INTRODUCTION:

FDA has issued guidelines to ANDA sponsors who intend to change components or composition, manufacturing site, scale-up=scale-down of manufacturing, and=or manufacturing process and equipment for immediate release (IR) 1 and modi¢ed release (MR) solid oral dosage forms during the post-approval period. .

The changes are done like ;

1. Prior Approval Supplement: Major changes that require FDA approval before implementation

2. Supplement—Changes Being Effected (30 Days): Moderate changes that require 30 days’ notice before implementation

3. Supplement—Changes Being Effected (0 Day): Moderate changes that can be implemented immediately

4. Annual Report: Minor changes that can be implemented immedi- ately and ¢led in the next Periodic Report

This guidance was a ¢rst attempt beyond the Case of Federal Regulation (CFR) to provide industry with clear and definitive language regarding the regulatory noti¢cation process and requirements for post-approval changes. It also attempted to reduce the regulatory burden for industry.

The changes can be done in terms of :

· Components and composition of the drug product

· Manufacturing site change

· Scale-up of the drug product

· Manufacturing equipment

· Packaging

Level of changes can be done:

Level	Definition
1	Changes that are unlikely to have any detectable impact on formulation quality and performance
2	Changes that could have a significant impact on formulation quality and performance
3	Changes that are likely to have a significant impact on formulation quality and performance

Component Changes:

The addition or deletion of an ingredient can have an adverse e¡ect on the dissolution pro¢le of the finished product and on the in vivo bioequivalence to the reference listed drug.

Level	Definition	Category and eple	Test documentation	Filing documentation
Minor² changes	Changes unlikely to have any detectable impact on formulation quality and performance	i. Deletion=partial dele- tion of color or flavor or change in the ingre- dient of the printing ink ii. Changes in excipient (% w=w) of total for mulation not greater than 5%	i. Chemistry: Compen- dial release and stabi- lity testing Stability: Long-term stability testing on one batch in annual report ii. Dissolution: None beyond application= compendial require- ment iii. In vivo BE: None	Annual Report (all information including long-term stability data)
Moderate changes	Changes could have significant impact on formulation quality and performance as a result of change in therapeutic range, solubility, and permeability	Changes in technical grade of an excipient or changes in excipient amount greater than expressed in level 1, but total additive effect of all excipients should not be greater than 10%	i. Chemistry: Compendial release, batch record Stability: one batch with3 months’ accelerated stability data insupplement and one batchon long-term stability ii. Dissolution: Using case A, B, and C as described in the guidance iii. InVivo BE: None if situation does not meet above dissolu- tion description	Changes Being Effected (CBE) Supplement with long-term stability data
Major changes	Changes likely to have a significant impact on formulation quality and performance as a result of change in therapeutic range, solubility, and permeability	i. Qualitative and quan- titative changes to a narrow therapeutic drug beyond the ranges of excipients noted in level 1 ii. High solubility and permeability drug, low permeability and high solubility drug and high permeability and low solubility drugs not meeting the dissolution criteria as stipulated in the gui- dance iii. Changes in the excipi- ent ranges of low solubility, low perme- ability drugs listed under level 1	i. Chemistry: Compen- dial release and batch records Stability: (a) 3 months’ accelerated stability testing on one batch in supplement and long- term stability data on one batch in Annual Report if significant body of information is available; (b)3 months’accelerated (supplement) and long-term stability (Annual Report) on up to three batches ii. Dissolution: Multi- point dissolution pro- file in compendial medium at 15, 30, 45, 60, and 120 min or until asymptote is reached iii. InVivo BE: Full BE study except for the cases when in vitro= in vivo correlation is established	Prior Approval Supplement on all information including accelerated stability and long-term stability in Annual Report

Site Changes ³

The sponsor of an ANDA must include in its application the site of manufac- ture, where the drug product will be produced, tested, packaged, and=or labeled.

Level	Definition	Test documentation	Filing documentation
(Minor changes)	1 Site change within facility and humidity), and controls, no changes made in manu- facturing batch records	i. Chemistry: Compendial release ii. Dissolution: Compendial release iii. In-vivo BE: None	A Annual Report
(Moderate changes	1 Site change within a contiguous campus or between facilities in adjacent city blocks using same equip ment, SOPs, environment conditions (temperature and humidity), and controls, no changes made to manu- facturing batch records	i. Chemistry: Updated batch records, com- pendial release, Stability: Long-term sta- bility on one batch reported in Annual Report ii. Dissolution: Compendial release InVivo BE: None	Changes Being Effected (CBE) Supplement, Annual Report
Major changes	1 Changes in manufacturing site to a different campus. Same equipment, SOPs, environment conditions and controls should be used at the new site. No changes in the manufacturing batch records	i. Chemistry: Updated batch records, com- pendial release, Stability: 3 months’ accelerated stability data reported in supplement, long-term stability data on up to three batches in Annual Report ii. Dissolution: CaseB of the guidance, multipoint profile in compendial medium at 15, 30, 45, 60, and 120 min or until an asymptote is reached. Dissolution profile should be similar at both current and pro posed site iii. InVivo BE: None	Changes Being Effected (CBE) Supplement, Annual Report

Change in Batch Size ⁴:

Change in batch size from pivotal=pilot scale bio-batch to larger or smaller production batches tends to change the operating parameters. Therefore, all the parameters, such as mixing time, speed, etc., are adjusted according to the equipment (large or small) used in the process.

Minor changes

1 Change in batch size by 10 times the pilot=bio-batch using equipment having the same design and operating principles as that used to produce the test batch. The batch should be manufac- tured under full compliance with cGMPs and SOPs using the same formulation and manufacturing procedures

i. Chemistry: Compendial release, notification of changes, and updated batch records in annual report, Stability: Long- term stability on one batch

ii. Dissolution: Compendial release

iii. In vivo BE: None

Annual Report including long- term stability data.

Moderate changes

1 Site change within a contiguous campus or between facilities in adjacent city blocks using same equip ment, SOPs, environment conditions (temperature and humidity), and controls, no changes made to manu- facturing batch records

iii. Chemistry:

Updated batch records, com- pendial release, Stability: Long-term sta- bility on one batch reported in Annual Report

iv. Dissolution: Compendial release

v. InVivo BE: None

Changes Being Effected (CBE) Supplement, Annual Report

Major changes

1 Changes in manufacturing site to a different campus. Same equipment, SOPs, environment conditions and controls should be used at the new site. No changes in the manufacturing batch records

iv. Chemistry: Updated batch records, com- pendial release, Stability: 3 months’ accelerated stability data reported in supplement, long-term stability data on up to three batches in Annual Report

v. Dissolution: CaseB of the guidance, multipoint profile in compendial medium at 15, 30, 45, 60, and 120 min or until an asymptote is reached. Dissolution profile should be similar at both current and pro posed site

vi. InVivo BE: None

Changes Being Effected (CBE) Supplement, Annual Report

Equipment change ⁵:

Any change in manufacturing equipment other than that used in the approved application requires appropriate validation studies to demon- strate that the new equipment is similar to the original equipment.

a. Changes from nonautomated to automated equipment to move ingredients

b. Changes to alternative equip ment of the same design and operating principles (same or different capacity

i. Chemistry: Notification of change, compendial release, and Updated batch records Stability: Long- term stability on one batch

ii. Dissolution: Compendial release

iii. In vivo BE: None

Annual Report including long- term stability data

1 Changes in ^6,7equipment to a different design and Different operating principles.

i. Chemistry: Compendial release, notification of change, updated batch records Stability: (a) Significant body of data available, which includes 3 months’accelerated stability data in sup- plement and long-term stability on one batch reported in Annual Report; (b) significant body of data not available, Which includes 3 months’accelerated stabi- lity on up to three batches in supplement and long- term stability onup to three batches reported in annual report

ii. Dissolution: Case C dissolution profile of the gui- dance, which is multipoint dissolution, provides in water, 0.1N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 for the proposed and currently accepted for- mulation

iii. In vivo BE: None

Prior Approval Supplement with justification for change, Annual Report including long-term stability data

PROCESS CHANGE:

Change in manufacturing process or technology from that currently used by the applicant may have the potential for adverse e¡ects on the identity, strength, quality, purity, or potency of a drug product.

CONCLUSION:

In the process of developing a new drug product the scale up changes are done in terms of Composition, Manfacturing process, Equipment and change of site and these changes are done after approval of FDA.

REFERENCE:

1. Guidance for Industry.Changes to an Approved NDAor ANDA.USDepartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), November 1999, CMC.

2. Guidance for Industry. Immediate Release Solid Oral Dosage Forms—Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation. Center for Drug and Research (CDER), November 1995, CMC 5.

3. Guidance for Industry. SUPAC-IR=MR: Immediate Release and Modi¢ed Release Solid Oral Dosage Forms—Manufacturing Equipment Addendum. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), January 1999, CMC9 (Revision 1).

4. Guidance for Industry. Comparability Protocols—Chemistry, Manufacturing, and Controls Information. FDA, Center for Drug Evaluation and Research (CDER), February 2003, http://www.fda.gov=cder=guidance=5427dft.pdf.

5. O⁄ce of the Federal Register. 21 CFR 314.80. Revised as of April 1, 2002: 119^122.

6. Guidance for Industry. Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clari¢cation of What to Report. Food and Drug Administration, August 1997.

7. Food and Drug Administration. MedWatch FDA Form 3500=3500A. http:==www.fda.gov=cder=guidance=5427dft.pdf, June 1993

Received on 05.03.2022 Modified on 26.04.2022

Asian J. Res. Pharm. Sci. 2023; 13(1):29-32.

DOI: 10.52711/2231-5659.2023.00005