Notice from the Center for Drug Evaluation of the National Medical Products Administration on the Release of the “Technical Guidance Principles (Trial) for the Design and Research of Functional Score Lines in Oral Tablets of Generic Chemical Drugs” (No. 35 of 2020)

　　Release date: 20201022

　　To promote the research and development of chemically generic oral solid dosage forms, under the guidance of the National Medical Products Administration, the Center for Drug Evaluation has organized the drafting of the “Technical Guidance Principles for the Design and Research of Functional Score Lines in Chemically Generic Oral Tablets (Trial)” (see attachment). In accordance with the requirements of the “Notice from the Comprehensive Department of the National Medical Products Administration on Issuing Procedures for the Publication of Pharmaceutical Technical Guidance Principles” (NMPA Comprehensive Drug Administration [2020] No. 9), and after review and approval by the National Medical Products Administration, these principles are hereby released and shall take effect as of the date of their publication.

　　Hereby notified.

　　Center for Drug Evaluation, National Medical Products Administration

　　October 21, 2020

　　Functional scoring design for oral tablets of generic chemical drugs and Research Technical Guidance Principles (Trial)

　　Table of Contents

　　I. Overview 2

　　II. Design of Functional Score Lines for Oral Tablets of Generic Chemical Drugs 2

　　III. In Vitro Study of Notched Slices 3

　　(1) Basic Requirements 3

　　(2) Immediate-release tablets 3

　　(3) Sustained- and Controlled-Release Tablets 4

　　(4) Stability Study During Use 5

　　IV. References 5

　　I. Overview

　　This principle applies to chemically generic oral tablets that feature separable functional score lines. Separable-scored tablets are those equipped with one or more score lines designed to facilitate dose division. Studies have shown that the presence or absence of score lines, as well as their shape and depth, and the shape, size, thickness, and curvature of the scored tablets, can all potentially affect the accuracy of dose division, thereby impacting the safety and convenience of clinical use by patients.

　　To refine the technical requirements for the research and submission of generic chemical drugs, we have now developed Technical Guidance Principles for the Design and Research of Functional Score Lines on Oral Tablets of Generic Chemical Drugs, drawing on relevant technical requirements from regulatory agencies around the world and taking into account the Chinese Pharmacopoeia as well as the current status of generic drug R&D and manufacturing in China.

　　The drafting of this guideline is based on the current understanding of the issue. As relevant regulations continue to be refined and technical requirements for drug research are raised, this guideline will be continuously revised and improved.

　　II. Design of Functional Score Lines for Oral Tablets of Generic Chemical Drugs

　　Generic drugs should have the same active ingredients, dosage forms, specifications, indications, routes of administration, and dosing regimens as the originator drugs. Identical, functionally designed score lines ensure that patients can divide generic tablets in the same manner as they would with the originator drug (the reference preparation). Therefore, to fully guarantee interchangeability in clinical use, the functionally designed score lines with divisibility features on generic tablets should be consistent with those of the reference preparation.

　　III. In Vitro Studies on Notched Slices

　　(1) Basic Requirements

　　1. Selection of the segmentation method

　　It is necessary to conduct examinations using manual slicing methods, while also employing mechanical slicing methods such as slicers and knives, to ensure that products meet the required standards under different slicing principles.

　　2. Research samples

　　Batch samples of pilot-scale or larger should be selected during the development process (at least one batch) for study. For products available in multiple specifications, studies should be conducted on each specification that features functional scoring.

　　3. Quality Requirements

　　The quality of the split portions should meet the critical quality attributes required for the whole tablet.

　　(2) Immediate-release tablets

　　1. Weight difference

　　Randomly select 30 whole slices, break each slice apart, and weigh one subdivided portion from each slice—no need to weigh the remaining portions. Calculate the average weight. No more than one subdivided portion may have a weight falling outside the range of 85% to 115% of the average weight. If more than one subdivided portion falls outside the 85% to 115% range, or if even one subdivided portion falls outside the 75% to 125% range, the batch shall be deemed nonconforming.

　　2. Content Uniformity

　　If, after division, the theoretical dose of the divided portion is less than 25 mg or the proportion of the active pharmaceutical ingredient in the formulation is less than 25%, the content uniformity of the divided portion shall be tested and must comply with the “Chinese…”

　　The requirements of the “Uniformity of Content Test” in the Chinese Pharmacopoeia.

　　3. Split weight loss

　　Take 15 whole tablets and divide them at the upper and lower limits of the intended hardness range for whole tablets.

　　Do not detect; after segmentation, the total weight of the resulting segments, when compared to the 15 whole slices, should have a weight loss within:

　　The weight loss during the breaking process should not be included in the calculation if the total weight of 15 tablets is within 3.0%.

　　4. Brittleness

　　At the upper and lower limits of the proposed hardness range for the entire tablet, take the divided portions separately and perform the friability test. The results shall meet the requirements of the “Method for Determination of Friability of Tablets” in the Chinese Pharmacopoeia.

　　5. Dissolution rate

　　The split portions shall undergo dissolution testing, and the dissolution results must meet the release quality standards for the finished product. The number of test samples shall be no fewer than 12 split units.

　　(3) Sustained- and Controlled-Release Tablets

　　1. Tablets using skeletal sustained-release technology

　　In addition to meeting the relevant requirements for immediate-release dosage forms mentioned above, dissolution profiles should also be determined separately for the divided portions and the intact tablet at both the upper and lower limits of the intended hardness range for the whole tablet. The similarity factor (f2) should then be compared, and the results must meet the specified requirements.

　　2. Tablets produced using coated-tablet compression technology (i.e., products made by compressing pellets) must, in addition to meeting the relevant requirements for immediate-release dosage forms mentioned above, also undergo testing after division.

　　The similarity factor (f2) between the dissolution profiles of the individual pellets and the whole tablets after tableting should meet the requirements.

　　3. In general, dissolution curve determination should be conducted in the medium specified by the quality standards, and the number of test samples should be no fewer than 12 divided units.

　　(4) Stability Study During Use

　　The product’s storage conditions, packaging format, and clinical usage should be taken into account, with reference to...

　　“Technical Guidance Principles for Stability Studies of Chemical Drugs (Active Pharmaceutical Ingredients and Preparations)” — Develop reasonable stability testing conditions and time limits, and examine the stability of the divided portions during actual use.

　　IV. References

　　[1] FDA Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation.

　　[2] FDA ANDA Submissions: Standards for Refusal to Accept.

　　[3] USP <705> quality attributes of tablets labeled as having a functional score.

　　[4] EP Subdivision of tablets.

　　[5] WHO Pharmaceutical development of multisource (generic) pharmaceutical products – points to consider.