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The injection consistency evaluation may be comprehensively implemented as the NMPA takes frequent actions (3)

November 14, 2019 By zhulikou431

Point 7: The quality research must follow the ideas of ICH Q8 Guideline

Quality research is a priority in all pharmaceutical product development stages. Regarding the consistency evaluation of chemical drug injections, the Draft newly mentions the R&D route required by ICH Q8: QTPP-CQA-CPP-CP. For example, the Draft stipulates: The critical quality attributes (CQAs) of the preparation shall be established according to the quality target product profile (QTPP); the CQAs of injections normally include but are not limited to the research of the followings: character, identification, redissolution time, dispersion time, particle size distribution, re-dissolved solution character, solution clarity, solution color, osmotic pressure/osmotic pressure ratio, pH value, moisture, filling, filling/weight variation, content uniformity, visible foreign matter, insoluble particle, bacterial endotoxin, sterility, elemental impurities, residual solvent, related substance (isomer), and API crystal form/particle size and content, etc.

Injections are pharmaceutical products that directly enter human bodies, therefore, their safety has been a focus of regulators and applicants. The Draft increases the requirements for mutagenic impurities besides continuing to emphasize the necessity of related substance inspections, for example, it stipulates as follows: The occurrence of potential mutagenic impurities shall be determined according to relevant documents and RLD situation and by analyzing the production process and product degradation pathway, and targeted research shall be conducted if necessary, to control them according to the research results and relevant technical guidelines.

The valsartan event that occurred in the middle of 2018 was an oral solid product event, however, it’s very normal that the regulator extends its regulation to the injection area with the expansion of impacts of the problem. In general, it’s internationally recommended that the ICH M7 Guideline be used to research and control genotoxic impurities.

Another new characteristic of the Draft is the requirement for the elemental impurities: According to the provision of ICH Q3D, the elemental impurities in the preparations shall be determined through scientific and risk-based assessments, including the elemental impurities possibly brought in by APIs, excipients, pharmaceutical packaging materials, and production equipment, etc.

Point 8: Requirements for generic injection drugs’ comparison with RLDs are higher than those for oral preparations’ comparison therewith

It’s a general requirement in the consistency evaluation work that the products shall be compared with RLDs, however, as to the comparison degree, the requirements for oral solid preparations are generally not high. The Draft requires applicants to comprehensively compare their developed products with RLDs, specifically as follows: The developed products shall be comprehensively compared with the RLDs in terms of quality (including impurity profile), to guarantee their quality consistency. Investigation data of multiple batches of samples of the RLDs shall be provided in principle, which are data of the investigation into the CQAs closely related to the consistency evaluation.

Predictably, RLD procurement and standard procurement will also consume a large part of project funds.

Point 9: Many new requirements are increased to the stability study

The stability study is undoubtedly important in the lifecycles of pharmaceutical products. Besides the common requirements in the past, the Draft also proposes new requirements for injections: The accelerated and long-term tests of injection stability studies shall be conducted under conditions that meet the GMP; the stability study plans can be designed by taking into account characteristics of the injection products applied for, such as product specification, container, filling, and API and excipient concentrations and according to relevant technical guidelines, to investigate items that are subject to changes during the storage and may affect the preparation quality, safety, and/or effectiveness. If the injection formulation contains excipients such as antioxidant and bacteriostatic agent, the stability study shall also investigate the changes in the content of those excipients. Sterility tests shall be conducted at the beginning and end of the stability investigation; at other times, the packaging system tightness can be investigated instead through complete physical test methods (such as pressure/vacuum decay), with the methodology validation also conducted. The stability study data for not less than 6 months shall generally be provided. The storage conditions shall be determined according to the stability study results and with reference to the RLD information. The stability of generic drugs shall not be lower than that of RLDs.

The last sentence above is reasonable, however, seen from the review situation in recent years, many generic drug products with the stability inferior to that of RLDs have also been approved, which might be because of the use of the QRM guidelines.

Furthermore, the Draft also proposes that the stability test shall investigate the situation of the worst placement position, which is also a new change.

Point 10: The Draft requires high attention to the quality familiarity and process feature correlation of special injections

For some special injections (such as liposome, intravenous emulsion, microsphere and suspension injections), besides general technical requirements, the Draft also proposes the following specific requirements:

※Formulation and process: The formulations shall be consistent with the RLDs in principle. It’s recommended that the excipient models and excipient CQAs that may affect the behaviors in vivo of injections be studied. Production processes of special injections may affect the behaviors in vivo thereof, which shall be deeply studied; for special injections produced with aseptic processing, the sterility assurance measures and validation of each production step shall be paid special attention to. The production process and size of the exhibit batch and commercial batch shall be consistent in principle.

※Quality research: The CQAs to be investigated may include but are not limited to the followings: physicochemical properties (such as character, viscosity, osmolarity, and pH value), Zeta potential, particle morphology, size and distribution (such as D10, D50, and D90), in vitro dissolution/release behavior, free and bound drugs, and drug crystal form and crystal morphology. The quality comparison investigation data of the injections with samples of at least 3 batches of RLDs shall be provided in principle.

※BE/clinical trial considerations: Samples of the commercial batches shall be used for the BE tests and/or clinical trials. For specific injection varieties that have been published the guidelines by the FDA or EMA, the comparative studies with the RLDs are recommended to be conducted with reference to the technical requirements therein.

Point 11: New requirements have been raised for the package inserts and quality standards

Besides the requirement that applicants shall comply with the latest regulations in China, the Draft also raises the latest requirements for the package insert management and quality standard management:

※Package insert drafting: Applicants shall retrieve and track the changes to the package inserts of the RLDs and reasonably draft the package inserts of the pharmaceutical products subject to the consistency evaluation with reference to the latest edition of package inserts of the RLDs.

※Pharmaceutical product standards: If the inspection items included in the pharmaceutical product registration standards are less than those stipulated in the pharmacopeia or the quality indexes therein are lower than those required in the pharmacopeia, provisions of the pharmacopeia shall be implemented.

Point 12: Varieties not subject to the consistency evaluation need improving their quality

Many varieties with simple composition and long histories of clinical use are not required to be conducted the consistency evaluation in the Draft, however, they are still required to be improved their quality. For example, the provision is as follows: Sodium chloride injection, glucose injection, glucose and sodium chloride injection, water for injection, and some radiopharmaceuticals (such as technetium [99mTc]), etc. do not need to be conducted the consistency evaluation, however, they need to be conducted the quality improvement research and their sterilization processes and filter and packaging material selection (including compatibility research), etc. shall meet relevant technical requirements.


We suggest pharmaceutical enterprises do the following work, based on the above analysis and discussion:

---The technical team building shall select personnel with knowledge of the latest regulations and familiar with industrial production and intelligence gathering.

---Continue to strengthen ICH Guidelines learning, such as ICH M7/ICH Q3/ICH Q1.

---Accelerate the market research and evaluate whether the investment and return are balanced.

---Accelerate contacting external entities, to verify the packaging material compatibility and costs of other quality requirements.

---Accelerate contacting RLD suppliers to fast purchase the verified RLDs.

Read More:

The injection consistency evaluation may be comprehensively implemented as the NMPA takes frequent actions (1)

The injection consistency evaluation may be comprehensively implemented as the NMPA takes frequent actions (2)

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