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SUPPLIMENT NEW DRUG APPLICATION (SNDA)Variations to a prequalified product By sakshi dahiya mpharm 1st year
Supplement A supplement is an application to allow a company to make changes in a product that already has an approved new drug application (NDA). CDER must approve all important NDA changes (in packaging or ingredients, for instance) to ensure the conditions originally set for the product are still met. 2
Supplement Number A supplement number is associated with an existing FDA New Drug Application (NDA) number. Companies are allowed to make changes to drugs or their labels after they have been approved. To change a label, market a new dosage or strength of a drug, or change the way it manufactures a drug, a company must submit a supplemental new drug application (sNDA). Each sNDA is assigned a number which is usually, but not always, sequential, starting with 001. 3
Supplement Type Companies are allowed to make changes to drugs or their labels after they have been approved. To change a label, market a new dosage or strength of a drug, or change the way it manufactures a drug, a company must submit a supplemental new drug application (sNDA). The supplement type refers to the kind of change that was approved by FDA. This includes changes in manufacturing, patient population, and formulation. 4
Why change is required: May wish to alter / improve the product or to introduce additional safeguard To meet the market requirements-- scale up, add manufactuing site. 5
Post approval changes include: (1) components and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes. An applicant should consider all relevant CDER guidance documents &submit all necessary information to support a given change. 6
CONDITIONChanges may have potential impact on the quality, safety or efficacy of products. Any change to prequalified products are subject to approval by FDA &CDER. 7
GUIDANCE ON VARIATION AS PER US FDA Three categories of variations according to their potential impact on pharmaceutical quality Major changes:substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. These are labelled as Prior Approval Supplement. 8
Moderate changes: moderate potential to have an adverse effect. 2 types 1 requires the submission of a supplement to FDA at least 30 days before the distribution of drug product.labelled as Supplement - Changes Being Effected in 30 Days. 2 for which distribution can occur when FDA receives the supplement.labelled as Supplement - Changes Being Effected. 9
IfFDA disapproves may cease distribution. FDA say prior approval suppliment is required. Information is missing: distribution is delayed untill amendment is made. Minor changes:has minimal potential to have an adverse effect.The applicant must describe minor changes in its next Annual Report 10
GUIDANCE ON VARIATION TO APREQUALIFIED PRODUCT To facilitate classification of various types of changes, the variation guide is composed of 4 Appendixes - Appendix I: lists minor changes, including notification (N). - Appendix II: definition and examples of major changes - Appendix III: changes that make a new application /extension application necessary - Appendix IV: stability requirements for variations and changes to Pre-qualified FPPs 11
APPENDIX I – MINOR CHANGES Only few types of variation predominantly occur Change in batch size of FPP Additional new API source Extension shelf life of FPP Addition of FPP manufacturing site 12
APPENDIX II – MAJOR CHANGES Major changes Exceed the scope of minor changes—doesnt fulfil the conditions Do not yet reach the scope of Appendix III—new application necessary Examples: Change in the manufacturing process of the API Change in the composition of the FPP Change to the immediate primary packaging of the FPP Applicants responsibility to provide the relevant documentation to prove that the 13 intended change will not affect the quality of the prequalified product negatively
APPENDIX III – CHANGES MAKING A NEWAPPLICATION /EXTENSION APPLICATIONNECESSARY Changes to the API Change of the API to a different API, e.g. different salt/ester/derivative, different isomer Changes to the pharmaceutical form/ dosage form Change from an immediate-release product to a modified release dosage form or vice versa Change from a liquid to a powder for reconstitution, or vice versa Change or addition of a new route of administration. 14
APPENDIX IV - STABILITY REQUIREMENTSFOR VARIATIONS TO PRE-QUALIFIED FPPS Responsibility of the pre-qualified supplier to investigate whether or not the intended change will have an impact on the quality characteristics of APIs and /or FPPs and consequently on their stability. Base on the knowledge and experience acquired on APIs and FPPs (Stress testing, supportive data, accelerated and long- term testing) At the time of submission, 3 or 6 months stability data should be provided according to the nature of the change, stability of the API, dosage form of the 15 FPP,etc
CHANGES IN MANUFACTURING SITE:- Major changes eg:- Move to new site never inspected by FDA or cGMP. Transfer of aseptically processed sterile drug substance eg lyophilized drug. Finished drug product sterilized by terminal process. Manufacture of primery package when it control doge delivered eg aerosols Moderate changes eg:- Manufacture of drug product that is not. 16
otherwise provided for in this guidence. Minor changes eg:- for secondary packaging For labelling. Manufacture of drug substance intermediate other then the final intermediate. Ink imprinting of solid oral dogage form drug product. Sterilization site for packaging component when process is same. 17
CHANGES IN MANUFACTURING PROCESS Major changes eg:- When it effect release of drug eg modified release or controlled release. Change in sterility method. Addition or deletion of sterilization procedure. Replacing sterilizer with other of different principle. Addition of new equipment. Replace Class 100 aseptic fill area with barrier system. Change to aseptic process methed beyond 50%. 18
Replacing lyophilization equipment of different size. Change in sterilizer load limit from pre validated load limit. Change in pore size of filter. For natural product:-change in source material eg microbe,cell,plant. Change in process:- from dry to wet granulation. One type of drying to another. Change in route of synthesis of drug substance. Synthesis of drug substance that may effect impurity. Addition of ink cod imprint not currently used in CDER. 19
Moderate changes:- In drug substance or product except as otherwise provided for in this guidance. Change in filteration parameters flow rate, pressure, time. change from single to dual sterilizing filters. increase the bulk solution storage time by more than 50% Supplement - Changes Being Effected. A change in methods that provides increased assurance that the drug substance will have the characteristics of 20 identity, strength, quality, purity.
Minor changes:- changes to equipment of the same design minor change in an existing code imprint Addition or change in ink imprint when the ink is currently used on CDER- approved drug product. change in the order of addition of ingredients. increase the bulk solution storage time by no more than 50 percent. For natural increase or decrease in production. 21 Replacement with equipment of the same design.
Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the quality standards. acceptance criteria are numerical limits, ranges, or other criteria for the tests described. regulatory analytical procedure i.e specified in USP/NF. CONTAINER CLOSURE SYSTEM Major Changes:- Change from ampule to vial. Change that may effect drug product sterility assurance. 22 From single dose to multiple dose.
change to a flexible container system. change to a prefilled syringe dosage. Change in size of sterile container. Deletion of 2ndary package when it provide light,moisture protection. Addition of secondary package when it may effect impurity. Moderate changes:- Change in container size no of units in unit dosage form. Change in label amount. Addiion deletion of desiccant. Minor changes:- 23 Change from metal to plastic.
Change in child resistant pack. Increasing the wall thickness. change in or addition of a cap liner. Change in antioxidant,colorant,stabilizer. Change to new container already in NDA. A change in or addition of a seal. LABELING:- Major Changes:- Changes based on data from preclinical studies. Changes to the clinical pharmacology. Claims of superiority to another drug 24 product.
Changes based on postmarketing study results with new indication use. Revision of population based on data. Change in the labeled storage conditions. Moderate Changes:- Addition of an adverse event. Addition of a precaution,warning,contraindication arising out of a postmarketing study, adds about drug abuse, dependence,psycological effect. 25
Minor Changes:- Editorial changes eg distributer name add. Foreign language versions of the labeling. Changes in the layout of the package label. 26
CONCLUSION Any change to the content of the pre-qualified dossier should be reported The change should not adversely affect the quality, safety and efficacy of the pre-qualified product Position correctly the variation and submit necessary data Contact prequalification for assistance in classifying an unforeseen change pre-submission. 27