An Administrative Notice titled "Concept of Differences in the Confirmation of Consistency Between the Manufacturing and Marketing Approval Documents and the Actual Manufacturing and Testing Methods for Generic Drugs (Revised Version)" was issued on January 20, 2025. For generic drugs, discrepancies between approval details and actual conditions have been occurring since around 2021, leading to issues such as drug shortages. An associated issue that arose was the extent to which the writing of CTD Module 1 should be allowed. The MHLW had issued guidelines on October 30, 2024, addressing this matter, which have now been revised.
This section's judgment serves as a regulatory reference for pharmaceuticals in general. Below is a list extracted from the notification.
Items Not Considered as Differences（Reference # and the case）
QC
201: If an alternative name is used for items where the latest specification allows alternative naming. <Example> Acetic acid (glacial) and Acetic acid (100) in reagents and test solutions
202: If an operation described as "filtration" is pretreated using a membrane filter.
203: If a sample solution is pretreated using a membrane filter for the purpose of column protection, provided that it has been confirmed not to affect the accuracy and precision of the analysis.
204: If a pre-column or similar component is installed in the flow path for the purpose of column protection or ghost peak removal, provided that it has been confirmed not to affect the accuracy and precision of the analysis.
205: If a photodiode array (PDA) detector is used instead of an ultraviolet (UV) absorbance detector in HPLC.
206: If an ultrasonic device is consistently used to promote dissolution or dispersion.
207: If a test method other than the one specified in the specification is used for solvent evaporation or removal. <Example> Using a hot plate for heating instead of "heating on a water bath (or sand bath)" as stated in the specification
208: If a sample cooler is used without specifying its temperature, provided that it is not used for the purpose of ensuring sample stability.
209: If system suitability criteria are independently established in a chromatography test where no such criteria are specified in the official specification.
Production
210: If only excipients are pre-mixed.
211: If a disintegration process is performed during the addition of excipients.
212: If temporary heating is applied to promote dissolution or dispersion within a range that does not affect quality, provided that there is no need to define and control a specific temperature.
213: If air blowing is used to evaporate the solvent for explosion prevention, provided that it is only performed as a preliminary step before a continuous drying process.
214: If packaging materials that do not have moisture-proof or other functional properties and are not intended for stability purposes are used.
215: If there are variations in the notation of a sterile filter. <Example> 0.22 μm ⇔ 0.2 μm—Provided that the filter used has been evaluated for sterility validation and qualification.
Cases where the MAH should consult with PMDA as necessary to confirm validity
General（Reference # and the case）
301: Cases where it has been found that a minor change notification was not submitted within the designated period, despite prior notifications indicating that changes due to the revision of the JP or other regulatory updates could be temporarily filed through a minor change notification.
302: Incorrect entries regarding the manufacturing site name, location, manufacturing license/registration number, or validity period.
303: Incorrect entries regarding the referenced MF number or registration date.
304: Incorrect entries or variations in the compound name or chemical formula.
305: Incorrect entries regarding the name, material, or other details of manufacturing equipment or analytical instruments.
306: Incorrect entries regarding significant figures.
307: Incorrect entries regarding process parameters or process control values. <Example> Reaction temperature (105°C ⇔ 100.5°C), Loss on drying control value (<0.5% ⇔ <1.0%)
308: Incorrect entries regarding test conditions. <Example> HPLC ⇔ UHPLC
309: Incorrect entries regarding units and symbols. <Example> < ⇔ ≤, w/w% ⇔ w/v%, kg ⇔ L (liter), cm ⇔ inch
310: Incorrect entries regarding the sample dilution concentration in qualitative tests. However, discrepancies in quantitative tests are considered differences. <Example> 1→100 ⇔ Weigh 1 mg and add 100 μL.
311: If "accurately" is unnecessarily included in certain parts. However, if it is missing where it should be stated, it is considered a discrepancy.
312: If the actual manufacturing practice has been verified using a more appropriate and rational calculation formula than at the time of approval, but the formula was incorrectly recorded in the marketing authorization document due to input errors, such as switching the numerator and denominator.
Production
313: If the disintegration process is not described at the time of active ingredient addition. However, if particle size adjustment is performed, it is considered a discrepancy.
314: If the required conditions for manufacturing and testing environments, such as a darkroom or humidity control, are not stated, despite being essential for proper quality assurance.
315: If the pre-mixing process for preparing the dilution of the active ingredient (including the dilution of granulated or milled products containing the active ingredient) is not stated.
316: If the pre-drying process of excipients is not stated.
317: If the milling (granule sizing) process is not stated.
318: If the undercoating process in tablet printing involves spraying (coating) a component that is part of the coating composition, and is listed in the composition and quantity or essential characteristics section, within a minimal amount. However, if the component is not part of the coating composition, is not listed in the composition and quantity or essential characteristics section, or exceeds the minimal amount, it is considered a discrepancy.
319: If the granulation endpoint is not stated.
Site
320: If the "labeling" or "testing" process is not stated for the manufacturing site responsible for the packaging, labeling, and storage of the active pharmaceutical ingredient (API).
QC
321: If the solvent name in the HPLC specifications and test methods is stated as "○○○○," but in practice, "○○○○ for liquid chromatography" is used. <Example>
"Acetonitrile" → "Acetonitrile for liquid chromatography", "Ethanol" → "Ethanol for gas chromatography"
322: If a column with an internal diameter of 4.6 mm is used, while the specification states approximately 4 mm.
323: If sample solutions, mobile phases, buffer solutions, reagents, or test solutions (excluding standard substances) are scaled according to the sample size, provided that the concentration remains the same.
324: If the test method is based on a discontinued specification (e.g., Cosmetic Ingredient Standards) and requires documentation updates.
325: If a column temperature other than room temperature is used during measurement, but it is not stated in the documentation.
326: If alternative reagents or test solutions are used instead of those specified in the official compendium or the marketing authorization dossier, provided that an appropriate qualification assessment has been conducted.
※ If it is evident that the reagents or test solutions specified in the official compendium are difficult to obtain, consultation with the Pharmaceuticals Review and Management Division is advised. *A reagent or test solution is considered difficult to obtain if either of the following conditions applies: *It is not commercially available anywhere in Japan. All commercially available products do not meet the required specifications.
327: If an alternative test method is used because the method described in the official compendium is deemed inappropriate based on the current scientific standards. However, as a general rule, this applies only when the specified test method is truly impracticable. If the method could be performed by introducing new equipment or if it is deemed impracticable due to the convenience of the MAH or manufacturer, it is not considered impracticable and will be regarded as a discrepancy.
328: If the use of the supernatant obtained by centrifugation is replaced with the filtrate obtained by filtration, or vice versa, in sample preparation, but this change is not stated in the documentation.
Newly added by the latest notification
329: If a sample solution is pretreated using a membrane filter for column protection, and the accuracy and precision of the analysis have been evaluated, but this pretreatment is not stated in the documentation. However, this applies only when the impact on the accuracy and precision of the analysis without pretreatment has not been confirmed.
330: If a pre-column or similar component is installed in the flow path for the purpose of column protection or ghost peak removal, and the accuracy and precision of the analysis have been evaluated, but this pre-column or similar component is not stated in the documentation. However, this applies only when the impact on the accuracy and precision of the analysis without the pre-column or similar component has not been confirmed.
331: If a sample cooler is used considering sample stability, but its temperature is not stated in the documentation.
332: If temporary heating is applied to promote dissolution or dispersion within a range that does not affect quality, and a specific target temperature needs to be defined and controlled, but this temperature is not stated in the documentation.
333: If air blowing is used to evaporate the solvent for explosion prevention, and no drying process is set afterward, but the use of air blowing is not stated in the documentation.
※Note: This is a provisional translation. For accurate interpretation, please consult the relevant MAH in Japan.
