How GMP Non-Compliance can stop a Marketing Authorisation Application

According to the EMA, Scholar Rock Netherlands B.V. has announced that it is withdrawing a marketing authorisation application for Isembyld, which contains the active substance apitegromab, because of GMP problems at the product's manufacturing site in the USA. The clinical development programme had been progressing well.

A marketing authorisation application is not assessed solely on the basis of clinical efficacy and safety. The applicant must also demonstrate that the product can be manufactured consistently in accordance with Good Manufacturing Practice (GMP). Serious and/or ongoing GMP deficiencies at a contract manufacturer can affect the marketing authorisation application, because the applicant remains responsible for the quality of its outsourced activities and must ensure adequate control over contracted manufacturers.

Scholar Rock had been experiencing problems for some time with its contract manufacturer, 'Catalent Indiana Drug Product Manufacturing Site', which belongs to Novo Nordisk resp. Novo Holding. A brief search on the websites of the FDA (responsible for supervision of this manufacturer in the US) and Scholar Rock reveals a poor quality history for the site and provides further information.

For instance, an FDA Warning Letter dated 2025 addressed to Catalent Indiana details significant GMP violations, including the following:

• Inadequate root cause analysis of deviations
• Concerns regarding contamination during the manufacture of sterile medicinal products, e.g. due to mammalian hair
• Problems with media fills,
• Risks associated with closure stoppers.

Scholar Rock Netherlands B.V. was already a client as the sponsor at that time and subsequently received a Complete Response Letter (CRL) for the US marketing authorisation application for Apitegromab. A CRL may be issued for a wide variety of reasons if marketing authorisation cannot be granted in its current form. Examples of this may include inadequate manufacturing processes. Recommendations for rectifying the deficiencies may also be listed. According to Scholar Rock, the objections related to the manufacturing site and not to the efficacy or safety data for Apitegromab.

No real improvement was achieved. During a subsequent inspection in 2026, a so-called FDA Form 483 was issued, containing very similar observations:

• Glass particles and, once again, mammalian hair in finished sterile medicinal products,
• Rainwater in production areas,
• Delays in handling customer complaints and in investigating defective batches,
• Deficiencies in visual inspection, etc.

Scholar Rock continues to work closely with the FDA but has removed Catalent Indiana's filling and packaging facility from the BLA (Biologics Licence Application) for Apitegromab. The EU marketing authorisation application has now been withdrawn by Scholar Rock.

Why withdrawing the marketing authorisation application may be the most practical option

If a critical manufacturing site is affected, correcting ongoing deficiencies can take a considerable amount of time. If no suitable alternative site is available, a withdrawal can prevent the application from being rejected by the regulatory authority.

Editor's note: The FDA's Warning Letter and Form FDA 483 are to be distinguished from a decision by the EU authorities on the marketing authorisation application.

Sources:

• EMA announcement
• Withdrawal letter from Scholar Rock
• Warning Letter to Catalent Indiana
• Form 483 to Catalent Indiana
• Press release regarding the Complete Response Letter (CRL)
• Press release from August 2026