已上市化学药品变更研究的技术指导原则英文版.docx

GUIDELINE No.:

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Technical Guideline for Making Post Approval Changes to Chemical Drug
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April 2008

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Table of contents
I. Overview 2
II. Basic principles for performing studies post-approval changes to chemical drug products 3
III. Changes to Drug Substance Manufacturing Process 6
IV. Changes to excipients in a drug formulation 14
V. Changes to the manufacturing process for a drug product 22
VI. Changes to drug product strength and packaging size 30
VII. Change to drug prodcugt specificication 36
VIII. Changes to the drug prodcut shelf-life (expiration dating period) and/or storage conditions 41
IX. Changes to drug product packaging materials and the container closure syatem ... 37
X. Changes to the manufacturing site of an imported drug product 51
XI. Change to the manufacturing site of API used in an imported drug product and change to the manufacturing site of an imported API 48
XII. Changes in the site of Manufacture for API used in a domestic drug product..... Error! Bookmark not defined.
Appendix I Basic methods for comparison investigation of drug dissolution/release 36
Appendix II General considerations for exemption of in vivo bioequivalence (BE waiver) 72
Appendix III A partial list of of medicines with narrow therapeutic windows Error!
Bookmark not defined.
References 77
Glossary 79
Authors 80
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I. Overview
This guideline is primarily used to guide pharmaceutical manufacturers to carry out studies for post-approval changes (or changes) to chemical drug products. Changes here refer to the changes that involve source, methods, control conditions with respect to the manufacture, quality-control and use condition and related areas for a drug product that has been approved for marketing. These changes may affect the product’s safety, efficacy and quality controllability. The change study here refers to the study and qualification work to support a proposed change.
At present, the changes and change studies covered in this guideline’s include the following areas: the changes to API/drug substance (DS) manufacturing process, excipient for pharmaceutical use in formulation and its manufacturing process, registered specifications, strengths, shelf life (expiration dating period), storage conditions , drug product packaging materials and container closure system, the imported drug product manufacturing site, manufacturing site of imported API/DS or API/DS used in import drug products, and API manufacturing sites used in domestic drug products.
This guideline describes from technical point of view the studies and qualifications that should be performed when changes are to be made to the products. Pharmaceutical manufacturers should perform change studies and qualifications in accordance with the technical requirements of this guideline, and after the work is completed, submit supplemental application to appropriate food and drug regulatory authorities according to the requirements of Drug Registration Regulation (DRR).
In order to control the potential impact of a change to the safety, efficacy and quality controllability of the affected product, this guideline divides the all changes into 3 categories: Type I, minor changes that basically have no impact on the safety, efficacy and quality controllability of the affected product; Type II, moderate changes, for which studies should be performed to demonstrate that the changes have no effect on the safety, effectiveness and quality controllability of the affected product ; Type III, major changes that need a series of studies to demonstrate that the changes have no negative impact on the safety, efficacy and quality controllability of the affected product. The category of change types has taken into consideration the relevant regulation for supplemental application in of the current Drug Registration and Regulation (DRR) as well as relevant technical requirements of other countries in order to help the manufacturers to perform targeted change studies, summarize the study results into supporting information and make supplemental application to the regulatory agencies.
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The changes referred to in this guideline are post approval changes aiming at marketed chemical drug products. Therefore, changes and change studies should be based on the studies and cumulative data in the past from the drug registration stage and actual manufacturing processes. The more systematic and thorough the research work in registration phase was and the more sufficient the data were accumulated from the manufacturing processes, the more helpful it would be for the post-approval change study.
For specific requirements in this guideline, please refer to the technical guidelines for chemical drug research and development or other relevant technical guidelines previously issued. If there are other scientific investigation results with sufficient evidence available to demonstrate that the changes have no negative impact on the drug’s safety, efficacy and quality controllability, it is unnecessary to perform the change studies by following this guideline.
II. Basic principles for the studies in support of post-approval changes to chemical drug products
The studies for post approval changes (or changes) referred in this guideline are those performed to support changes to chemical drug products that have been approved for marketing. Research and development work in the studies should generally follow the principles below:
(1) Pharmaceutical manufacturers should drive the change studies and self-assessment of the study results.
Based on the needs in manufacturing, etc., pharmaceutical manufacturers propose changes and perform relevant studies. Pharmaceutical manufacturers should have a comprehensive and accurate understanding of the research & development work, manufacturing and properties of their products. They should clearly understand the reason for the proposed change, extent of the change to the products and the impact of the change to the product when a change is being consideration. Hence, changes to a chemical drug product should be driven by pharmaceutical manufacturers.
Pharmaceutical manufacturers should carry out a comprehensive study for the product’s quality, stability and biological properties before and after a change. Pharmaceutical manufacturers should also carefully analyze the study results and evaluate the impact of the proposed change to product quality, i.e., whether the product’s quality is the same and therapeutic effect is equivalent before and after the change. Self-assessment for the study results is specifically emphasized.
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(2) A complete and comprehensive evaluation for the impact of change to the safety, efficacy and quality controllability of the drug product.
Because drug research & development work and manufacturing processes are closely related, changes to manufacturing process, excipient with pharmaceutical application in the drug product formulation or quality standards etc., could affect the overall safety, efficiency and quality controllability of the drug product. If in-vitro studies can not accurately determine how a change affects the product, it is necessary to perform more in-depth studies, comprehensive evaluation for the impact of the change to the safety, efficacy and quality controllability of the drug product. This is also the starting point for the change study.
Generally, a change study should take into consideration of the following aspects:
1. Evaluation of Impact of Changes on Drug Products
When a change was made to a product, a study should be carried out to evaluate and assess the impact of the change to the safety, efficacy and quality controllability of the drug product, including evaluation of changes to product chemistry, physics, microbiology, biology, biological equivalence, and/or stability. The study should be designed based upon a comprehensive consideration about the specifics and type of the change, drug substance and /or dosage forms, and degree of impact of the change to the drug product, etc. For example, to evaluate any change of impurities in a drug product prior to and post a change, it is appropriate to first select or establish a suitable chromatographic method, and then perform a comparative analysis of the impurity profiles (types and amount of impurities) prior to and post a change. If new impurities appear after a change, or if levels of existing impurities exceed the established limits, then it is necessary to determine whether the impurity levels are acceptable or not with rationales according to the Appendix 1 or 2 of “Technical Guideline for Study of Impurities in Chemical Drug Products”； If it is not acceptable, then a decision tree should be referenced to decide the subsequent step of work including consideration for carrying out any needed toxicology studies.
In addition to the studies suggested under each change type in this guideline, it is also necessary to perform other selected important studies by taking into consideration of the characteristics and specifics of the change. For example, for some changes to a tablet manufacturing process, besides comparing dissolution/release performances, it is also necessary to assess if there are any changes to other physical parameters.
2. Evaluation of Sameness or Equivalence prior to and post Change
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Strictly speaking, it is unnecessary for a product to remain completely identical before and after a change, however, the product must keep the sameness and equivalence, namely, the product must have the same quality and clinical equivalence.
Based on the study and qualification about the chemistry, physics, microbiology, biology, biology equivalence and stability of a product, comprehensive analysis should be carried out to evaluate how a change would impact drug safety, efficacy and quality controllability. In general, by comparing and analyzing of the results before and after a change, it can be determined whether the results pre- and post change are equivalent. The comparison studies include dissolution and release as well as a thorough comparative analysis of a property, such as drug product stability, etc.
In some cases, however, the products are unable to retain the same equality or equivalence after the change, i.e., the change may have affected the product safety, efficacy and quality controllability. If a pharmaceutical manufacturer still wishes to implement the change, it must prove that the change will not negatively impact the product quality through a series of pharmacological and biological studies. For example, if the studies found that certain manufacturing process changes could result in new degradation products. However, further study shows that the degradation products will not raise concerns about the drug safety. Therefore, this change still can be implemented.
3. Considerations about the samples used for studies
If a change occurs at the manufacturing phase after a drug product has been approved for marketing, samples used for change studies and qualification should come from manufacturing at a scale greater than the pilot scale.
In general, quality comparison studies (e.g., dissolution, release comparison experiments) for a drug product in support of a change are performed using samples from 3 production batches prior to the proposed change and from 1-3 batches manufactured with the proposed changes incorporated.
Post change drug product stability study is usually performed using samples from 1~3 batches stored for 3~6 months under an accelerated and a long-term storage conditions. The stability results are compared with that of the 3 batches obtained from the manufacturing scale prior to the change. Specifics on the number of batches and testing duration should be determined based on the level of impact caused by the change to the product quality and stability. As for major change, or products with test results revealing a poorer product stability, it is suggested that more samples batches be selected and extended testing duration be adopted. With respect to a change for an injection product,
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stability sample batches and testing duration should be in accordance with the relevant technical requirements.
4. Related Changes
A change required to a product seldom occurs alone. For example, manufacturing site change may occur in parallel with changes to manufacturing equipments and processes; a change to a pharmaceutical excipient in a formulation may lead to changes to drug product specifications; or may result in changing packaging materials at the same time. In this guideline, changes paralleled to or consequential to another change are called Related Changes
With respect to Related Changes, studies can be performed according to the guiding principles for various types of changes in this guideline. Because these changes may affect the product’s safety, efficacy and quality controllability to different extents, i.e., related changes may be classified to different change types in this guideline, and studies may be carried out according to the respective technical requirements; however, the overall studies should be carried out to meet the higher technical requirements. For example: a change to an excipient in a drugs tablet formulation is within the scope of Type III change per this guideline; while making the change to the excipient, there is a need to add an HPLC test in the drug product specifications, and the latter change falls into Type I change for changing drug product registration specifications in this guideline. For the abovementioned related changes, change studies should follow the requirements for Type III changes for excipient and Type I changes for drug product specifications, respectively;. Overall, a Type III change on excipient may have more significant impact on the drug product safety, efficiency and quality controllability, relevant biological studies could be required.
III. Changes to Drug Substance Manufacturing Process
In this guideline, changes to a drug substance manufacturing process refer to those for a chemically synthesized drug substance including changes to sources of reagents and starting materials, changes to specifications of reagents, intermediates and starting materials, changes to reaction conditions, and changes to synthetic routes (including shortening synthetic routes and changing reagents and starting materials), etc. Changes to a manufacturing process may involve one or several of the changes mentioned above. In the latter case, studies relevant to each change need to be considered and performed. In principle, for a change to a synthetic route, the number of
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chemical reaction steps to synthesize a chemical drug substance should be at least more than one (excluding salt-formation and purification steps).
In short, changes to a drug substance manufacturing process should not a