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

Point 1: Applicants must comprehensively understand the products applied for

This latest Draft for Comment of Technical Requirements ("Draft") has high requirements for the strategic visions of applicants. The original text says: Applicants shall comprehensively understand the marketing backgrounds in China and abroad, safety and effectiveness data and post-marketing adverse reaction monitoring situations of the marketed injections and evaluate and confirm their clinical values. This requirement is appropriate under the background of in-depth and comprehensive advancement of current R&D. To successfully promote and apply for a project, the project leader of a pharmaceutical company must possess rich professional knowledge, accurately grasp regulations, appropriately master the R&D and industry combination and possess proper internal and external resources of the company. If an applicant cannot comprehensively understand and grasp the project taken charge of, the quality of the application data will be worrying. Therefore, this requirement of the NMPA makes sense.

Point 2: The guidelines for RLD selection are clear

The NMPA has issued guidelines for the selection of RLDs in the consistency evaluation of oral solid preparations, which also apply to the consistency evaluation of injections according to the Draft: Applicants shall select the RLDs according to the Procedures for the Selection and Determination of Reference Listed Drugs for Chemical Generic Drugs issued by the NMPA and carry out the consistency evaluation research with reference to those Technical Requirements and relevant technical guidelines in China and abroad. As mentioned above, there have been many aseptic preparations (including eye drops and injections) in the latest official list of RLDs.

Point 3: Document retrieval plays a key role in the formulation and process determination process

Unlike oral solid preparations, simple dosage forms of small molecule chemical pharmaceutical products generally do not need to be conducted clinical trials, in which case, the international Q1/Q2 guidelines shall be followed to ensure the generic injection drugs to have highly consistent quality effects and attributes with original drugs. The Q1/Q2 guidelines refer to that generic drugs of chemical drug injections need to be kept consistent with the original drugs in terms of API and excipient varieties and kept consistent therewith as far as possible in terms of API and excipient feeding quantity. To achieve this, pharmaceutical enterprise researchers need to strengthen their information retrieval ability.

For example, the Draft mentions the following details:

※Formulation-Excipient varieties and dosage in the injections shall normally be the same as those in the reference listed drugs (RLDs). Same excipient dosage refers to that the excipient dosage in the generic drugs shall be 95%-105% of the corresponding excipient dosage of the RLDs, and if there are special solvents, they shall be consistent with the special solvents of the RLDs in terms of formulations.

※Applicants may submit formulations different from the RLDs’ bacteriostatic agents, buffers, pH regulators, antioxidants and metal ion complexing agents, however, they shall indicate the differences, state reasons for choosing them and study and prove that the above differences do not affect the safety and effectiveness of the products applied for.

※Excipient concentration or dosage shall meet the limit requirements of FDA IID or be well-founded. In the event of excessive feeding, reference with relevant requirements of ICH Q8 is recommended.

Point 4: Aseptic processing and sterilization process research levels must meet the latest requirements of the industry

Aseptic products may be produced using the terminal sterilization process or non-terminal sterilization process, however, whichever process, the final aseptic products must have sterility assurance levels that meet the latest regulation requirements and industry consensus.

The Draft mentions the following details: (1) To effectively control the pyrogen (bacterial endotoxin), control over the APIs, excipients, and pharmaceutical packaging materials, and production course, etc. shall be strengthened, and the use of activated carbon is not recommended in the injection production. (2) Filter compatibility research shall be conducted according to the production process. Compatibility research shall be conducted for containers in direct contact with solutions such as silicone tubes according to the solution characteristics and production process. (3) If the RLDs are excessively filled, the excessive filling of the generic drugs shall be consistent with that of RLDs; if they are not consistent, the rationality shall be demonstrated.

Chinese pharmaceutical enterprises need to study the following guides if they want to develop the sterilization processes or aseptic processing meeting the current consensus of the international pharmaceutical industry and the latest regulation requirements:

※FDA Sterile Drug Products Produced by Aseptic Processing

※Japan PMDA Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing

※EU GMP Annex 1 and PIC/S aseptic guide

※PDA technical report on aseptic processing development and research

※EMA guideline on sterilization process development

※Relevant requirements of USP/EP/JP on sterilization processes

Furthermore, Chinese pharmaceutical enterprises must highly value environmental monitoring (EM) if they want to produce aseptic pharmaceutical products using aseptic processing. An enterprise in Shandong and an enterprise in Guangdong were successively warned by the European and U.S. drug regulators in 2018 because of defects in EM.

Point 5: The sterility validation efforts are important in the injection consistency evaluation

To achieve stable quality attributes of aseptic pharmaceutical products, enterprises need to make sure of the stability of critical process parameters and quality attributes in future commercial production besides the solid R&D, so that they can realize their product quality design expectations. Wherein, the sterility validation efforts are particularly important for aseptic products. Therefore, the Draft proposes the following detailed requirements:

(1) Sterilization/aseptic processing validation

At least the following validation reports shall be conducted and submitted for terminally sterilized pharmaceutical products:

• Pharmaceutical product terminal sterilization process report;
• Pyrogen removal validation of inner packaging materials in direct contact with pharmaceutical products, or the relevant certification data issued by suppliers;
• Packaging system tightness validation, with the methods appropriately validated;
• Hold time (including chemical and microbe) validation.

At least the following validation reports shall be conducted and submitted for aseptically filled products:

• Bacterial retention validation of the sterilization process;
• If methods other than filtration sterilization are used for sterilization, the sterilization validation of feed liquid/largely packaged drugs;
• Sterilization validation of the container sealing systems in direct contact with aseptic materials and products;
• Pyrogen removal validation of inner packaging materials in direct contact with products, or the relevant certification data issued by suppliers;
• Aseptic processing simulation test validation, making clear the measures to take after the test fails;
• Packaging system tightness validation, with the methods appropriately validated;
• Hold time (including chemical and microbe) validation.

(2) Production process validation

Process validation data, including the process validation plan and validation report

Point 6: Requirements for APIs, excipients, and pharmaceutical packaging materials are the strictest

Unlike oral solid preparations, generic drugs of chemical drug injections are required to keep the same excipient composition and quantity proportion with the original drugs as far as possible. Moreover, there are higher requirements for the quality specification and safety attribute of APIs and excipients.

For APIs, the Draft proposes: Preparation producers shall sufficiently research and assess the API quality in combination with the API production processes and according to existing guidelines and relevant documents (including the document No. 7 of the NMPA in 2008), and if necessary, revise related substance inspection methods, increase the inspection of solution clarity and color, residual solvent, bacterial endotoxin, and microbial limit, etc. and provide relevant validation data, to meet the injection process and quality control requirements; they shall also focus on studying and assessing elemental impurities and mutagenic impurities. Preparation producers shall, according to the needs for the continuous stable production of injections, comprehensively audit and assess API sources and quality and guarantee the supply chain stability in subsequent commercial production. In case of any change, they shall conduct studies and applications according to relevant technical guidelines.

For excipients, the Draft proposes: Excipients shall meet the requirements for injection, and strict internal control standards shall be developed. Excipients shall meet requirements of current Chinese Pharmacopoeia, unless under special circumstances.

Predictably, preparation producers will choose suppliers with caution because most excipients are not injection grade or aseptic grade although the quality of the Chinese excipient production industry has been improved after the implementation of the 2015 edition of Chinese Pharmacopoeia; and leading excipient suppliers that have taken precautions will have strong superiority in future market competition.

As inner packaging materials have direct and key influences on injections within the lifecycles thereof, the Draft proposes the following requirements: Packaging materials and containers used by injections, which are in direct contact with the pharmaceutical products, shall meet the packaging material standards issued by the NMPA or requirements of the USP, EP, or JP. Packaging materials and containers that can guarantee the pharmaceutical product quality shall be selected according to the pharmaceutical product characteristics and clinical use conditions.

The research on the compatibility of packaging materials and containers shall be conducted according to the Technical Guidelines for the Research on the Compatibility of Chemical Drug Injections and Plastic Packaging Materials (for Trial Implementation), Technical Guidelines for the Research on the Compatibility of Chemical Drug Injections and Pharmaceutical Glass Packaging Containers (for Trial Implementation), and Technical Guidelines for the Research on the Compatibility of Chemical Drug Injections and Elastomeric Seals (for Trial Implementation), etc.

The rationality of the packaging materials and containers used shall be determined according to the research results of accelerated tests and long-term tests, and sample inverse placement investigation, etc. are recommended to be added to the stability investigation process, to comprehensively study the compatibility between the contents and seals such as rubber stoppers. The quality and performance of the packaging materials and containers used by injections shall not be lower than those of the RLDs so that the pharmaceutical product quality can be consistent with the RLD quality.

We can see from the above requirements that generic injection drug producers must delve into the inner packaging materials used by RLDs and preferably conduct elemental analyses, to determine the influences of inner packaging materials on the products.

Read More:

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

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About the Author:

zhulikou431

Zhulikou431, as a senior engineer, PDA member, ISPE member, ECA member, PQRI member, senior aseptic GMP expert, has deep knowledge in aseptic process development and verification, drug development and registration, CTD document writing and review, regulatory audit, international certification, international registration , quality system construction and maintenance, as well as sterile inspection, environmental monitoring and other fields. In recent years, he has focused on the analysis of trends in the macro pharmaceutical field and the risk management of pharmaceutical enterprise mergers and acquisitions projects.

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