SUPAC, BACPAC, Post Marketing Surveillance

Product Development & Technology Transfer

1. PRODUCT DEVELOPMENT AND TECHNOLOGY TRANSFER (MQA – 104 T) UNIT I SUPAC, BACPAC, Post Marketing Surveillance Presented By V. Manikandan, Roll No. 2061050003, M. Pharm (Pharmaceutical Quality Assurance) – I Year, Batch : 2020-2022, Department of Pharmacy, Annamalai University. Submitted to Dr. R. Murali, M. Pharm., Ph. D, Assistant Professor, Department of Pharmacy, Annamalai University.

2. Scale Up and Post Approval Changes (SUPAC) Introduction In the process of developing the new product the batch size used in the earliest human studies are small. The size of the batch is gradually increased (scale up) The scale up and the changes made after approval in the composition manufacturing equipment and change of site have become known as scale up and post approval changes (SUPAC). Currently finalized SUPAC guidance a re as b elow SUPAC – IR ( Immediate Release ) – Nov.1995. SUPAC – IR Questions and Answer – Feb.1997. PAC-ATLS ( Post Approval Changes – Analytical testing Laboratories changes )- Apr.1998. SUPAC – MR (Modified Release ) – Sep.1997. SUPAC SS (Semisolid – Non sterile ) – May 1997.

3. Component and Composition Changes Focus on the changes in amount of excipient in the drug product. Not focus on change in the amount of the drug substance. Level 1 Changes Definition of level, t hese are unlikely to have any detectable impact on formulation quality and performance Examples : Deletion or partial deletion of an ingredient intended to affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient. Changes in excipient, expressed as percentage (w/w) of total formulation. Test Documentation Chemistry documentation Stability testing (long term data) Dissolution Documentation None In Vivo Bioequivalence Documentation None.

4. Filling Documentation Annual report(long term stability data). Level 2 Changes Definition of level, t hey have a significant impact on formulation quality and performance. Level 2 changes vary depending on three factors : Therapeutic range Solubility Permeability Examples: Change in the technical grade of an excipient: Avicel PH102 vs. Avicel PH200 Changes in excipient, expressed as percentage (w/w) of total formulation Test Documentation Chemistry Documentation Level 1 + 1 batch with 3 month accelerated stability study

5. Dissolution Documentation Case A – High permeability, High solubility Case B –Low permeability, High solubility Case C- High permeability, Low solubility In Vivo Bioequivalence Documentation None. Filling Documentation As level 1 + Accelerated stability study Level 3 Changes Definition of level, t hey have a significant impact on formulation quality and performance. Level 3 changes vary depending on three factors : Therapeutic range Solubility Permeability.

6. Test Documentation Chemistry Documentation Level 1 + 1 month accelerated stability of 1 batches or 3 batches. Dissolution Documentation Case B – Low permeability, High solubility In Vivo Bioequivalence Documentation Full bioequivalence study. Except IVIVIC verified. Filling Documentatio n As level 1 + Accelerated stability study Site Changes It includes the changes in location of the site of manufacturing facilities for both company owned and contract manufacturer. It do not include scale up.

7. Level 1 Changes Definition of level, s ite change within a single facility where same equipment, SOP, Environment condition and common personnel. Test Documentation - Chemistry, dissolution are according to compendial and vivo BE not required. In Vivo Bioequivalence Documentation - None. Filling Documentation - Annual report. Level 2 Changes Definition of level, s ite change within a contiguous campus or between facilities in adjacent city blocks. Test Documentation - Level 1 + one batch long term stability in chemistry. Filling Documentation - Annual report Level 3 Changes Definition of level, s ite change to different campus. Test Documentation - None

8. Chemistry Documentation One batch for accelerated stability (3month)+One batch for long term stability for SBOIA or 3 batches for accelerated and long term stability Dissolution testing – Case B. In Vivo Bioequivalence Documentation - None Filling Documentation - Annual report Change i n Batch Size Post approval changes in the size of a batch from the pilot scale bio batch material to larger or smaller production. Scale down below 1,00,00 dosage units is not covered by this guideline. Scale up changes should be property validated and if needed, inspected by appropriate agency personnel. Level 1 Changes Definition of level, c hanges in the batch size up to and including factor of 10 times the size of the pilot/ bio batch where The equipment is of same design and principle. Both manufacture, According to the CGMP compliance. Same SOP`S followed.

9. Test Documentation - Level 1 + one batch long term stability in chemistry. Filling Documentation - Annual report Level 2 Changes Definition of level, c hanges in the batch size up to and including factor of 10 times the size of the pilot/ bio batch where The equipment is of same design and principle. Both manufacture, According to the CGMP compliance. Same SOP`S followed. Test Documentation - As per level 1 + one batch with three month accelerated stability + Case B dissolution testing. Manufacturing Changes Equipment Changes Process Changes Equipment Changes Level 1 , c hange from non-automated or vice versa to more ingredients. Change to alterative equipment of same design and the operating principle of the same or different capacity. Test and filling documentation - as per level 1 batch size change 22.

10. Level 2, c hange in equipment to a different design Test and filing documentation - As per level 3 of the site change except Case C dissolution of Case B. Process Changes Level 1 , this changes includes process changes like mixing time and operating speed within application/validation range. Test and filing document - as per level 1 of site change. Level 2, this changes includes process changes like mixing time and operating speed outside the application/validation range. Test and filing documentation - as per the l evel 2 changes in site changes. Level 3 , c hange in the type of the process used in the manufacture of the product, such as a change in from the wet granulation to the direct compression of dry powder. Documentation - As per the level 3 changes of component and composition changes.

11. Bulk Active Chemical Post Approval Changes (BACPAC) This guidance provide recommendation to holders of NADAs (New animal drug application), ANADAs (Abbreviated new animal drug application),VMFs (Veterinary Master F iles) Post approval changes include, Site of manufacture Scale of manufacture Equipment Specifications Manufacturing process of intermediates in synthetic pathway leading to drug substances The Guidance Covered, S ite, scale, and equipment changes involving the synthetic steps up to and including the step that produces the final intermediate S pecification changes for raw materials, starting materials, and intermediates, except the final intermediate M anufacturing process changes involving the synthetic steps up to and including the final intermediate.

12. Types of Changes Site, Scale, and Equipment Changes The manufacturing site, scale of manufacture, and manufacturing equipment changes discussed in this section do not include any modifications to the synthetic pathway (i.e., the same starting materials, intermediates, solvents, and reagents are involved). Site Changes Changes to a different manufacturing site should be reported. Changes within the same manufacturing site need not be submitted to the Agency, and equivalence testing as described in this document need not be carried out. Test documentation (submitted as amendments to master files and/or in annual reports or supplements to the applications, as appropriate) should include. The name and address of the new facility. A concise description of the manufacturing steps being transferred, a summary of any variation in equipment or operating conditions, and a statement that the synthetic pathway is identical at the new site. Evaluation of the impurity profile and physical properties.

13. Scale Changes Scale changes include increases and decreases in the batch size of intermediates, Including the final intermediate, beyond those approved in the original application. Equipment Changes A change to new equipment need not be submitted to the Agency, even where equipment is specified in the approved application. Specification Change Specification changes for the final intermediate are not included in this guidance, nor are certain specification changes for raw materials, starting materials, and intermediates derived from natural sources or biotechnology (see section I). Test documentation (submitted in amendments to master files and/or in annual reports to the applications, as appropriate) should include

14. Specification Changes That Provide Greater Assurance of Quality Test documentation (submitted as amendments to master files and/or in annual reports to the applications, as appropriate) should include, Rationale for the proposed change and a brief description of any new analytical procedures, including a discussion of improvements over existing procedures. Updated specifications. Some specification changes that fall within the scope of section V.B.3 would clearly not affect the quality of downstream intermediates or the drug substance and therefore no evaluation of equivalence would be needed. Elimination of a redundant test (e.g., deletion of a boiling point test for a solvent where a chromatographic assay test is routinely performed). Manufacturing Process Changes This category encompasses a wide range of process related changes. New specifications may be called for when different solvents, reagents, starting materials, or intermediates are involved,

15. Changes That Do Not Involve New Starting Materials or Intermediates Changes in unit operations (e.g., addition, deletion, change in the order, repetition of an existing unit operation on a routine basis) . Addition or deletion of raw materials (e.g., solvents, reagents) or ancillary materials (e.g., resins, processing aids) Changes in solvent composition (other than for an analytical procedure, which would be covered under Specification Changes) Operating conditions (e.g., temperature, pH, reagent stoichiometry, time). Test documentation (submitted as amendments to master files and/or in annual reports or supplements to the applications, as appropriate) should include, Description of change Specifications for new reagents and solvents and Certificates of Analysis from the suppliers, if applicable Evaluation of the impurity profile and physical properties.

16. Changes in the Route of Synthesis in One or More Steps Involving Different Starting Materials and/or Intermediates (except the final intermediate) Test documentation (submitted as amendments to master files and/or in supplements to the applications, as appropriate) should include , Description of the change with details of the new synthetic procedure, the operating conditions, and controls of critical steps and intermediates Appropriate structural characterization data for new intermediates Specifications for any new starting materials and/or intermediates Evaluation of the impurity profile and physical properties. Changes in Which an Intermediate Is Redefined as a Starting Material This change is often in response to an increase in commercial availability of the proposed starting material. In general, the specification for the proposed starting material should

17. Test documentation (submitted as amendments to master files and/or in supplements to the applications, as appropriate) should include, Rationale for the proposed change and overview of current synthetic procedure Evidence that the intermediate complies with the current definition and/or expected characteristics of a starting material A new or revised specification, a description of new or revised analytical procedures for the redefined starting material, and, if appropriate, additional tests and/or tightened acceptance criteria for downstream intermediates A list of sources of the redefined starting material A description of how the suitability of a new supplier or revised process from an existing supplier will be assessed Evaluation of the impurity profile and physical properties.

18. Post Marketing Surveillance Despite CDER's vigilant premarket review, active post marketing surveillance of drug adverse effects is also essential. Because all possible side effects of a drug can't be anticipated based on preapproval studies involving only several hundred to several thousand patients, FDA maintains a system of post marketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug approval process. FDA monitors adverse events such as adverse reactions and poisonings. The Agency uses this information to update drug labeling, and, on rare occasions, to reevaluate the approval or marketing decision.  This page describes how CDER works to assure the ongoing safety and effectiveness of drug products currently marketed in the United States. The  FDA Adverse Event Reporting System  (FAERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products.

19. The ultimate goal of FAERS is to improve the public health by providing the best available tools for storing and analyzing safety reports. The reports in FAERS are evaluated by a multidisciplinary staff safety evaluators, epidemiologists and other scientists in the Center for Drug Evaluation and Research's (CDER) Office of Surveillance and Epidemiology to detect safety signals and to monitor drug safety. As a result, the FDA may take regulatory actions to improve product safety and protect the public health, such as updating a product's labeling information, sending out a "Dear Health Care Professional" letter, or re-evaluating an approval decision. The  MedWatch  program is for health professionals and the public to voluntarily report serious reactions and problems with medical products, such as drugs and medical devices. It also ensures that new safety information is rapidly communicated to the medical community thereby improving patient care. All data contained on the MedWatch form will be entered into the AERS database. The  MedWatch page  includes sections on how to report an adverse event, safety information, and publications. For more information on how to report adverse events, see  Reporting Problems to FDA .

20. The  Division of Drug Marketing, Advertising and Communications page  also contains other useful drug advertising and surveillance information. After a drug is approved and marketed, the FDA uses different mechanisms to assure that firms A dhere to the terms and conditions of approval described in the application T hat the drug is manufactured in a consistent and controlled manner. This is done by periodic, unannounced inspections of drug production and control facilities by FDA's field investigators and analysts. Manufacturers of prescription medical products are required by regulation to submit adverse event reports to the FDA. The  MedWatch  site provides information on mandatory reporting by manufacturers. In addition, drug manufacturers must submit either error and accident reports or drug quality reports when deviation from current good manufacturing practice regulations occur.

21. Therapeutic Inequivalence Reporting. In the past 10 years, FDA's Center for Drug Evaluation and Research has received an increase of reports of drug products that fail to work in patients because the product simply has no effect or is toxic. These problems are usually attributed to switching brands of drugs. As a result, on Sept. 14, 1988, FDA created in CDER the Therapeutic Inequivalence Action Coordinating Committee (TIACC) to identify and evaluate reports of therapeutic failures and toxicity that could indicate that one product is not equivalent to another similar product.

22. References https://www.fda.gov The Pharmaceutical Sciences ; The Pharma Path Way ‘Pure a nd Applied Pharmacy’ By D. A Sawant, Pragathi Books Pvt .Ltd.

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