Throughout the pharmaceutical product lifecycle, supplier changes constitute one of the most common types of regulatory submissions and are a key area of focus for regulatory authorities.

Changes in suppliers of active pharmaceutical ingredients, pharmaceutical excipients, or packaging materials may affect the quality, safety, and efficacy of the final dosage form; therefore, systematic studies and regulatory submissions must be conducted in accordance with applicable laws and regulations. So, what compliance tasks are actually required when a supplier changes? This article systematically outlines the process across five dimensions: regulatory basis, assessment of change categories, research and validation, submission pathways, and alignment with the quality management system. 1. Clarifying Regulatory Basis and Principal Responsibilities

1. Core Regulatory Framework

The principal regulations and guiding principles relevant to supplier changes include:

• The Measures for the Administration of Post-Marketing Changes to Drugs (Trial): These measures stipulate that, in the event of a change to an active pharmaceutical ingredient, the applicant shall determine the change management category in accordance with the applicable provisions and implement or report the change following approval or filing; moreover, any updated change information must be promptly entered into the registration platform.

“Technical Guidance Principles for Pharmaceutical Change Studies of Marketed Chemical Drugs (Trial)”: Stipulates that when changes occur to APIs and excipients, the marketing authorization holder shall conduct necessary studies on the finished dosage form based on the nature of such changes.

“Q&A on Active Pharmaceutical Ingredient (API) Changes in the ‘Technical Guidance for Pharmaceutical Change Studies of Marketed Chemical Drugs (Trial)’” (No. 27, 2024): Further clarifies the specific technical requirements when the supplier of an API used in a formulation changes.

Announcement No. 56 of 2019 issued by the National Medical Products Administration clarifies that, for marketed drug formulations, any change in the suppliers of active pharmaceutical ingredients or excipients and packaging materials shall be supported by studies conducted in accordance with the relevant guidance principles and shall be implemented in compliance with the current regulations on drug registration.

2. Principal Responsibilities of the Parties

• The marketing authorization holder of a pharmaceutical preparation bears principal responsibility for the quality of the drug and, in accordance with the requirements of pharmaceutical registration management and post‑marketing production management, shall conduct audits of the quality management systems of suppliers of active pharmaceutical ingredients and excipients to ensure compliance with medicinal‑grade standards.

The API registrant is responsible for maintaining the registration information on the registration platform, promptly updating it upon any changes, and notifying the relevant finished‑product holders of the relevant circumstances in a timely manner prior to implementing such changes.

If a supplier’s changes affect downstream customers, it shall notify them and obtain their approval; downstream pharmaceutical manufacturers shall establish communication and information-sharing mechanisms with their suppliers and clearly specify change-notification requirements in the quality agreement.

2. Assessing Change Management Categories

Supplier changes are not treated as a one-size-fits-all; rather, based on the extent of their impact on drug quality, they are classified into three categories: minor changes, moderate changes, and major changes.

1. Minor Changes

The following situations may be managed as minor changes and do not require scientific evaluation or validation:

• Reducing the number of approved suppliers of an active pharmaceutical ingredient;
• Changing the name of an API supplier (with no change to the legal entity).

2. Moderate Changes

The following situations are typically managed as moderate changes:

• The active pharmaceutical ingredient (API) after the change is an already approved API, and the quality of the API remains consistent before and after the change (e.g., impurity profile, critical physicochemical properties, etc.);
• Alternatively, although the quality of the API differs before and after the change, the quality of the finished dosage form remains consistent (e.g., dissolution profiles, impurity profiles, critical physicochemical properties, etc.).

Note: A change in the supplier of the active pharmaceutical ingredient used in the formulation is classified as a medium-level change.

3. Major Changes

The following situations shall be managed as major changes:

• The active pharmaceutical ingredient (API) after the change has not yet been approved (its registration status is “I”);
• A change in the API supplier results in inconsistent quality of the corresponding finished dosage form.

Special Note: Any change in the suppliers of active pharmaceutical ingredients, excipients, or packaging materials that results in the product’s registration status being “I” is classified as a major change.

3. Conduct research and validation work

Once the classification of change management has been determined, the corresponding research and validation activities must be carried out. The following are the main research contents:

1. Supplier Qualification Review and Documentation Preparation

The following supporting documents for the new, post‑change supplier must be provided:

• Valid approval documentation for the active pharmaceutical ingredient (API), such as the Notice of Approval for Marketing Application of a Chemical API, registration information, and quality standards;
• The “API Authorization Letter”;
• The supplier audit report (including the production license, GMP certificate, and change traceability records, etc.);
• The API internal control specifications and in‑house/out‑of‑house inspection reports from the formulation manufacturer, etc.

2. Comparative Quality Study of the Active Pharmaceutical Ingredient

A comprehensive comparative quality study of the API before and after the change should be conducted:

• Impurity profile comparison: Should include all detectable impurities.

Consistency of the impurity profile means that: newly identified impurities are no higher than the identification thresholds specified in ICH Q3A and related guidelines; the levels of existing impurities and the total impurity content remain within the limits set in the quality standards; residual amounts of any newly used solvents comply with ICH Q3C and related guidelines; and any new inorganic impurities meet the requirements of ICH Q3D and associated guidance.

Comparison of Key Physicochemical Properties: Key physicochemical properties relevant to formulation quality (such as polymorphism, particle size, etc.) should remain consistent.

Genotoxic impurities: Mutagenic impurities should be evaluated in accordance with ICH M7, and controlled as necessary.

Analytical Method: It is recommended to use the same analytical method to determine the impurity levels in batch samples before and after the change; if a new method is developed, method validation data should be provided and the new method should be compared with the original method.

3. Comparative Study of Formulation Quality

A comparative quality study should be conducted on formulations prepared using the API before and after the change:

• Comparison of dissolution profiles: For oral solid dosage forms, when the API supplier is changed, the dissolution profiles of the formulations before and after the change must comply with the relevant guidance requirements.

If the quality standards for the product do not include a dissolution test, it is recommended to establish an analytical method and conduct method validation.

Impurity profile comparison: The impurity profiles of the finished dosage forms before and after the change should remain consistent.

Comparison of Key Physicochemical Properties: The key physicochemical properties of the formulation should remain consistent before and after the change.

4. Stability Studies

Risks should be assessed based on the characteristics of the active pharmaceutical ingredient, the manufacturing process, critical quality attributes, key physicochemical properties relevant to the formulation, and stability, among other factors, to comprehensively determine the number of batches required for the study.

If, due to prolonged production downtime, no pre-change product is available, historical data from the pre-change product may be used for a comparative analysis with the post-change product, provided that the data are complete, accurate, and comparable.

5. Research Strategy for Multi-Specification Dosage Forms

For dosage forms that come in multiple specifications and share the same formulation and manufacturing process, it is permissible to conduct studies on the specification most sensitive to changes in the active pharmaceutical ingredient; the number of study batches for the other specifications may be appropriately reduced, provided that sufficient justification is provided. In general, low-dose medications are administered at the lowest available strength, while other drugs are used at the highest strength. Due to the higher risk associated with complex dosage forms, reducing the number of batches is not recommended. For formulations with multiple specifications and differing formulation processes, studies should, in principle, be conducted for each specification.

4. Determine the submission pathway and complete the submission

Based on the change management category, determine the corresponding submission pathway:

1. Minor change—Annual report

Minor changes can be reported to the regulatory authority via the annual report after implementation; no prior approval or filing is required.

2. Medium-Level Changes – Filing

Medium-level changes shall be filed with the drug regulatory authority of the province, autonomous region, or municipality directly under the central government where the applicant is located prior to implementation.

Changes to the filing‑based category have been reclassified as matters under provincial‑level regulatory oversight; requirements may vary across provinces. Holders are required to submit registration applications in accordance with the most recent local regulations of their respective provinces.

3. Major Changes—Supplementary Application

Major changes shall be subject to a supplementary application and may be implemented only upon approval by the national drug regulatory authority.

If the amended active pharmaceutical ingredient has not yet been approved, the relevant change documentation shall be submitted concurrently with the supplementary application for the finished dosage form.

5. Enhance the alignment of the quality management system

Supplier changes are not one-off events; they must be integrated into the company’s quality management system:

1. Establish a change control procedure

Companies should establish a written, comprehensive change control procedure to ensure that the entire change process is controlled and approved.

The change control procedure shall specify the processes for the submission, evaluation, review, approval, and implementation of changes to raw materials, excipients, packaging materials, quality standards, and other relevant elements.

2. Conclusion or Renewal of the Quality Agreement

The quality agreement should clearly specify the supplier’s obligations and procedures for notifying of any changes, ensuring that any changes that could affect product quality are identified and addressed promptly.

3. Handling of Related Changes

When changing the supplier of an active pharmaceutical ingredient (API), if the registration standards for the API differ among suppliers, and if the in-house control standards and registration standards of the corresponding finished dosage forms need to be adjusted accordingly, a related change application shall be submitted. Following the change, the quality control level of the finished dosage form must not be lowered.

4. Updating Registration Platform Information

The API registrant shall promptly update any changes in information on the registration platform.

Supplier change is a systematic undertaking and by no means as simple as merely “switching to another supplier.” Enterprises shall rigorously follow the compliance pathway of regulatory basis → category assessment → research and validation → submission and approval → system alignment. Among these, accurate classification of the change is the prerequisite, thorough research and validation constitute the core, a standardized submission pathway serves as the safeguard, and a robust quality system forms the foundation. Shanghai Hengyuehe Biopharmaceutical Co., Ltd. has been deeply engaged in the pharmaceutical intermediates and active pharmaceutical ingredient sectors for more than a decade, boasting a GMP-compliant production facility and a comprehensive quality management system. As a trusted partner, Hengyuehe can collaborate with clients to conduct supplier audits, perform quality‑comparative studies, and provide the technical documentation required for regulatory submissions, thereby helping clients seamlessly and efficiently manage supplier‑change activities in compliance with applicable regulations.