China implements a filing system for the management of active pharmaceutical ingredients (APIs), excipients, and packaging materials (referred to as AEPs).
AEP filers submit common technical documents (CTD) to the Center for Drug Evaluation (CDE) through its AEP filing platform. Once generic APIs successfully undergone an independent review, or AEPs have undergone an associated review with finished dosage forms, their filing statuses will be changed from “I” to “A”, indicating that they have obtained marketing authorization.
Table 1 below shows the filed information on CDE’s platform as of December 13, 2023.
Table 1: Filed AEPs on CDE’s platform by 13/12/2023
Filed AEP | API | Excipient | Packaging material |
Filed total | 16,574 | 5,838 | 13,978 |
Status “A” | 12,344 | 2,826 | 7,230 |
Managing post-approval changes for AEPs is a crucial aspect of drug lifecycle management. Changes in AEPs, such as modifications in manufacturing processes, batches, quality standards, can impact the quality of AEPs, which in turn affects the finished dosage forms (FDFs).
To effectively handle these changes, CDE encourages drug marketing authorization holders (MAHs) to establish quality agreements with AEP suppliers and/or manufacturers to promptly obtain relevant information. When changes occur in AEPs, it is essential for MAHs to conduct necessary research on the FDFs based on the AEP changes. MAHs are also obligated to continuously improve the manufacturing processes of the approved FDFs, and enhance the safety, efficacy, and quality control of FDFs.
This report introduces the responsibilities of AEP filers and drug MAHs in managing post-approval changes of AEPs. It also covers the categories of post-approval changes of AEPs and provides the information on the fees associated with applying for these changes.
For post-approval changes that are not addressed by the current regulations and guidance, we recommend that applicants engage in communication with CDE, or consult with us for further advice.
Please download the pdf document at the end of this page if you wish to read this article offline.
Part 1 For API Manufacturers: Categories of Post-approval Changes to APIs and Relevant Obligations
1.1 Categories and specific situations of API changes
1.1.1 Changes in API manufacturing process
1.1.1.1 Definition, Categories, and Specific Situations of changes in API manufacturing process
Changes in the API manufacturing process mainly refer to modifications in the chemical synthesis process of chemically synthesized APIs or modifications in the chemical synthesis process and subsequent manufacturing process of semi-synthetic APIs. This generally includes:
Changes in the synthesis route (such as extending/shortening the synthesis route, changing starting materials, etc.).
Changes in manufacturing conditions.
Changes in material control or process control, and other possible changes.
Changes in the manufacturing process may involve only one of the above situations or multiple situations mentioned above. For changes in the synthesis route, the selection of starting materials in the modified synthesis route should comply with ICH Q11 Guideline.
Table 2: Categories and specific situations of changes in API manufacturing process
Change category | Specific situation |
Minor change | (1) Introducing new process control methods or establishing more stringent process control limits to better manage drug production and ensure drug quality. If the aforementioned changes are made due to process defects or stability issues identified during the API manufacturing process, the changes should be categorized as major changes and the manufacturers should submit applications for implementing the changes. (2) Enhancing the quality standards or starting materials and intermediates. (3) Modifying the quality standards or grades of reactants and solvents used in the API manufacturing process, without reducing their quality. (4) Changing the production equipment used in the process steps before, during, or after the final reaction while keeping the materials, design, and operating principles unchanged. The impurity profile and key physicochemical properties of the API (such as particle size, crystal form, etc.) remain unchanged. (5) Changing the supplier (referring to the actual manufacturer, same hereafter) of the starting materials, while keeping the synthesis route of the starting materials unchanged and ensuring that the quality of the starting materials is not reduced. |
Moderate change | (1) Extending the process route based on the approved process route, using the original starting material as an intermediate, where the extended process route aligns with the original starting material. (2) Changing the synthesis route of the starting material without reducing its quality. (3) Changing (except for major changes) the reactants, solvents, production conditions, etc., in the process steps before the final reaction, while keeping the impurity profile of the API consistent. If the added or changed solvents were already used in the original API synthesis process, they can be managed as minor changes. (4) Incorporating rework process as a fixed production step, resulting in changes in the registered manufacturing process. (5) Changing (except for minor change (2)) the quality standards of starting materials and intermediates, while ensuring that the quality control level of the modified starting materials and intermediates is not reduced. (6) Changing the production equipment used in the final reaction and subsequent process steps, including changes in material, design, and operating principles, while keeping the impurity profile and key physicochemical properties (such as particle size, crystal form, etc.) of the API unchanged. (7) In case of sterile APIs: ① Changing the filtration parameters of the sterilization filtration process (including flow rate, pressure, time, or volume, but with pore size unchanged). ② Transitioning from a single sterilization process filer to two sequential sterile-grade filters in series. |
Major change | (1) Changing (except for moderate change (1)) the synthesis route of the API. (2) Changing the synthesis route of the starting material, resulting in a change in the quality of the starting material. (3) Changing the manufacturing process during or after the final reaction, such as altering the crystallization solvent type. (4) Modifying process parameters that may impact the critical quality attributes (CQAs) of the API. (5) Adding a rework process to the registered manufacturing process. (6) Relaxing or removing approved quality controls and process controls for starting materials and intermediates, which may lead to changes in the impurity profile and key physicochemical properties of the API. (7) Changing the equipment used in the manufacturing process of the active pharmaceutical ingredient, which may result in changes in the impurity profile or key physicochemical properties. (8) Changing the manufacturing process of sterile API, possibly affecting the level of sterility assurance in the following situations: ① Changing the sterilization/aseptic process of the API, such as transitioning from one process (e.g., sterilization filtration, dry heat sterilization, radiation sterilization) to another. ② Changing the pore size of the sterilizing filter used in the aseptic manufacturing process. (9) Other changes that may cause inconsistencies in the impurity profile and key physicochemical properties of the API compared to before the change. |
Notes: Impurity profiles can be considered consistent when the comparative study results meet the following conditions:
(1) Newly added impurities do not exceed the identification thresholds specified in the Technical Guidelines for the Impurity Studies on Chemical Drugs, ICH Q3A, and other regulations.
(2) Existing impurities (including stereoisomers) and the total impurity content are within the limits defined by the quality standards. If there are no specifications in the standards, they should be within the testing range of multiple batches manufactured using the original process.
(3) Residual solvent levels of newly used solvents comply with the relevant requirements of the Technical Guidelines for the Study of Chemical Drug Impurities, ICH Q3C, and other relevant regulations.
(4) New inorganic impurities comply with the relevant requirements of the Technical Guidelines for the Impurity Studies on Chemical Drugs, ICH Q3D, and other relevant regulations.
(5) The mutagenic impurities should be investigated according to ICH M7, and be controlled when necessary.
1.2 Obligations of API manufacturers regarding post-approval changes to APIs
For technical changes of APIs marked “A”, the API manufacturers should submit a change application in accordance with the relevant regulations on drug registration, and implement the changes after getting approval.
Other changes related to the API, including changes to the API’s excipients and packaging materials, should be promptly updated on CDE’s filing platform. A summary of these changes should be included in the annual report for the previous year, which is submitted in the first quarter of each year.
Table 3: Obligations of API manufacturers regarding post-approval changes to APIs
API manufactured in China | API manufactured outside China | ||
Applicant/filer | AEP manufacturer | Chinese agent commissioned by the overseas manufacturer, or the overseas manufacturer’s resident office in China | |
API (and its excipient and packaging material)’s change | Technical change | The API applicant should submit an application to CDE, implement the change after approval, update the filed information on CDE’s platform, and include the change in the annual report | |
Non-technical change | After implementing the change, the API filer should update the filed information on CDE’s platform, and include the change in the annual report. | ||
Part 2 For Excipient Manufacturers: Categories of Post-approval Changes to Excipients and Relevant Obligations
2.1 Categories and specific situations of post-approval changes to excipients
Regarding post-approval changes to excipients, China has no official regulations. However, the International Pharmaceutical Excipients Council’s Technical Guidance for the Changes Control of Pharmaceutical Excipients (Draft), provides guidance for the industry.
According to the guidance, excipient filers should proactively notify the finished dosage form MAHs that use their excipients about any changes that may impact the quality of FDFs. If the changes involve modifications to the filed information, the filers should update the information on CDE’s platform.
Post-approval changes of excipients are classified into two categories: technical changes and non-technical changes.
Non-technical changes primarily involve modifications to the information of the excipient filer. Common non-technical changes include, but are not limited to:
(1) Changing the name of the excipient (the name should have been confirmed. If applicable, it should also be approved according to the requirements of the National Medical Products Administration (NMPA)).
(2) Changing the information of the excipient filer, such as the company name, registered address, and manufacturing address.
(3) Changing the address of research data storage site.
(4) Changing the Chinese domestic agent for excipients imported to China.
(5) Changing the packaging specifications (excluding changes to inner packaging materials, barrier packaging materials, or any changes that do not affect product quality).
Technical changes mainly involve modifications to the production site, manufacturing process, quality standards, and other aspects of pharmaceutical excipients. Common technical changes include:
(1) Changes to the manufacturing site, such as changes in the production location of the excipient filer, and changes from one manufacturing site to another within the same company.
(2) Changes in formulation and raw materials, such as changes in the formulation, source of raw materials (including animal and plant sources), changes in raw material manufacturers, and changes in formulation ratios (beyond the range specified by the original process control requirements).
(3) Changes in manufacturing processes and process controls, such as changes in production flow, changes in process parameters of key processing steps, changes in sterilization processes and parameters (such as for sterile excipients), and changes in chemical reagents and other materials used during production.
(4) Changes in production equipment, such as optimization of equipment to increase production capacity, replacement of outdated equipment, etc.
(5) Changes in quality standards, including physical, chemical, and microbiological specifications and their analysis methods.
(6) Changes in storage conditions, retest periods/expiry dates, such as changes in storage conditions, extension or reduction of retest periods, or adjusting expiration dates.
(7) Changes in inner packaging or barrier packaging, such as changes in the types and composition of inner packaging and barrier packaging materials.
(8) Other technical changes that may have an impact on the quality and intended use of pharmaceutical excipients.
2.2 Obligations of excipient manufacturers regarding post-approval changes to excipients
The excipient manufacturers should sufficiently evaluate and confirm the changes, communicate with CDE regarding the category of the changes, and then proceed with the application/filing and implementation of the changes.
Part 3 For Packaging Manufacturers: Categories of Post-approval Changes of Packaging Materials and Relevant Obligations
China’s authorities have yet to implement any official regulations regarding post-approval changes of packaging materials. However, the China National Pharmaceutical Packaging Association released the Technical Guidance for Research on Pharmaceutical Packaging Material Changes, which serves as a reference for the industry.
3.1 Categories and specific situations of post-approval changes to packaging materials
According to the guidance, changes of pharmaceutical packaging materials are categorized into two groups: non-technical changes and technical changes.
Non-technical changes mainly refer to changes in the registered information of pharmaceutical packaging materials. Common non-technical changes include:
(1) Changes in the company name, registered address name, and production address name of the pharmaceutical packaging material company.
(2) Changes in certificate documents provided by the company.
(3) Changes in the address for research data storage.
(4) Changes in the Chinese domestic agent for imported pharmaceutical packaging materials.
Technical changes primarily involve modifications in production addresses, manufacturing processes, and quality standards. Common technical changes include:
(1) Changes to the manufacturing sites, including relocation/reconstruction/expansion, technology transfer/outsourced production, company mergers and restructuring, that result in site changes.
(2) Changes to raw materials and formulations, such as changes in major raw material suppliers, major raw material polymer grades, major additive suppliers, and formulation ratios.
(3) Changes to manufacturing processes and process controls, including changes in process flow (e.g., injection molding/extrusion); process changes critical processing steps.
(4) Changes in sterilization processes, major production equipment, major testing devices, starting materials, additives/cleaning agents/other materials directly in contact with the product during manufacturing; changes in online automatic detection methods and frequencies; changes in quality control of intermediate products, etc.
(5) Changes in quality standards, including modifications to product scope/specifications, changes in physical and chemical properties and their testing methods; changes in biological performance and its testing methods; adjustments in shelf life and its determination criteria.
(6) Product packaging changes, including changes to packaging materials packaging types used for pharmaceutical packaging materials.
(7) Other technical changes that may affect the quality and intended suitability of pharmaceutical packaging materials.
3.2 Obligations of packaging material manufacturers regarding post-approval changes to packaging materials
The pharma packaging material filer should conduct a comprehensive evaluation of the changes based on a comparative analysis between before and after the changes, taking into account the potential drugs to be packaged.
The evaluation includes assessing the impact of the packaging products and their intended suitability (within factors such as protective properties, compatibility, safety, and functionality) within the packaging system (including components).
It is recommended that the category of packaging material changes and the measures for application/filing be determined and implemented after communication with CDE.
Part 4 For Finished Dosage Form (FDF) Companies: Categories of Post-approval Changes of AEPs Used in FDFs and Relevant Obligations
4.1 Categories and specific situations of post-approval changes to APIs used in FDFs
4.1.1 Post-approval changes to manufacturing process of APIs used in FDFs
Please refer to 1.1.1.
4.1.2 Post-approval changes to suppliers of APIs used in FDFs
The changes to suppliers of APIs used in an FDF should not have a negative impact on the safety, efficacy, and quality control of the FDF.
Table 4: Categories and specific situations of post-approval changes to suppliers of APIs used in FDFs
Change category | Specific situation |
Minor change | Reducing the number of API suppliers; changing the name of the API supplier (without changing the entity) |
Moderate change | After the change of API, the newly-used API has been approved (with filing status marked “A”). |
Major change | After the changes, the newly-used API has not been approved (with filing status marked “I” or not even filed). |
4.2 Categories and specific situations of post-approval changes to excipients used in FDFs
4.2.1 General requirements for changes to excipients
Changes to excipients in the formulation of a preparation includes changes in the type, quality, supplier, and technical grade of the excipients.
In general, changes in excipient types are considered major changes, with the exception of changes in colorants and flavoring agents.
For ordinary oral solid dosage forms, making changes to the formulation of the coating material is considered minor changes if the same formulation has already been approved for use in other drugs and does not affect the dissolution behavior, quality, and stability of the finished dosage form.
Changes in the quantities of excipients in the formulation should be compared against the originally approved formulation (such as batches for the pivotal clinical trial or bioequivalence study), rather than comparing them to the formulation after minor or moderate changes. Changes in the quantity of preservatives in non-sterile semi-solid dosage forms are considered separately and are not included in the total change amount. Major changes in preservative quantity may be exempted from conducting bioequivalence studies. Changes in excipient quantities not covered by the Technical Guidelines for Research on Post-approval Changes to Chemistry, Manufacturing, and Controls of Chemical Drugs (Trial) are managed as major changes.
For changes in suppliers and technical grades of excipients of FDFs with dosage forms not covered by the Technical Guidelines for Research on Post-approval Changes to Chemistry, Manufacturing, and Controls of Chemical Drugs (Trial), it is allowed to refer to guidelines on the covered dosage forms.
In the case of the replacement of an excipient, if the newly-used excipient has not been filed or is in the “I” filing status, the change should be managed as a major change.
4.2.2 Post-approval changes to excipients in immediate-release oral solid dosage forms
4.2.2.1 Minor post-approval changes to excipients in immediate-release oral solid dosage forms
Minor changes to excipients in immediate-release oral solid dosage forms include, but are not limited to:
(1) Changing the excipient supplier while keeping the same technical grade, ensuring that the quality of the excipient is not compromised.
(2) Improving the quality standards of the excipient, e.g., tightening quality control limits, or changing the quality standards due to updates or addendums to pharmacopoeia monographs.
(3) Removing all or part of colorants and flavoring agents.
(4) Substituting the ingredient of the printing ink with another ingredient already approved use in registered drugs.
(5) Changing the quantity of excipients*.
*Changes to the quantity of excipients should be calculated as a percentage (w/w) of the total weight of the original approved formulation (referring to the total weight of the tablet core or capsule contents, the same applies below) and it should be within the percentage range specified in the table below.
Table 5: Minor changes to the quantity of excipients in immediate-release oral solid dosage forms
Excipient | Percentage (w/w) of excipient in the previously approved formulation | |
Filler | ±5 | |
Disintegrant | Starch | ±3 |
Other | ±1 | |
Binder | ±0.5 | |
Lubricant | Calcium stearate or magnesium stearate | ±0.25 |
Other | ±1 | |
Glidant | Talc | ±1 |
Other | ±0.1 | |
The quantity of APIs is calculated at 100% of the labeled amount, and the total sum of all excipient quantity changes should not exceed 5%. For example, if a formulation includes active ingredient A, lactose, microcrystalline cellulose, and magnesium stearate, and there are changes in the quantities of lactose and microcrystalline cellulose, the total sum of changes should not exceed 5%. For instance, if lactose increases by 2.5% and microcrystalline cellulose decreases by 2.5%, the total change sum would be 5%.
The total weight of a single-dose prescription should be the same as the previously approved weight or fall within the approved weight range. Otherwise, the change should be managed as a moderate or major change.
If the same excipient serves different functions in the formulation, it is recommended to categorize the excipient’s quantity change based on the most stringent requirement. For example, if starch functions as both a binder and a disintegrant, the recommended limit for minor changes would be 0.5%.
4.2.2.2 Moderate post-approval changes to excipients in immediate-release oral solid dosage forms
Moderate changes to excipients in immediate-release oral solid dosage forms include, but are not limited to:
(1) Changing the type of colorants or flavoring agents, or increasing their quantities. The quantities are generally less than 2% (w/w) of the total weight of the formulation. The colorants and flavoring agents used should comply with relevant regulations and standards. This change should not affect the differences in specifications, the taste compliance for pediatric medications, or pose potential safety issues.
(2) Changing the technical grade of the excipient, such as substituting microcrystalline cellulose PH101 with microcrystalline cellulose PH200. The technical grade of the excipient is primarily related to the quality standards, purposes, and impurity status of excipient.
(3) Changing the quality standards of excipient, excluding minor change (2), while ensuring that the quality control level is not lowered.
(4) Changing the quantity of excipients**.
**Changes to the quantity of excipients should be calculated as a percentage (w/w) of their proportion to the total weight of the previously approved formulation. These changes exceed the range of minor changes but are within the range specified in the table below. However, this does not apply to drugs with narrow therapeutic windows or drugs with low solubility and low permeability (BCS Class IV drugs).
Table 6: Moderate changes to the quantity of non-release-controlling excipients in sustained/extended-release or enteric-coated dosage forms
Excipient | Percentage (w/w) of excipient in the previously approved formulation | |
Filler | ±10 | |
Disintegrant | Starch | ±6 |
Other | ±2 | |
Binder | ±1 | |
Lubricant | Calcium stearate or magnesium stearate | ±0.5 |
Other | ±2 | |
Glidant | Talc | ±2 |
Other | ±0.2 | |
The quantity of APIs is calculated at 100% of the labeled amount, and the total of excipient quantity changes should not exceed 10%. The change in the total weight of a single-dose formulation should not exceed 10% of the previously approved total weight.
4.2.2.3 Major post-approval changes to excipients in immediate-release oral solid dosage forms
Major changes to excipients in immediate-release oral solid dosage forms include, but are not limited to:
(1) Changes in the quantity of excipients that exceed the rage of moderate changes.
(2) Changes in the quantity of excipients in drugs with narrow therapeutic windows that exceed the range of minor changes.
(3) Changes in the quantity of excipients for drugs with low solubility and low permeability (BCS Class IV drugs).
4.2.3 Post-approval changes to excipients in oral sustained/extended-release or enteric-coated dosage forms
For sustained/extended-release or enteric-coated drugs, appropriate evidence (such as drug release mechanisms and preparation methods) should be provided to demonstrate which excipients significantly affect drug release, known as release-controlling excipients, and which excipients have minimal impact on drug release, known as non-release-controlling excipients.
Taking film-coated sustained-release tablets as an example, the materials used for the sustained-release coating (such as ethyl cellulose), plasticizers, and pore-forming agents can be classified as drug release-controlling excipients, while excipients such as microcrystalline cellulose used as fillers in the tablet core belong to non-release-controlling excipients.
The calculation methods for changes in these two types of excipients' quantities are different, and the allowable limits for changes are also different.
4.2.3.1 Minor Changes to excipients in oral sustained/extended-release or enteric-coated dosage forms
The minor changes are classified into two categories: changes to non-release-controlling excipients and changes to release-controlling excipients.
Minor changes to non-release-controlling excipients includes but are not limited to:
(1) Changing the excipient supplier while maintaining the same technical grade and ensuring that the quality of the excipients does not degrade.
(2) Improving the quality standards of excipients, such as tightening the quality control limits, or changing the quality standards due to updates or addendums to pharmacopoeia monographs.
(3) Removing all or part of the colorants or flavoring agents, or substituting the ingredient of the printing ink with another ingredient already approved for use in registered drugs.
(4) Changing the quantity of excipients.
Changes to the quantity of non-release-controlling excipients should be calculated as a percentage (w/w) of their proportion to the total weight of the previously approved formulation. These changes should be less than or equal to the percentage range specified in the table below.
Table 7: Minor changes to the quantity of non-release-controlling excipients in sustained/extended-release or enteric-coated dosage forms
Excipient | Percentage (w/w) of excipient in the previously approved formulation | |
Filler | ±5 | |
Disintegrant | Starch | ±3 |
Other | ±1 | |
Binder | ±0.5 | |
Lubricant | Calcium stearate or magnesium stearate | ±0.25 |
Other | ±1 | |
Glidant | Talc | ±1 |
Other | ±0.1 | |
The quantity of APIs is calculated at 100% of the labeled amount. The total of all excipient quantity changes should not exceed 5%.
The total weight of a single-dose formulation should be the same as the previously approved total weight or within the specified total weight range. Otherwise, it should be studied as a moderate or major change.
Minor changes to release-controlling excipients include but are not limited to:
(1) Changing the excipient supplier while maintaining the same technical grade and ensuring that the quality of the excipients does not degrade.
(2) Improving the quality standards of excipients, such as tightening the quality control limits, or changing the quality standards due to updates or addendums to pharmacopoeia monographs.
(3) Changing the quantity of excipients.
Minor changes to the quantity of release-controlling excipients should be calculated as a percentage (w/w) of their proportion to the total weight of all drug release-controlling excipients in the previously approved formulation, and should not exceed 5%. The overall product weight should be the same as the previously approved weight; otherwise, it should be studied as a moderate or major change.
For example, consider a formulation consisting of active ingredient A, sustained-release coating material, and plasticizer. If the changes in this formulation comply with the requirements for minor changes, the combined percentage of changes in the sustained-release coating material and plasticizer should not exceed 5% of their total weight. For instance, if the amount of the sustained-release coating material increases by 2.5% and the amount of the plasticizer decreases by 2.5%, the total sum of changes would be 5%.
4.2.3.2 Moderate changes to excipients in oral sustained/extended-release or enteric-coated dosage forms
Moderate changes also classified into two categories: changes to non-release-controlling excipients and changes to release-controlling excipients.
Moderate changes to non-release-controlling excipients include but are not limited to:
(1) Changing the type of colorants or flavoring agents, or increasing their quantity, with the quantity generally being less than 2% (w/w). The colorants and flavoring agents used should comply with relevant regulations and standards. This change should not affect the products of different strengths, or affect the taste compliance in pediatric medication, or pose potential safety issues.
(2) Changing the technical grade of excipients.
(3) Changing the quality standards of excipients, excluding minor changes (2), without lowering the quality control level.
(4) Changing the quantity of excipients.
Moderate changes to the quantity of non-release-controlling excipients should be calculated as a percentage (w/w) of their proportion to the total weight of the previously approved formulation. These changes should be less than or equal to the percentage range specified in the table below.
Table 8: Moderate changes to the quantity of non-release-controlling excipients in oral sustained/extended-release or enteric-coated dosage forms
Excipient | Percentage (w/w) of excipient in the previously approved formulation | |
Filler | ±10 | |
Disintegrant | Starch | ±6 |
Other | ±2 | |
Binder | ±1 | |
Lubricant | Calcium stearate or magnesium stearate | ±0.5 |
Other | ±2 | |
Glidant | Talc | ±2 |
Other | ±0.2 | |
The quantity of APIs is calculated at 100% of the labeled amount. The total of quantity changes to all non-release-controlling excipients should not exceed 10%, and the total of quantity changes to single-dose formulation should not exceed 10% of the previously approved total weight.
Moderate changes to release-controlling excipients include but are not limited to:
(1) Changing the technical grade of release-controlling excipients.
(2) Changing the quality standards of release-controlling excipients, excluding minor changes (2), without lowering the quality control level.
(3) Changing the quantity of release-controlling excipients.
The API should be dosed at 100% of the labeled amount. Changes in the quantity of release-controlling excipients should be calculated as a percentage (w/w) of their proportion to the total weight of all release-controlling excipients in the previously approved formulation. These changes exceed the range of minor changes but should not exceed 10%. Changes in the total weight of a single-dose formulation should not exceed 10% of the previously approved total weight.
4.2.3.3 Major changes to excipients in oral sustained/extended-release or enteric-coated dosage forms
Major changes include but are not limited to:
(1) Changes in the quantity of non-release-controlling excipients have exceeded the range of moderate changes.
(2) Changes in the quantity of release-controlling excipients have exceeded the range of moderate changes.
(3) Changes in the quantity of excipients for drugs with a narrow therapeutic window have exceeded the range of minor changes.
4.2.4 Post-approval changes to excipients in non-sterile semi-solid dosage forms
4.2.4.1 Minor changes to excipients in non-sterile semi-solid dosage forms
Minor changes include but are not limited to:
(1) Removing all or part of colorants or flavoring agents.
(2) Improving the quality standards of excipients, such as tightening the quality control limits, or changing quality standards due to updates or addendums to pharmacopoeia monographs.
(3) Changing the quantity of excipients. The changes in the quantity of each excipient should not exceed 5% of its previously approved amount, and the total of all excipient quantity changes should not exceed 5%. However, changes in the quantity of diluents (such as water) due to formulation modifications is allowed to be beyond this range.
(4) Changing the quantity of preservatives, with the change not exceeding 10% of the previously approved amount.
(5) Changing the supplier of base, which is a single chemical entity with a purity level over 95%, or changing the other excipient suppliers or technical grades.
4.2.4.2 Moderate changes to excipients in non-sterile semi-solid dosage forms
Moderate changes include but are not limited to:
(1) Changing the quantity of excipients. The changes in the quantity of each excipient exceed the minor changes but should not exceed 10% of the previously approved amount. The total of all excipient quantity changes should not exceed 10%. Changes in the quantity of diluents (such as water) due to formulation modifications are allowed to be beyond this range.
(2) Changes in the quantity of preservatives are greater than 10% of the previously approved amount but should not exceed 20%.
(3) Base supplier changes that are not covered by minor changes.
(4) Changes in the technical grade of the base.
(5) Change in the quality standards of excipients, excluding minor changes (2), without lowering the quality control level.
4.2.4.3 Major changes to excipients in non-sterile semi-solid dosage forms
Major changes include but are not limited to:
(1) Changes to the quantity of excipients that are beyond the range of moderate changes.
(2) Changes (including the removal of preservatives) to the quantity of preservatives exceeding 20% of the previously approved amount.
4.3 Post-approval changes to packaging materials and containers of finished dosage forms
Changes to packaging materials and containers can potentially impact the physicochemical properties, impurity profiles, content, and stability of the drug. The risk associated with these changes depends on factors such as the route of administration, performance of the packaging materials and containers, and compatibility between the packaging and the drug.
In general, changes to the packaging materials and containers of drugs should have a beneficial effect on ensuring the quality and stability of the drugs. They should not have adverse effects on the protectiveness, functionality, safety, and quality.
Table 9: Minor, moderate, and major changes to packaging materials and containers of finished dosage forms
Change category | Specific situation |
Minor change | (1) Changes in the quantity of packaged APIs and single-dose drugs, e.g., weight per sachet, the number of capsules per blister pack, the number of vials per box of injection, etc. (2) Changes in the material and/or type of packaging materials and containers for APIs and non-sterile solid dosage forms that are not specified by the Technical Guidelines for Research on Post-approval Changes to Chemistry, Manufacturing, and Controls of Chemical Drugs (Trial). The changed packaging materials and containers have been used in approved drugs with the same route of administration and demonstrate the same or better suitability. (3) Changes in the supplier, size, and/or shape of packaging materials and containers that are not specified in Technical Guidelines for Research on Post-approval Changes to Chemistry, Manufacturing, and Controls of Chemical Drugs (Trial). |
Moderate change | (1) Changes in the packaged quantity of multi-dose dosage forms, such as the number of tablets per bottle, the weight per syringe, the milliliters per bottle, etc. (2) Changes in the material and/or type of packaging materials and containers for liquid/semi-solid dosage forms (excluding inhalations, injections, and ophthalmic formulations) and sterile and/or liquid APIs. For example, changing the packaging material for oral liquid medicines from polypropylene bottles to polyester bottles. (3) Changes in the material and/or type of packaging materials and containers for non-sterile solid dosage forms in the following situations: changes between blister packaging, bottle packaging, and sachet packaging, or changing from double aluminum blister to aluminum-plastic blister. (4) Changes in the supplier, size, and/or shape of packaging materials and containers for injections. |
Major change | (1) Changes in the material and/or type of packaging materials and containers for inhalations, injections, and ophthalmic dosage forms. For example, changing from a three-layer coextruded infusion bag to a five-layer coextruded infusion bag, changing from a polypropylene infusion bottle to an upright polypropylene infusion bag, changing from a sodium-calcium glass infusion bottle to a five-layer co-extruded infusion bag. (2) Changes in the supplier, size, and/or shape of the metered-dose delivery device for inhalation dosage forms. (3) Removal of secondary packaging (such as high-barrier outer bags) that provides additional protection for the drug. (4) Changes from previous packaging materials and containers to packaging materials and containers that involve new materials, new structures, and higher risks due to new uses. (5) Changes to packaging materials and containers that have been included in filing management, while the changed packaging materials and containers have been filed or are in a filing status of “I”. |
4.4 Obligations of dosage form MAHs regarding post-approval changes to AEPs
The MAH needs to assess the impact of changes in APIs, excipients, and packaging materials on the safety, efficacy, and quality controllability of finished dosage forms.
Based on magnitude of the impact, post-approval changes of finished dosage forms are classified into three categories: minor changes, moderate changes, and major changes.
For post-approval changes to FDFs manufactured in China, the change filer/applicant is the Chinese domestic MAH.
For post-approval changes to FDFs manufactured outside China, the change filer/applicant is the Chinese domestic agent commissioned by the foreign manufacturer, or the foreign manufacturer’ resident office in China.
Table 10: Application/notification/reporting obligations of dosage form MAHs regarding post-approval changes of AEPs
Magnitude of the impact of AEP’s changes on FDF | Change category | FDF manufactured in China | FDF manufactured outside China |
Minor | Minor change | After implementing the change, the MAH should include the change in the MAH’s annual report. | |
Moderate | Moderate change | The MAH should first notify the local provincial-level medical products administration, then implement the change, and finally include the change in the MAH’s annual report. | The applicant should first notify CDE, then implement the change, and finally include the change in the MAH’s annual report. |
Major | Major change | The MAH/applicant should submit a supplemental application to CDE, implement the change after getting CDE’s approval, and finally include the change in the MAH’s annual report. | |
Part 5 Supplemental Application Fees for Post-approval Changes to APIs and FDFs
Fees are required for supplemental applications for major post-approval changes to APIs and FDFs, but not for excipients or packaging materials.
Table 11: Fees for supplemental applications for major post-approval changes to APIs and FDFs
API/FDF manufactured in China | API/FDF manufactured outside China | |
Technical review required | ¥99,600 | ¥283,600 |
Technical review not required | ¥9,600 | ¥9,600 |
Contact BaiPharm
We have over 10 years of experience in drug registration in China, the United States, and Europe. We provide the following services regarding regulatory compliance for APIs, excipients, and packaging materials (AEPs).
Preparing the outline and catalog of documents for filing AEPs.
Analyzing the gaps in data, conducting preliminary review, and providing advice to clients based on the review requirements for finished dosage forms.
Reviewing, translating, writing, and submitting documents for AEP filing.
Tracking the review progress of CDE, answering the questions in the deficiency letter, and submitting supplemental documents.
Updating the filed AEP’s information, including changes to basic information, minor changes, moderate changes, and major changes.
Submitting annual reports for filed AEPs.
