biological. In principle, these two should not be manufactured at the same site to avoid cross-contamination and environmental pressure. Cross-border segmented production has long been the norm internationally, and I believe China is moving in exactly the right direction by gradually opening up.

Naturally, practical challenges remain. For instance, regulations require that either the MAH or the trustee must have at least three years of commercialisation experience. However, many innovative drug developers can never gain that experience without an initial approval, creating a chicken-and-egg dilemma. I believe such issues must be resolved through deeper regulatory communication. If a company can demonstrate a genuine clinical need for an innovative drug and the team possesses the requisite experience and capability, China’s National Medical Products Administration (NMPA) is actually willing to explore solutions alongside the firm. Our lead product has already received four Breakthrough Therapy Designations (BTDs); such credentials carry considerable weight during negotiations.

PharmCube: What differences still exist between China and the US regarding ADC manufacturing processes and CMC requirements?

Weichang Zhou: Since China joined the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) in 2017, the broad domestic regulatory framework and standards have aligned with international ones. Current differences are mostly seen in specific execution during the commercialisation stage.

In the US, for example, PPQ batches can be sold directly as commercial products. In China, however, one must wait for batches produced after the on-site inspection has been passed. This means the transition from approval to launch is much tighter for Chinese firms. Even with the approval in hand, inventory might not be fully ready.

Another easily overlooked difference is the process characterisation phase prior to PPQ. US companies rely on vast amounts of data to support the definition of Critical Process Parameters (CPP) and Critical Quality Attributes (CQA) ranges. Some Chinese companies are less rigorous in this regard, relying more on empirical judgment. Consequently, drugs already approved in China occasionally receive Form 483s [used to communicate concerns discovered during inspections] during US regulatory audits. This is not because the standards are unclear, but because the details at the execution level have not yet caught up.

Furthermore, basic requirements such as aseptic operations are highly scrutinised by international auditors. These must be performed to a perfect-score standard in daily operations rather than being treated as a last-minute rush before an audit.

PharmCube: In practice, how should CMC teams manage the timing of their communications with regulatory agencies?

Weichang Zhou: Once the Phase II clinical endpoint data is obtained and preparations for Phase III begin, the CMC team should start frequent engagement with the regulator. By this stage, the company is usually all in. Given the massive investment required for Phase III, there is an inevitable desire for positive data and a rapid launch; CMC must initiate the relevant regulatory communications in parallel.

However, earlier is not necessarily better. Without solid clinical data, regulators may not be willing to spend time on in-depth discussions. Conversely, if you wait until you have excellent data, you might regret not completing CMC communications sooner, as the product approval speed could be hindered. This tests a team’s experience, judgment, and the courage to plan ahead and 'begin with the end in mind'. This is precisely where the difficulty of CMC lies.

PharmCube: You emphasise that CMC must begin with the end in mind. Why is this mindset so vital? Are there any striking examples?

Weichang Zhou: There is a classic case in the industry. Decades ago, the US company Immunomedics began developing a TROP2 ADC. While early clinical data was consistently good, they struggled for years with CMC and manufacturing issues. The drug's launch was repeatedly delayed, and the company’s share price once fell below USD 1. Later, after the CMC hurdles were gradually cleared and the product was finally approved, Gilead Sciences acquired the entire company for a staggering USD 21 billion.

This case is a stark warning. CMC is a support department in the early stages, but if it fails later on, it becomes a chokepoint that determines the company’s survival. For a drug with annual sales of USD 2 billion, a one-month delay in approval could mean a loss of approximately USD 200 million. Yet, the company might have originally caused this outcome simply to save a few million or tens of millions in CMC investment. As the saying goes, pay me now or pay me later — if you do not invest now, the cost will be far higher in the future.

'Beginning with the end in mind' requires an enterprise to consider, when preparing the very first batch of clinical samples, that they may eventually need to expand abroad, find partners, and meet the regulatory standards of the US and other markets. For example, some raw materials used during development in China may come from suppliers who have never undergone an FDA or European Medicines Agency (EMA) audit; such materials cannot be directly purchased or used overseas. If global expansion is the intent from the outset, one should prioritise materials that are globally available and have mature compliance records. The difference in material costs might be negligible, but the direct and indirect losses caused during the technology transfer stage could reach eight-digit figures.

For early-stage biotechs with tight budgets, this is indeed a dilemma, and those who have not experienced it find it hard to grasp how heavy the price can be. In the long run, however, only the teams that dare to make upfront investments in CMC and truly understand how to 'begin with the end in mind' can avoid setbacks and convert scientific innovation into sustainable commercial value.