CDE answers the common problem of chemical drugs - generic drugs

Question 1: Our company is now developing a single dose of oral solution, the prescription of the original development agent added preservatives, considering that the addition of preservatives is still harmful to the human body, and this oral liquid does not contain protein or polysaccharide components, the sweetener is sucralose, not easy to be infected
.
Therefore, our company's research and development has removed the preservatives of the product, and at the same time strengthened the control of the product process, 1
.
The solution is sterilized and filtered by 0.
22um filter membrane before filling.
2.
Steam sterilize
the filled solution at 105°C for 30 minutes.
The results of multiple batches of samples and the microbial limit check for stability studies after 6 months were satisfactory
.
In this case, is it feasible to add no preservatives to the product?

     Answer: Considering the control requirements of the current oral solution production environment, the characteristics of the dosage form and the prescription characteristics of the oral solution, the possibility of microbial contamination and reproduction of the oral solution during production and storage is greater
.

In the above problems, although the prescription composition of the product and whether it is easy to cause microbial contamination have been analyzed, there is no sufficient literature and test data to support it, and the prescription of the original development agent and the use of preservatives in the original development agent have not been studied
in depth.
The effectiveness of the measures taken to reduce microbial contamination in the production process mentioned in the above question has not been confirmed by verification
.
In addition, the microbial limit test is the same as the sterility test, due to the unevenness of microbial distribution and large microbiological test error, even if the microbial limit test of the sample meets the requirements, it cannot fully represent the microorganisms of the sample to meet the requirements
.

In summary, for oral solutions, the risk of microbial contamination exceeding the standard will be much greater than that of preservatives used in prescriptions
.

If preservatives are used in prescriptions, comprehensive screening studies
should be conducted on the type, dosage, quality control standards, etc.
of preservatives.

Question 2: Our company is developing an oral solid preparation, after research and analysis of the prescription of the original developed agent, it is determined that an antioxidant is used in its prescription, but the antioxidant with a legal source and a medicinal approval number cannot be purchased in China, can I use the food grade standard?
Answer: In principle, in addition to the approved registration of pharmaceutical excipients, more attention should be paid to the selection and fixation of suitable suppliers through comprehensive supplier audits, comparative research of products of different suppliers, formulation of internal control quality standards for excipients, prescription process research and quality control research of preparations, etc.
, and formulate strict internal control quality standards for excipients to effectively ensure product quality; For the excipients used, the approval documents, source certificates, quality standards and inspection reports
of pharmaceutical excipients should be provided.
For the colorants, flavor correctants, antioxidants and other excipients used in the prescription, if there are no pharmaceutical products on the market, food-grade products can also be used, in which case it is necessary to pay more attention to the selection of suppliers and the quality control
of excipients.
In addition, similar problems may exist for topical preparations, which can be referred to the above management principles
.

Question 3: What research work needs to be done to modify the method of dissolution and release determination during clinical practice?
A: Drug research is a coherent and continuously advancing system engineering, the corresponding pharmaceutical research work should still be carried out during the clinical trial, and the product quality and the requirements for a certain testing item should be improved
with the improvement of the same variety and the same testing items at home and abroad.
During clinical trials, changes in quality requirements of the same variety at home and abroad should be tracked, and the pharmaceutical work
that has been completed in preclinical time should be reviewed.
If the quality requirements of the same variety at home and abroad have been improved, corresponding research should be carried out and the product quality requirements
should be improved.

For generic drugs that have obtained clinical approval (including 3 classes of new drugs), if the dissolution comparison with the original product in multiple dissolution media is not carried out before clinical trials, the above dissolution comparison
should be carried out using clinical trial samples.
Under the premise of determining that the quality of the sample is equivalent and equivalent to the original product, the dissolution test method
in the quality standard is clarified.
Generally speaking, if the dissolution method of the original research enterprise or foreign pharmacopoeia is available, it is recommended to use a consistent dissolution determination method and determine
it by measuring the dissolution of the bioequivalence research sample.
Of course, under the premise that the in vivo data is acceptable, a different dissolution determination method
than the original product can also be established.
On this premise, the preclinical determination methods for determining dissolution, including the large and small cup method and the content determination method, can be appropriately adjusted according to the characteristics of drug solubility, biofilm permeability, and drug dosage and specification
.

It should be noted that the adjusted dissolution method should be able to respond sensitively to changes in product quality, and should not relax the evaluation requirements for product quality, nor affect the quality of
the product.

Question 4: If the dissolution rate of an immediate-release original drug reaches more than 85% in 15 minutes, does the dissolution rate of the generic preparation must also be above 85% in 15 minutes, and then the similarity
can be compared with similar factors.

A: When comparing dissolution curve similarity, a variety of methods can be used, including model independent method applying similarity factors, model independent multivariate confidence region method, and model dependency method
。 The use of similarity factor (f2) is a simple model independent method, and when comparing similar factors, there are certain prerequisites, such as: the dissolution determination time point should be three to four or more; The test conditions should be strictly the same; The dissolution time points of the two curves should be the same (e.
g.
, 15, 30, 45, 60 minutes); The mean value should be used for calculation, the percentage of variant lines at earlier time points (such as 15 minutes) should not be higher than 20%, the percentage of variant lines at other time points should not be higher than 10%, and the dissolution of only one time point should reach more than 85%, ensuring that the dissolution of the drug is more than 90% or reaching the dissolution platform
.

When the average dissolution of the original development agent and the generic preparation in a variety of dissolution media within 15 min reaches more than 85%, it can be considered that the dissolution behavior of the original development agent and the generic preparation is basically the same, and there is no need to measure the dissolution curve with multiple sampling points and compare
the similarity factor (F2).

Different countries have slightly different criteria for determining the similarity of dissolution curves, such as the "Technical Guidelines for Dissolution Testing of Oral Solid Dosage Forms" issued by the FDA, and the "Guidelines for Bioequivalence Testing of Generic Drugs" and "Guidelines for Bioequivalence Testing of Solid Dosage Prescriptions after Modification" issued by the Ministry of Health, Labour and Welfare of Japan.


Question 5: The specification of a generic drug is 1mg, while the specification of the original development agent is 2mg
.
When comparing the similarity of dissolution curves, can 2mg original product be used as a reference preparation? Similarly, can the original research of different dosage forms be used as a reference?
A: One of the characteristics of imitation products is that their quality should be comparable
to the original development agent.
If the same specification of the original development agent is available, it is recommended to use the same specification of the original development agent for quality comparison
.
When the same specification of the original development agent is not available, other specifications can be used for comparison
.

Question 6: For the stability study of direct contact with pharmaceutical packaging materials with changes to marketed products, according to the guiding principles, one of them: 3-6 months accelerated and long-term stability test
for new packaging needs to be provided.
How long does a long-term stability study take? Is it also 3-6 months, or does it need to be expired?
Answer: At present, the stability research requirements for direct contact with pharmaceutical packaging materials before and after the change are: if the samples before and after the change have been compared for at least 6 months of accelerated test and 6 months of long-term retention test, and the stability change trend of the samples before and after the change is basically no difference, the validity period before the change can be used, but the maximum is determined to be 24 months
。 If only the stability study of the changed sample is carried out, the validity period is generally determined according to the long-term retention test, such as when the long-term retention test is less than 12 months, but the 6-month accelerated test results show that the sample stability is good, the validity period can be set to 12 months
.

For the case of changing the injection preparation from glass packaging to plastic packaging, it is generally recommended to determine the validity period according to the long-term sample retention test, such as when the long-term sample retention test is less than 12 months, but the 6-month accelerated test results show that the sample stability is good, the validity period can be set to 12 months
.

Q7: What technical information should be provided for quality research references?
Answer: Reference substance (standard) is the physical control of the implementation of drug quality standards, is an important carrier of measurement value transmission, is a special special measuring instrument used to check drug quality, a benchmark for measuring drug quality, a substance control to determine the authenticity of drugs, and a material standard
for calibration testing instruments and methods.
For national drug standards, it is a standard material
for drug measurement and characterization issued by the state.
Pharmaceutical reference materials must have the conditions of uniform material, stable performance, and accurate measurement in order to play the role of
unified value.
In drug research and development, reference substances (standards) involve important links such as quantitative traceability, product characterization, impurity control, etc.
, and their preparation and calibration are closely related to preclinical basic research such as quality research, stability research and even dose determination in pharmacological and toxicological research, so the preparation and calibration of drug reference substances (standards) is an important content of
drug technical review.
Generally speaking, the use of reference materials in drug research and development can generally refer to the following principles:
1.
The reference substance (standard product) used has been issued and provided by the Chinese Pharmacopoeia (see the 2010 edition of the Chinese Pharmacopoeia Part II Appendix X.
V.
G), and when the use method is the same, the current batch number reference (standard product) provided by the Central Inspection Institute should be used, and its label and instruction manual should be provided, indicating its batch number, and other sources of reference materials should not be used; When the method of use is different from the method of use in the instructions, such as qualitative reference substances used for quantitative use, standards for potency determination used as physical and chemical quantification, UV method or volumetric reference substances used as chromatographic quantification, etc.
, appropriate and verified methods should be used to recalibrate, and calibration methods and data should be provided; If the reference substance for chromatographic content determination is used as UV method or volumetric method, and the quantitative reference substance is used as qualitative, etc.
, it can be directly applied without recalibration
.

2.
When there is no reference substance (standard product) supply from the Central Inspection Institute, the following reference materials can be used for standard formulation and other preliminary basic research work:
(1) Reference substances (standard products) issued by foreign drug administration authorities or pharmacopoeia commissions or working reference substances (standard products) of foreign pharmaceutical enterprises, but color photos of their packaging labels and copies of instructions for use should be provided, indicating the batch number, expiration date, use method and other information, which can ensure the traceability of their quantitative values;
(2) The applicant calibrates or entrusts the province to complete the calibration of the reference substance (standard product), and provides the research data and relevant information of the reference material when declaring, which generally includes the following contents:
(1) Principal component reference substance - research data on preparation process, structure and content, as well as generic name, chemical name, structural formula, molecular formula, molecular weight, various impurity content (moisture, residual solvents, inorganic salts, etc.
), principal component content determination data (different analysis techniques) , use, storage conditions and other information
.

(2) Impurity reference - preparation process, structure (UV, IR, NMR, MS, ANALYSIS OF X-ray diffraction or provide control pattern) and content (different analytical techniques) research data, as well as chemical name, structural formula, molecular formula, molecular weight, use, storage conditions and other information
.

(3) Mixed reference (positioning) - the preparation process, structure of each component (UV, IR, NMR, MS, X-ray diffraction analysis or provide control pattern) and purity research data, as well as chemical name, structural formula, molecular formula, molecular weight, content (if necessary), qualitative specific methods and limit requirements
.

At the same time, the applicant should contact the Central Inspection Institute in time to negotiate the calibration of the reference substance (standard product), so that the statutory reference material
can be obtained in time after the product is put on the market.

3.
If the reference substances used in the quality standards cannot be provided normally by the Central Inspection Institute under the current circumstances, it is recommended that the applicant clarify the availability of the reference materials and corresponding measures
after the product is marketed in the declaration materials.

4.
The known impurities involved in the quality standards should be clearly defined in the quality standards with their common names (or chemical names), chemical structural formulas, molecular formulas, molecular weights and other relevant information to accurately refer to and control specific known impurities
.

5.
Under normal circumstances, in order to ensure the accurate use and control of reference materials, it is necessary to provide quality standards for reference substances (standards), and specify exclusive control items, such as the specific rotation of enantiomer impurities
.

Question 8: A few points to note about the analysis method of generic drug impuritiesA: 1.
In the comparative study of generic drug impurity spectrum, it is necessary to pay attention to whether the product is included in the pharmacopoeia of ICH member countries, whether there is a significant difference between the detection method and the declaration method, and whether the method comparison study has been carried out

。 If there is a large difference between the declaration method and the pharmacopoeia method of ICH member countries, a comparative study of the method including detection capacity and sample measurement results should be carried out, and on this basis, a detection method
with good specificity, high sensitivity, and sufficient detection of relevant impurities should be selected.

It should be noted that in the study and verification of impurity consistency, analytical means cannot be equivalent to routine detection, and separation techniques (such as HPLC method) should be combined with mass spectrometry analysis (or diode array detection) or use analytical markers (such as impurity references) to jointly grasp its material consistency
from information such as chromatographic behavior, UV characteristics, molecular weight and molecular fragment characteristics.

2.
If the relative retention time of the HPLC method is used to identify a specific unknown impurity, it is necessary to verify the durability of the method, and specify the brand, specification, particle size, mobile phase flow rate and other analytical conditions of the column in the quality standard to ensure that the detection method has sufficient reproducibility, and it is not enough to specify the type of chromatographic packing material according to the pharmacopoeia standard format
.

3.
Regarding the quantitative methods of impurity analysis, there are usually the following:
(1) impurity reference method, that is, the external standard method
.
For the control of known impurities, if this method is used, attention should be paid to qualitative and quantitative studies of the reference substance, accurate calibration of the content, and provision of relevant research information
.

(2) Add the principal component of the correction factor self-control method, that is, the internal standard method with the principal component as the control, the correction factor can be determined at the time of detection, but the impurity reference substance needs to be provided, and the measured correction factor can also be loaded into the quality standard when the method is established for future routine inspection, without providing impurity reference for a long time, but it is only suitable for the control
of known impurities.

(3) The principal component self-control method without correction factor is essentially an internal standard method that uses the principal component as the control, but its premise is that the impurities and the response factors of the principal components are the same, and are suitable for impurities with the same or similar chromophores as the principal components, and this method does not cause too much error
in the case that the relevant substances and the principal components have similar molecular structures.

It is necessary to pay attention to the stability investigation using its own control method to investigate the relevant problems related to the change of substances, because the content of the main drug itself will also decrease, so the main drug as the reference standard for impurity calculation will affect the uncertainty of the determination results of impurities, especially for drugs with poor stability, the main drug degradation is significant, the numerator and denominator of the calculation formula are variables, and the calculation results and the evaluation of impurity changes will produce greater error
.

(4) The peak area normalization method is simple and fast, but due to the impurity response factors are not necessarily the same, the heterogeneous mass and principal component quantity are not necessarily in the same linear range, and the integration accuracy and accuracy of the instrument for trace impurities and constant principal components are different, a large error
can be generated.

In order to ensure the accuracy and reliability of the impurity determination results, under normal circumstances, the correction factor can not be corrected when it is 0.
9~1.
1, and the self-control quantification without correction factor is directly used; beyond this range, if the quantitative method of the principal component self-control method is adopted, the correction factor must be corrected, that is, the "principal component self-control method with correction factor" to ensure the accuracy of impurity quantification; If the correction factor is outside the range of 0.
2~5.
0, indicating that the UV absorption of the impurity and the main component is too different, the role of the correction factor will be significantly affected, at this time, the detection conditions such as the detection wavelength should be changed so that the correction factor is located in the above range, or another standard material close to the impurity is used as a reference substance (such as another specific impurity that is easy to obtain from the reference substance and the standard has been quantified by the external standard of the reference substance), and the correction factor is re-established; If the correction factor still cannot be adjusted to the appropriate range, it is necessary to consider the use of appropriate impurity methods such as the impurity reference standard method to quantify
.

The application of correction factors is similar to the use of absorption coefficients, and certain prerequisites are required, such as the same detection wavelength, analysis method, chromatographic conditions, etc
.
It should be noted that when the retention time of impurities is different, the peak shape and peak area will be greatly different, and the calibration effect of the correction factor will also have a significant impact, so the retention time of the chromatographic peak should be relatively constant, and the quality standard needs to specify the relative retention time limit for the chromatographic peak of the relevant specific impurity
.

For the control of specific impurities, the study and determination of correction factors are very necessary
.
To assess whether the impurity quantification needs to be corrected by correction factors, and whether the correction factors can play an effective calibration role, the correction factors should first be determined, and the calibration should be evaluated according to the requirements of relevant technical guidelines, and corresponding comparative research data
should be provided.
These research data should include the comparison data of the external standard method of impurity reference substance, the principal component self-control method with correction factor, and the principal component self-control method without correction factor on the quantitative determination results of the same multiple batches of samples, as the support and basis
for whether calibration is required or whether the test results can be effectively corrected.

Question 9: How to choose a quality comparison study control drug
in the research and development of generic drugs A: The goal of generic drug research and development is to design and produce the same drugs that can replace the marketed products, and the safety and efficacy of the original products on the market have been systematically studied and verified.
The established quality assurance system can ensure that under the same circumstances, the two will have the same clinical efficacy and safety
.
Therefore, through comparative research with the original research product (control drug) on the market, the consistency of its material base and the equivalence of quality characteristics are proved to "bridge" the safety and effectiveness
of the marketed drug 。 Reference drugs are the benchmark and basis of generic research and development, so in the search for consistency with the listed product substances, quality, etc.
, the selection of control drugs is crucial, especially in China, there is currently no authoritative "orange book" catalog for reference, even if the same variety, the quality level of commercially available products has a large difference, such as the misuse of poor products as a reference, the adverse factors may be transmitted or even superimposed in the imitation process, affecting the improvement
of the level of imitation.

The selection of control drugs can refer to the following suggestions:
1.
Prefer original research products, if the original research enterprise products have been imported into China, the original research imported products
should be used.

2.
If the original research products or original imported products cannot be obtained, the same listed products in ICH member countries can be used, that is, imitation products
listed in the United States, the European Union or Japan.
If the above-mentioned imitation products of origin have been imported into China, their imported products
can be used.

3.
In the case that the products described in 1 and 2 cannot be obtained, if the domestic enterprise uses the sterile API of the above origin to directly dispense the sterile powder needle, it can also use the product as a reference drug for quality research such as impurity spectrum, but it is necessary to provide relevant supporting documents to explain that the preparation is indeed directly packaged for the above-mentioned imported APIs, and explain the production plant, batch number and other product information
of the API.

For other preparations, due to the possible use of excipients, solvents, etc.
are more complicated, or the use of certain processes that may produce heat, such as: fluidized bed granulation, drying, tableting, coating, etc
.
Even if the preparation is prepared with imported raw materials, its impurity spectrum may be different from the original product, and such preparations should not be used as a reference drug
for quality comparison.

4.
If the generic drug is still marketed and used in the above-mentioned ICH member countries, the applicant does not use the listed product in that country as a control sample for impurity research, but uses samples from other origins (including domestic products) as a quality comparison control drug, which is generally not recognized
.

When it is really impossible to purchase the above-mentioned foreign listed products (especially APIs), such as BP, USPS, EP and other ICH member countries' pharmacopoeia have been included, and the quality control items such as impurities are relatively strict (such as azithromycin, clarithromycin, etc.
), in line with the requirements of the current technical guidelines for impurity research, the analysis and study of impurities can be carried out in strict accordance with the pharmacopoeia standards (including the effectiveness of detection methods, the use of impurity references, Control of specific impurities, non-specific impurities, total impurities, etc.
), and comply with pharmacopoeia requirements, and do not appear abnormal impurities
.
At the same time, comparative studies such as impurity spectrum show that when its quality is not lower than that of domestic listed products, it can also be considered that the impurities have been effectively controlled
.
It is no longer mandatory to compare the quality of the original product with the research
.

If the API and the preparation are imitated and developed at the same time, when the original API cannot be obtained, if the excipients have no interference, the comprehensive comparative study of the impurity spectrum can be carried out by the preparation, that is, the prepared preparation and the original development agent product carry out comparative research on the quality characteristics such as the impurity spectrum, so as to indirectly prove the consistency
of the impurity spectrum of the API.

5.
If the generic drug is not listed in the above-mentioned ICH member countries, that is, when the enterprise cannot obtain foreign samples and imported samples that meet the above requirements, such as furoxicillin sodium, cefthiamidine, etc.
, it is recommended to conduct research and limit determination in accordance with the technical guidelines for impurity research and the relevant ideas and technical requirements for impurity research of innovative drugs, and use a number of domestic listed preparations as a comparison to carry out in-depth impurity research and control.
The quality of the new products should not be lower than the quality of
the domestic listed products.

6.
For drugs declared and registered according to the modified dosage form, the generic target is the product after the modified dosage form, but in order to avoid the impact of error transmission and superposition factors on the R&D product, the control drug of the quality comparison study (especially the comparative study of impurity spectrum) should select the original dosage form product of the original R & D enterprise, rather than the modified dosage form products that have been marketed by other enterprises, such as oral solid preparations, the difference in dosage form should be considered when conducting comparative research on dissolution behavior.
If necessary, it is necessary to carry out comparative research
on the dissolution curve in a variety of media with the same dosage form with a good R&D foundation.

Question 10: One API uses imported raw material intermediates to complete the final step of synthesis
in China.
It is understood that the current FDA requires that the number of reaction steps of synthetic APIs should be at least three steps; The EU requires at least one step of chemical reaction to be produced
at the declaring enterprise.
Is it feasible for us to do so?
A: The question is essentially how to choose the starting materials
.
The selection of starting materials is not only according to the length of the reaction steps to choose, because the quality of the starting materials has a greater impact on the preparation process of the API, especially the structure of the starting materials is more complex, or the synthesis route is shorter will have an important impact, on the one hand, the impurities introduced by the starting materials may participate in the subsequent reaction to form a series of side reaction impurities or directly remain in the final product, which in turn affects the quality of the final product; On the other hand, imperfections or changes in the process and process control of purchased starting materials may affect the quality of
starting materials.
Therefore, controlling the quality of starting materials is an important part of the API quality control system, and the quality of drugs needs to be fully reflected
from the source.

In addition to meeting the requirements of relevant guidelines, the selection of starting materials should also comply with the following principles:
1.
It should be an important structural component of
the API.

2.
The API manufacturer should have a comprehensive and accurate understanding of the impurities of the starting materials (including toxic impurities such as residual solvents and heavy metals), and on this basis, appropriate analysis methods should be used to control them, and reasonable limit requirements
should be formulated according to the impact of each impurity on the subsequent reaction and the quality of the final product.

3.
The starting materials should have a stable commercial source that can meet the large-scale production of
APIs.

4.
The supplier of starting materials should have a perfect production and quality control system, and have a good communication and cooperation relationship with the API manufacturer to ensure that it can always produce the starting raw materials that meet the requirements in accordance with the unified requirements, and if there is a change in its process or process control, the API manufacturer should be notified in time so that the necessary change research and declaration
can be carried out in time.

As an API factory to select starting materials need to do related work:
1.
In addition to selecting starting materials in accordance with the above principles, API manufacturers should also conduct strict supplier audits of starting material suppliers in accordance with the requirements of relevant regulations and guidelines to ensure that starting material suppliers have the ability to produce
。
2.
According to the process of the starting raw material, the process impurities (including toxic impurities such as residual solvents and heavy metals) are comprehensively analyzed, and whether the types and contents of each impurity will affect the subsequent reaction and the quality of the final product are studied
in detail 。 Through the in-depth analysis of the preparation process of the drug, the influence of the level of impurities of the starting materials on the preparation process of the API is clarified, and then the impact on the quality of the final product is analyzed, and the impurities related to the starting materials are purposefully controlled through the relevant verification work, and reasonable control items, methods and limits are formulated, and the methodological verification
of the relevant methods is required.

Question 11: For a certain drug, foreign research results show that there are polymorphic and crystalline patents, how to conduct relevant research
on the crystal form of this product.

Answer: For the imitation of polymorphic drugs, first of all, it is necessary to ensure that the material base of the generic drug is consistent, and the crystal form should also be consistent with the original product; If there are intellectual property issues with the crystal form, relevant research should be carried out on the polymorph during development, clarify which characteristics (biological or physical properties) of the drug will be affected by the inconsistency of the crystal form, and select a reasonable crystal form
on this basis.

Q12: Is it necessary to do human bioequivalence tests when applying for a change of origin of imported sustained-release preparations? If a human bioequivalence test is required, can only a single-dose test be performed as required by the relevant FDA guidelines? A: Due to the possibility of having a significant impact on the drug, it is necessary to conduct a human bioequivalence test on the basis of a comprehensive pharmaceutical comparison study with the sample before the change to verify the bioequivalence of the product before and after the change.


If only the change in origin is involved, and the formulation prescribing process has not changed, the human bioequivalence test
for single dose administration can be carried out according to the relevant FDA guidelines.

Question 13: When the dosage form of compound ordinary tablets is changed to compound sustained-release tablets, is it necessary to conduct a comparative study of the dissolution curve with compound ordinary tablets? If unilateral sustained-release tablets are already on the market, is it necessary to conduct a comparative study of dissolution curves with unilateral sustained-release tablets?
Answer: As a modified dosage form variety to develop compound sustained-release tablets, like the research and development ideas of other modified dosage form varieties, first of all, we should combine the characteristics of specific varieties, consider the rationality of the modified dosage form, and carry out research and development work
on the premise that the topic has sufficient basis.
In the R&D work, the dissolution curve should be compared with the compound ordinary tablets to investigate and evaluate the difference
between the extended-release tablets and the ordinary tablets in vitro dissolution behavior.
If unilateral sustained-release tablets are already on the market, a comparative study of the dissolution curves should be carried out separately with unilateral sustained-release tablets to investigate and evaluate the similarities and differences
between the developed compound sustained-release tablets and the listed single-release tablets in vitro.

Question 14: If the original imported preparation of a drug is ordinary tablets, and there are already oral disintegration tablets registered according to the modified dosage form in China that have been approved, if the generic oral disintegration tablets are made, will the pharmaceutical comparative study be compared with the ordinary tablets of the original factory or with the oral disintegration tablets that have been marketed? Should the reference preparation of the BE test choose the original factory ordinary tablet or the marketed oral disintegration tablet?
Answer: To imitate oral disintegration tablets, it is first necessary to combine the clinical application characteristics of the drug, consider whether the dosage form of oral disintegration tablets is reasonable in accordance with the requirements of the new regulations on modifying the dosage form varieties, and carry out research and development work under the premise of reasonable dosage form
.
In the research and development work, the pharmaceutical research can be compared with the ordinary tablets of the original research factory and the listed oral disintegration tablets, the impurity comparison study with the ordinary tablets of the original research factory, and the dissolution comparison study
with the domestic oral disintegration tablets.
The reference preparation of the BE test is recommended to choose the original factory ordinary tablets, because although the in vitro dissolution of domestic oral disintegration tablets may be different from the original factory ordinary tablets, the BE test results carried out when they are listed according to the modified dosage form should be biologically
equivalent to the original factory ordinary tablets.
For the BE test of imitation oral disintegration tablets, the ordinary tablets of the original research factory should still be selected as the reference preparation to avoid the influence of error transmission and superimposed factors on the test results
.
In addition, imitation of other preparations marketed according to modified dosage forms, such as dispersible tablets, etc.
, can also refer to this idea for relevant research work
.

Question 15: Carry out the development of a generic ordinary tablet, the original research factory of the tablet in China approved the import of 10mg and 20mg specifications (the two specifications of raw and auxiliary materials are increased in equal proportions), but now the original research factory only 20mg specification products in domestic localized production and sales, 10mg specification is no longer imported
.
Is it possible to imitate 10mg products? Since the original 10mg specification is no longer on the market in China, can the imitation 10mg specification product use the original manufacturer's 20mg specification product as a pharmaceutical research control drug and BE test reference preparation? A: Regarding whether 10mg specifications can be imitated, first of all, the rationality of the specifications should be evaluated from the perspective of clinical application, and if the 10mg specifications are reasonable specifications, they can be imitated.


Under the premise of reasonable specifications, the generic 10mg specification product can be used as the control drug for pharmaceutical research and the reference preparation
for BE test by using the 20mg specification product marketed in China by the original research factory.