Post approval of drugs
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This document discusses recommendations for post-approval changes to approved drug applications. It defines major, moderate, and minor changes and provides examples. Major changes require prior approval from the FDA before distribution. Moderate changes require submission of a supplement to the FDA either 30 days or 60 days before distribution depending on the type of change. Minor changes are described in annual reports. The document provides recommendations for changes in several areas including components and manufacturing processes, specifications, packaging, labeling, and multiple related changes. It also notes some of the major differences in requirements for changes to biological products versus drug products.
Post approval of drugs
- 1. Post approval of drugs
- 2. Holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make post approval changes should follow in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act
- 3. Which provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes An applicant must provide Specific information to assess the effect of the change 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
- 4. Reporting categories A major change - substantial potential Moderate change- moderate potential Minor change- minimal 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.
- 5. A major change requires the submission of a supplement and approval by FDA prior to distribution of drug product This type of supplement is called, a Prior Approval Supplement And an applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons (e.g., drug shortage) or if a delay in making the change described. This type of supplement is called, Prior Approval Supplement - Expedited Review Requested.
- 6. • There are two types of moderate change. One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product . • This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected in 30 Days
- 7. • FDA informs the applicant within 30 days of receipt of the supplement if information is missing, distribution must be delayed until the supplement has been amended this type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected. • If, after review, FDA disapproves supplement it may order the manufacturer to cease distribution of the drug products made using the disapproved change
- 8. • The applicant must describe minor changes in its Annual Report . In annual reports, the list should be included in the summary section. Assessment of the Effects of the Change The holder of an approved application under section 505 of the Act must assess the effects of the change before distributing a drug product
- 9. Equivalent comparing test results from pre- and post change material and determining if the test results are equivalent. Adverse effect Some manufacturing changes have an adverse effect on the identity, strength, quality, purity, or potency of the drug product
- 10. Recommendations are provided for post approval changes in (1) components and composition, (2)manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, (6) labeling (7) miscellaneous changes and (8) multiple related changes
- 11. COMPONENTS AND COMPOSITION Changes in the qualitative or quantitative formulation, including inactive ingredients, as provided in the approved application, are considered major changes requiring a prior approval supplement
- 12. Major changes for manufacturing site A move to a different manufacturing site, except one used to manufacture or process a drug substance intermediate, when the new manufacturing site has Never been inspected by FDA Does not have a satisfactory CGMP inspection An aseptically processed sterile drug substance or drug product to a newly constructed or refurbished aseptic processing facility or area that does not manufacture similar to approved drug products
- 13. Moderate changes for manufacturing site • A move to a different manufacturing site for the primary packaging of any drug product that is not otherwise listed as a major change A move to a different manufacturing site for testing if (1) the test procedures approved in the application or procedures that have been implemented via an annual report (2) All Post approval commitments made by the applicant relating to the test procedures have been fulfilled
- 14. Minor changes for manufacturing site A move to a different manufacturing site for secondary packaging. A move to a different manufacturing site for labeling. A move to a different manufacturing site for the manufacture or processing of drug substance intermediates other than the final intermediate. A change in the contract sterilization site for packaging components when the process is not materially different from that provided for in the approved application
- 15. Manufacturing process-major changes Changes that may affect the controlled (or modified) release, metering or other characteristics (e.g., particle size) of the dose delivered to the patient, including the addition or deletion of a code imprint by embossing, debossing, or engraving on a modified-release solid oral dosage form.
- 16. 2. Changes that may affect drug product sterility assurance including Changes in the sterilization method (e.g., gas, dry heat, irradiation). These include changes from sterile filtered or aseptic processing to terminal sterilization, or vice versa.
- 17. • For Drug product · Dry to wet granulation or vice versa. · Change from one type of drying process to another (e.g., oven tray, fluid bed, microwave). • . For Drug substance · Filtration to centrifugation or vice versa. · Change in the route of synthesis of a drug substance
- 18. Moderate changes for manufacturing process An increase or decrease in production scale during finishing steps that involves different equipment. Changes to filtration parameters for aseptic processing (including flow rate, pressure, time, or volume, but not filter materials or pore size rating)
- 19. Minor change for manufacturing process For drug products, changes to equipment of the same design and operating principle and/or changes in scale except as otherwise provided for in this Guidance 2. A minor change in an existing code imprint for a dosage form. For example, changing from a numeric to alphanumeric code
- 20. specification Conformance to a specification means that the material, when tested according to the analytical procedures listed in the specification, will meet the list changed acceptance criteria Major changes Relaxing an acceptance criteria Establishing a new regulatory analytical procedure
- 21. Moderate changes Any change in a regulatory analytical procedure other than those identified as major changes or editorial changes. A change in an analytical procedure used for testing raw materials used in drug substance manufacturing, in-process materials prior to
- 22. Minor Changes For drug substance and drug product, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application
- 23. Packaging containers Major changes Moderate changes Minor changes For liquid and semisolid dosage forms, a change in polymeric materials (e.g., plastic, rubber) of primary packaging components single unit dose container to a multiple dose container size and shape of a container A change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams, milliliters) of a non sterile drug product in a unit-of-use container A change in the size and/or shape of a container for a non sterile solid dosage form A change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams) of non sterile solid dosage form in a multiple-unit container
- 24. labelling Major changes Moderate changes Minor changes Changes based on post marketing study results, including, labeling changes associated with new indications and usage Changes to the clinical pharmacology or the clinical study section reflecting new or modified data. Changes in the layout of the package or container label that are consistent with FDA regulations Editorial changes, such as adding a distributor's name
- 25. Miscellaneous changes Major changes Minor changes Moderate changes Changes to an approved stability protocol 4. An extension of an expiration dating period based on (1) data obtained under a new or revised stability testing protocol that has not been approved in the application 5. Changes to a drug product under an application that is subject to a validity Reduction of an expiration dating period to provide increased assurance of the identity, strength, quality, purity, or potency of the drug product An extension of an expiration dating period based on full shelf life data on production batches obtained under a protocol approved in the application
- 26. multiple related changes Multiple related changes involve various combinations of individual changes. For example, a site change may also involve equipment and manufacturing process changes or a components and composition change may necessitate a change in a specification
- 27. Major differences in drugs and biological products REQIREMENT BIOLOGICS DRUGS Manufacturing facility Introduction of prokaryotes including yeast into a multiproduct eukaryotic fermentation suite Introduction of a different host/media-type into an approved multi-product facility country of origin of the source animals, its use and previous acceptance). NOT REQUIRED Addition or deletion of excepients
- 28. biologics drugs Manufacturing process Accelerated stability results Scale-up of the manufacturing process: a. at the fermentation stage b. the purification stage Results of a minimum of three (3) months of accelerated and three (3) months of real time/real temperature testing of the changed drug substance. Changes in granulation procedures For 6 months
- 29. Requirement Biologics drugs In manufacturing process Information assessing the risk with respect to potential contamination with adventitious agents (e.g., impact on the viral clearance studies, BSE/TSE risk). generation of a new Working Cell Bank (WCB) Changes to the seed bank: a. new Master Seed Bank _ _ _
- 30. requirement biologics drugs Change in facility action limits of the environmental monitoring program Its necessary but not stringent