This document discusses various guidelines related to product development and technology transfer in the pharmaceutical industry. It covers SUPAC, BACPAC, and post-marketing surveillance. SUPAC provides guidance for scale-up and post-approval changes, categorizing changes into different levels based on their potential impact. BACPAC guidance addresses post-approval changes for bulk active pharmaceutical ingredients. Post-marketing surveillance involves monitoring adverse drug events after approval to ensure ongoing safety and effectiveness.

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 are as below
• 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, these are unlikely to have any detectable impact on formulation quality and performance
• Examples :
i. 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.
ii. 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, they have a significant impact on formulation quality and performance.
• Level 2 changes vary depending on three factors :
i. Therapeutic range
ii. Solubility
iii. Permeability
• Examples:
i. Change in the technical grade of an excipient: Avicel PH102 vs. Avicel PH200
ii. Changes in excipient, expressed as percentage (w/w) of total formulation
Test Documentation
• Chemistry Documentation
i. Level 1 + 1 batch with 3 month accelerated stability study

5. • Dissolution Documentation
i. Case A – High permeability, High solubility
ii. Case B –Low permeability, High solubility
iii. 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, they have a significant impact on formulation quality and performance.
• Level 3 changes vary depending on three factors :
i. Therapeutic range
ii. Solubility
iii. Permeability.

6. Test Documentation
• Chemistry Documentation
i. Level 1 + 1 month accelerated stability of 1 batches or 3 batches.
• Dissolution Documentation
i. Case B –Low permeability, High solubility
• In Vivo Bioequivalence Documentation
i. Full bioequivalence study. Except IVIVIC verified.
Filling Documentation
• 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, site 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, site 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, site 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 in 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, changes 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, changes 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, change 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, change 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 level 2 changes in site changes.
• Level 3, change 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 Files)
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,
• Site, scale, and equipment changes involving the synthetic steps up to and including the step that produces the
final intermediate
• Specification changes for raw materials, starting materials, and intermediates, except the final intermediate
• Manufacturing 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
i. Adhere to the terms and conditions of approval described in the application
ii. That 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 and Applied Pharmacy’ By D. A Sawant, Pragathi
Books Pvt .Ltd.

23. THANK YOU