Technical Guidelines for the Study of Quality Properties of Chewable Tablets (Chemicals) (Draft for Solicitation of Comments) Released

Transferred from: CDE Editor: On September 26, CDE publicly solicited opinions
on the "Technical Guidelines for the Study of Quality Properties of Chewable Tablets (Chemicals) (Draft for Comments)" 。 The main idea of the drafting of this guiding principle is to combine the preparation characteristics of chewable tablets, and refer to the relevant guidelines issued by the FDA and domestic and foreign pharmacopoeia, etc.
, mainly proposing that in the research and development of chewable tablets, it is necessary to study and evaluate the quality attributes that affect patient acceptability and in vivo behavior, and focus on the research and control standards of key quality attributes such as the hardness, disintegration time limit and dissolution degree of chewable tablets, aiming to provide technical guidance for the research and development of chewable tablets and meet the regulatory needs
of enterprise research and regulatory authorities 。 The main contents of this Guiding Principles include five chapters: Overview, General Considerations, Quality Attribute Research and Evaluation, Annexes, and References
.

The Chinese Pharmacopoeia 2020 edition of the four general rules 0101 stipulates that "chewable tablets shall not be inspected for disintegration time limit"
.
This Guidelines recommend that disintegration timelines be studied in the drug development of chewable tablets and that the disintegration time-bound test should be included in the quality criteria for chewable tablets that do not have a dissolution test in the quality criteria and are not suitable or well-founded to support the need for a dissolution test
.
In order to clarify the technical requirements for the research on the quality properties of chewable tablets (chemicals), so as to better guide enterprises to conduct research and unify regulatory requirements, our center has organized and drafted the "Technical Guidelines for the Research of Quality Properties of Chewable Tablets (Chemicals) (Draft for Comments)"
after research and discussion with experts and the industry.
We sincerely welcome all sectors of the community to put forward valuable comments and suggestions on the draft for comments, and timely feedback to us for follow-up improvement
.
The time limit for soliciting comments is 1 month
from the date of publication.
Please send your feedback to the email
address of the contact person below.
Contact: Wu Xiaofei; Wang Hongliang Email: wuxf@cde.
org.
cn;wanghl@cde.
org.
cn Thank you for your participation and support
。 Technical Guidelines for the Study of Quality Attributes of Chewable Tablets (Chemicals) of the Drug Evaluation Center of the State Drug Administration on September 26, 2022 (Draft for Comment) I.
Overview Chewable tablets refer to tablets swallowed in the oral cavity and are suitable for different patient groups that cannot or are unwilling to swallow the whole tablet due to the size of the tablet or difficulty swallowing, including children, adults, the elderly, patients with dysphagia or poor gastrointestinal function, which can reduce the burden of the drug on
the gastrointestinal tract 。 Chewable tablets are usually developed to avoid the risk of choking that may result from swallowing the whole tablet and/or to promote the dissolution of the active ingredient, etc.
Tablets must be swallowed after chewing
, and the instructions for use indicate that they must be swallowed after chewing.
The general name of tablets that can be swallowed or chewed under the instructions for use does not reflect chewable tablets, but also needs to meet the relevant technical requirements of
chewable tablets.
Safety and effectiveness are essential
for the clinical use of drugs.
For chewable tablets drugs, if the quality attributes are not fully studied and controlled in the development, especially the key quality attributes such as hardness, disintegration time and dissolution, it is easy to lead to adverse events in clinical use, such as gastrointestinal obstruction caused by the patient's swallowing or incomplete chewing, tooth damage caused by excessive tablet hardness and other esophageal irritation, etc.
, or the whole piece is swallowed or incomplete chewed resulting in insufficient dissolution of the active ingredient within the
specified time 。 These guidelines have been drafted to propose the key quality attributes that should be considered when developing chewable tablets of drugs, and to comprehensively study and control them to avoid or reduce the occurrence of adverse events in clinical use, improve patient acceptability, and ensure the safety, efficacy and quality controllability
of drugs.
These guidelines apply to the research and development
of chewable tablets or instructions for chewable tablets belonging to regular-release preparations (chemical drugs) or instructions indicating that tablets can be taken after chewing.
These Guiding Principles represent only the current views and perceptions
of the drug regulatory authorities.
As science and technology progress, the relevant content of these Guiding Principles will continue to be refined and updated
.
Second, the overall consideration of chewable tablets should have the characteristics
of easy chewing, easy to accept taste, moderate size and shape, easy to disintegrate to promote dissolution, etc.
The applicant should develop the chewable tablet drug based on the concept of Quality by Design (QbD), and when determining the quality profile (QTPP) of the target product, the quality of the final product should meet the characteristics that the chewable tablet should have, and then the key quality attributes (CQA)
of the chewable tablet should be established according to the quality profile of the target product 。 In general, the key quality attributes of chewable tablets include in addition to the usual traits, identification, related substances (including isomeric impurities), mutagenicity impurities, elemental impurities, content uniformity / weight differences, microbial limits, content, etc.
, but also include hardness, disintegration time limit, dissolution degree and quality attributes
that may affect the bioavailability and bioequivalence of drugs.
In addition, attention should be paid to other quality attributes
such as the size, shape, thickness, and taste (ease of swallowing, palatability) of chewable tablets that may affect the acceptability of the patient's use.
In the process of research and development of chewable tablet drugs, comprehensive analysis and research of its quality attributes is not only conducive to the optimization and determination of prescription composition, process steps and process parameters, but also provides a basis for the formulation of reasonable and effective material control, process control, product quality standards and other control strategies to ensure that the final product always meets the expected quality requirements
.
This Guiding Principles mainly put forward the need to study and evaluate the quality attributes that affect patient acceptability and in vivo behavior in the drug development of chewable tablets, and focus on the research and control standards of key quality attributes such as hardness, disintegration time and dissolution of chewable tablets
.
Third, quality attribute research and evaluation (1) patient acceptability and in vivo behavior Patient acceptability may have a significant impact on the patient's adherence to medication, thereby affecting
the safety and efficacy of drugs.
When designing and developing chewable tablets, it is recommended to design the appropriate tablet size, shape, etc.
according to the target patient population to reduce the risk of
asphyxia or gastrointestinal obstruction caused by swallowing or incomplete chewing of the entire tablet 。 If the target product is a new drug that must be swallowed after chewing, it is necessary to assess the risk of asphyxia or gastrointestinal obstruction that may be caused by the misuse of the whole tablet, and demonstrate the reasonableness of the choice of tablet size, shape, etc.
If necessary, under the usage or precautions of the instructions, it is necessary to emphasize that the relevant information must be completely chewed before swallowing or indicate that the whole piece is prohibited to swallow to control the risk; If the target product is a generic drug that must be swallowed after chewing, the rationality of the choice can be demonstrated by evaluating the readiness to swallow or by comparing the quality attributes with the reference preparation; If the target product is chewable and swallowed, the rationality of the choice can be demonstrated by evaluating the ease of swallowing
.
In the process of drug prescription development of chewable tablets, it is recommended to combine the quality profile of the target product and take the quality attributes and other key quality attributes that affect patient acceptability as the investigation indicators to fully screen and study
the types and dosages of excipients in the prescription.
To promote the disintegration of tablets and the dissolution of active ingredients, it is recommended to add appropriate disintegrants to the prescription
.
At the same time, in order to improve the palatability of the preparation, suitable excipients (including flavor masking agents, sweeteners and flavor corrections) can be added and raw and
excipients of suitable particle size can be screened.
In addition, the interaction between raw and auxiliary materials and excipients, as well as the possible impact of the interaction on the production process, should be analyzed and evaluated, and the necessary research
should be carried out.
During clinical trials or human bioequivalence studies of chewable tablets, it is recommended to collect information related to patient acceptability and in vivo behavior, such as ease of swallowing, palatability, difficulty in chewing, etc
.
Comprehensive analysis and evaluation of patient acceptability and in vivo behavior of the developed product in conjunction with the relevant information collected, and further optimization of the prescribing process if necessary to improve patient acceptability and reduce the risk of asphyxia or gastrointestinal obstruction caused by the patient's swallowing or incomplete chewing of the
entire tablet 。 In the drug development of chewable tablets, it is necessary to fully understand and evaluate the qualitative properties that affect their in vivo behavior, and appropriate in vitro tests can be used to evaluate or characterize the in vivo behavior of chewable tablets drugs, such as: in vitro dissolution tests using lytic media that simulate the physiological environment of the gastrointestinal tract after fasting and postprandial meals (such as artificial gastric juice and artificial intestinal fluid containing enzymes), especially for drugs with poor solubility of active ingredients; Chewable tablets may be soaked in a small amount of simulated saliva for a short time prior to the hardness determination to provide a basis
that can support the formulation of higher hardness control limits than recommended.
In addition, in vitro physiological mediator simulation trials, the use of physiological mediators that are consistent with the characteristics of the target patient population can better reveal or characterize the in vivo behavior
of chewable tablets.
For chewable tablets applying for marketing authorization for new drugs, the applicant should also evaluate
whether the drug has occurred or there is potential oral mucosal absorption.
The degree of absorption of the drug in the oral mucosa depends mainly on factors
such as the solubility, permeability and stability of the active ingredient of the drug.
(2) Key quality attributes Hardness, disintegration time limit and dissolution degree as the key quality attributes of the quality evaluation and control of chewable tablets, it is recommended to pay attention to and study them in the early stage of chewable tablet research and development, which is not only conducive to the screening and optimization of prescriptions, process steps and process parameters, but also provides a basis
for the establishment of effective process control and quality standards.
It is recommended that according to the characteristics of the target product, combined with the key quality attribute research and stability inspection results of multiple batches of samples, for generic drugs, a reasonable and effective control strategy should be formulated in combination with the quality comparison study results of the reference preparation to ensure that the quality of the product meets the requirements
。 In general, it is recommended that the dissolution check be included in the final product quality standards; For chewable tablets that do not have a dissolution test in the quality standard and are not suitable or have sufficient basis to support the need for a dissolution test, the disintegration time limit test should be included in the quality standard; Hardness can be tested and controlled during production; For the quality standards have been included in the dissolution degree examination, the disintegration time limit examination can no longer be carried out, but for chewable tablets that are too hard, too large or specific in shape, etc.
, which are likely to cause adverse events in the use of patients, it is recommended to combine the relevant research results and if necessary, the disintegration time limit is included in the quality standard or intermediate internal control standard
.
1.
Hardness Chewable tablets should have a suitable hardness, which is convenient for the target patient population to chew and swallow, and can withstand the external impact in the process of production, packaging, transportation, distribution and so on to avoid wear or crushing
.
In addition, the patient's teeth should not be damaged because it is too hard, or the patient should choose to swallow
directly because the hardness is too high to chew.
Hardness refers to the force
required to crush a tablet on a specific plane.
Usually the use of suitable tablet hardness tester, under the specified conditions, a continuous determination of 10 tablets, record the average hardness and the hardness value
of each piece.
During the measurement, pay attention to the measurement direction of the tablet on the test bench and ensure that the measurement direction of each piece is consistent
during the measurement.
For ordinary round sheets, the direction of hardness determination is usually radial
.
For special-shaped tablets, notch tablets or imprinted tablets, etc.
, the influence of different measurement directions on hardness determination should be evaluated, and a reasonable measurement direction
should be selected in combination with the research results.
The hardness of chewable tablets should be low, and it is generally recommended that the average hardness be controlled below 12kgf/kp or 120N, and ensure that the hardness of each piece should be within a reasonable range of changes to ensure the uniformity
of product quality.
In some specific cases, a higher hardness acceptance limit may be considered
.
For example, exposure to saliva for a short period of time before chewing can result in significant disintegration or significant reduction in hardness of the tablet, but this needs to be demonstrated by in vivo studies or in vitro tests
.
For in vitro tests, the tablets can be soaked for a short time (e.
g.
, ≤ 30 seconds) in a small amount (e.
g.
, 1 ml) of simulated saliva (see attachment for preparation method) before being tested
。 In the actual chewing process, the force borne by the chewable tablets is often axial crushing force, and the difficulty of chewing is not only affected by the hardness, but also closely related to the shape, size, thickness of the tablet, as well as the age, sex, health status of the target patient, etc.
If fully and reasonably demonstrated, a higher hardness acceptance limit can also be formulated, but the applicant should provide relevant supporting verification information, Chewable tablets to demonstrate that they meet the acceptance criteria for this hardness can be easily chewed by the target patient population without causing damage to the teeth or other adverse events
such as gastrointestinal infarction.
2.
Disintegration time limit The disintegration time limit of chewable tablets should be short to avoid gastrointestinal infarction that occurs in patients due to swallowing the whole tablet or not chewing it completely
.
It is recommended that the disintegration time limit study
of chewable tablets be carried out in accordance with the "Disintegration Time Limit Inspection Method" of the four general principles of the Chinese Pharmacopoeia.
Unless otherwise specified, it should comply with the Chinese Pharmacopoeia requirements for the disintegration time limit of oral ordinary tablets; If chewable tablets prepared by other special processes are used, they should meet the disintegration time limit requirements
of the Chinese Pharmacopoeia for the corresponding tablets.
3.
Dissolution After oral administration of chewable tablets, the absorption of the drug depends on the dissolution of the active drug from the complete tablet or the tablet after chewing and the penetration in the gastrointestinal tract
.
Therefore, the in vitro solubility test of chewable tablets should follow the general principle of the solubility test of ordinary oral solid preparations, that is, the active ingredients in chewable tablets should be fully dissolved from the tablets in the case of chewing or unchewed
.
Also considering that some patients may swallow the whole tablet without chewing, it is recommended to use complete tablets for in vitro dissolution test
of chewable tablets, unless otherwise specified.
Based on the relevant physical and chemical properties of the API and the dissolution characteristics of the preparation, and with reference to the Technical Guidelines for the Solubility Test of Ordinary Oral Solid Preparations, as well as domestic and foreign pharmacopoeias, the applicant can develop and establish a dissolution method
for chewable tablets.
For chewable tablets applying for marketing authorization for new drugs, it is recommended to determine the dissolution criteria based on acceptable clinical trial samples, key bioavailability tests and/or dissolution data of samples for bioequivalence tests; If the stability study batch, the key clinical trial batch and the sample to be listed are bioequivalent, the dissolution standard
can also be developed based on the data of the sample used for the stability study.
For chewable tablets applying for marketing authorization for generic drugs, it is recommended to determine the dissolution standard
based on acceptable samples for bioequivalence tests, dissolution data of registered batches, etc.
In addition, the comparative study
of the dissolution curve of imitation preparations and reference preparations should be carried out with reference to the relevant technical guidelines such as the "Guidelines for the Determination and Comparison of the Dissolution Curves of Ordinary Oral Solid Preparations".
4.
Other key quality attributes Regarding other key quality attributes of chewable tablets, it is recommended to refer to the relevant guidelines issued by the State Bureau or ICH or the requirements of domestic and foreign pharmacopoeias to carry out relevant research
.
IV.
Annex Simulated saliva composition: The following is listed as a prescription composition of simulated saliva (pH 6.
8) for reference
.
Ingredients Dosage Anhydrous Magnesium Chloride (MgCl2) 100mg Calcium Chloride Dihydrate (CaCl2‧2H2O) 220mg Disodium hydrogen phosphate heptahydrate (Na2HPO4‧7H2O) 1350mg Potassium Dihydrogen Phosphate (KH2PO4) 680mg Potassium Chloride (KCl) 750mg Urea (CO(NH)2) 600mg Sodium Chloride (NaCl) 600mg Purified Water to 1000ml V.
References (Space Limiting, Omitted) 《 Technical Guidelines for the Study of Quality Properties of Chewable Tablets (Chemicals) (Draft for Comments)" Drafting Instructions I.
Drafting Purpose As a tablet swallowed after chewing in the mouth, chewable tablets are convenient for clinical use, especially for children, the elderly, patients with
dysphagia or poor gastrointestinal function.
However, at present, in addition to the Chinese Pharmacopoeia 2020 edition of the four general rules 0101 of the brief introduction of chewable tablets, there are no clear guidelines or technical requirements to guide the development and research
of chewable tablets drugs 。 In the previous drug development of chewable tablets, disintegrants are usually not added to the prescription, and there is insufficient investigation and control of the quality properties of chewable tablets, especially the key quality attributes such as hardness, disintegration time and dissolution, which can easily lead to adverse events in clinical use, such as gastrointestinal obstruction caused by the patient's swallowing or incomplete chewing, tooth damage caused by excessive hardness of tablets, and other esophageal irritation, etc.
, or the whole piece is swallowed or not completely chewed so that the active ingredient is not fully dissolved within the specified time, This in turn affects the safety and efficacy of the patient's medication
.
In August 2018, the FDA officially issued the "Quality Properties Considerations for Chewable Tablets", which provides technical guidance
for the quality properties that industry needs to focus on when developing chewable tablets.
In order to avoid or reduce the occurrence of adverse events in the clinical use of chewable tablets, improve the acceptability of patients, and ensure the safety, efficacy and quality controllability of drugs, the Drug Review Center has drafted these guidelines
with reference to the relevant technical requirements issued by foreign regulatory agencies and domestic and foreign pharmacopoeias, etc.
, and combined with the current situation of domestic research and development 。 Second, the drafting process (1) the drafting of the preliminary research and demonstration of the preparation of this guiding principle, the ICH, FDA, EMA and domestic related guidelines and domestic pharmacopoeia and related literature, mainly including the quality of chewable tablets (FDA, hereinafter referred to as FDA guidelines), pharmacokinetic as the endpoint evaluation index of the ANDA submitted drug bioequivalence research guidelines (FDA), chewable tablet drug guidelines (FDA), ICHQ6A, USP-NF submitted by ANDA <2>, <1217>, BP2022AppendixXVII, Chinese Pharmacopoeia 2020, etc
.
With reference to the above guiding principles and literature, this principle
is formulated on the basis of fully considering the current research situation in China.
(2) Formulation or revision of the Guiding Principles These Guiding Principles have been included in the 2022 annual Guiding Principles Revision Plan of the Drug Review Center, and the first draft will be prepared in May 2022 and discussed by the professional meeting of the review team; On June 6, 2022, the departmental technical committee discussed and reviewed, and after the meeting, it was revised in accordance with the opinions of the technical committee; On July 27, 2022, an expert seminar was held, and a total of 6 academic experts (including experts from the State Pharmacopoeia Commission, the Drug Inspection Institute, universities and research institutes) and 5 industry experts were invited to discuss and review the guiding principles, and according to the consensus reached by the expert meeting, further revised and improved the relevant content to form a draft
for comments.
Chewable tablets as a special administration of tablets, must be chewed before swallowing, its quality attributes are different from ordinary oral tablets, especially the taste, hardness and other quality attributes
that affect the acceptability of patients.
At the same time, in the clinical use of chewable tablets, there may be patients swallowing the whole tablet or incomplete swallowing after chewing, in order to ensure the safety and effectiveness of the patient's medication, the disintegration time limit and dissolution should also be studied and controlled
as key quality attributes.
The technical requirements for other properties of chewable tablets (such as: properties, identification, related substances, mutagenicity impurities, elemental impurities, content uniformity/weight differences, microbial limits, content, etc.
) are basically consistent with oral ordinary tablets and will not be repeated in this guideline
.
The main idea of drafting these guidelines is to combine the characteristics of the preparation of chewable tablets and refer to the phases issued by the FDAThe guidelines and domestic and foreign pharmacopoeias mainly propose that in the research and development of chewable tablets, the quality attributes that affect patient acceptability and in vivo behavior need to be studied and evaluated, and the research and control standards of key quality attributes such as hardness, disintegration time and dissolution of chewable tablets are mainly proposed, aiming to provide technical guidance for the research and development of chewable tablets drugs and meet the regulatory needs
of enterprise research and regulatory authorities.
This principle was drafted with full reference to the ICH, FDA, EMA and relevant domestic guidelines
.
IV.
Main Content The main contents of these Guiding Principles include five chapters: overview, overall considerations, quality attribute research and evaluation, annexes and references
.
Section 1 Overview: It mainly elaborates the background, purpose and opinions of the drafting of these Guiding Principles, and clarifies that the scope of application of the Guiding Principles is chewable tablets or instructions for the use of regular-release preparations (chemical drugs) that can be chewed and taken after use, including new drugs and generic drugs
。 Section 2 General Considerations: introduces the characteristics that chewable tablets should have, elaborates that the applicant should develop chewable tablets based on the concept of Quality by Design (QbD), and emphasizes that the key quality attributes (CQA) of chewable tablets should include hardness, disintegration time and dissolution degree in addition to the usual CQA, and should also pay attention to and study
the quality attributes that may affect the acceptability of patients.
In addition, it is emphasized that in the process of research and development, it is necessary to conduct a comprehensive analysis and study of the quality attributes of chewable tablets, and formulate a reasonable control strategy based on the research results to ensure that the final product always meets the expected quality requirements
.
Section 3 Quality Attribute Research and Evaluation: This chapter is the core part of this guideline, which is divided into two sub-chapters: patient acceptability, in vivo behavior, and critical quality attributes
.
Subsection (a) describes the quality attributes
that should be paid attention to and studied at different times in the design, prescription development, clinical trials or human bioequivalence studies of chewable tablets that affect patient acceptability 。 Emphasize that in the design of chewable tablets, choose the appropriate size, shape, etc.
, in order to reduce the risk of asphyxia or gastrointestinal obstruction caused by swallowing or incomplete chewing of the whole tablet, and it is necessary to demonstrate the reasonableness of the choice of tablet size, shape, etc.
; In the development of prescriptions and clinical research, the taste and difficulty of chewing tablets should be focused on examining to improve the acceptability of patients, and the evaluation method of taste can refer to the "Technical Guidelines for the Design and Evaluation of Taste of Children's Drugs (Draft for Public Comment)"
published by the Drug Review Center.
Secondly, it explains the need to fully understand and evaluate the qualitative properties that affect the behavior in vivo in chewable tablet drug development, and lists some in vitro tests
that can evaluate or characterize the in vivo behavior of chewable tablet drugs.
In addition, chewable tablets are oral solid preparations, generally absorbed through the gastrointestinal tract, emphasizing that for chewable tablets applying for marketing authorization for new drugs, there should be an assessment
of whether the drug has oral mucosal absorption.
Section (2) emphasizes that hardness, disintegration time and dissolution should be regarded as the key quality attributes of the quality evaluation and control of chewable tablets, and in the research and development of chewable tablets, the above key quality attributes should be comprehensively studied, and general suggestions
are put forward on whether to combine the characteristics of the product and the research results, whether to set the hardness, disintegration time and dissolution into the final product quality standards or into the process control.
Secondly, with reference to FDA guidelines and domestic and foreign pharmacopoeias, general recommendations
are put forward on the research methods and control standards of hardness, disintegration time limit and dissolution respectively 。 Section 4 Annex: Refer to FDA Guidelines and Literature (Abhay Gupta1, Nallaperumal Chidambaram, MansoorA.
Khan.
AnindexforevaluatingdifficultyofChewingIndexforchewabletablets[J].
DrugDevelopmentand IndustrialPharmacy, 2015, 41(2): 239-243), citing prescriptions for the formulation of simulated saliva for research reference
.
Section 5 References: List the relevant guidelines, pharmacopoeias and literature referred to in the drafting of these Guiding Principles
.
V.
Issues that need to be explained The Chinese Pharmacopoeia 2020 edition of the four general principles 0101 stipulates that "chewable tablets shall not be inspected for disintegration time limit"
.
This Guidelines recommend that disintegration timelines be studied in the drug development of chewable tablets and that the disintegration time-bound test should be included in the quality criteria for chewable tablets that do not have a dissolution test in the quality criteria and are not suitable or well-founded to support the need for a dissolution test
.
The above technical requirements of these Guiding Principles are inconsistent with the provisions of the Chinese Pharmacopoeia
.
At the expert seminar held, the issue was focused and discussed in depth, and it was believed that the development of guiding principles is based on current views and perceptions, and has a certain degree of foresight, and it is of guiding significance
for the development of high-quality drugs for the industry.
It is recommended that, after the implementation of these Guidelines, applicants should conduct relevant research with reference to the technical requirements of these Guidelines for newly declared chewable tablets; For drugs that have been marketed chewables, manufacturers are encouraged to carry out the necessary relevant changes to improve product quality
by referring to the technical requirements of the Guiding Principles.