INTRODUCTION:

Post approval changes are the changes which are made for approved pharmaceutical products. While making these changes sufficient data should be provided in order to determine the impact of the change on the quality of the approved products as it is related to safety, efficacy and effective use of the products. The changes could be related to any information on formulation of registered or listed goods or other aspects of manufacture, labelling. These changes shall not be implemented until it is notified to the agency and approved by them.

There are various reasons for making changes to pharmaceutical products after the original regulatory approval is obtained. Change control procedures should detail how changes are evaluated and implemented and how these change impacts stability and the data needed to support the change.

The regulatory group will determine the strategy for submission based on a review of the technical assessment of the change and the appropriate regulatory guidance. The changes or variations occur in case of Business continuity, to maintain flexible conditions and economy, process improvisations, fulfil regulatory agency requirements and support continuous improvement and optimization of manufacturing process and the quality of the medicinal products.

Classification of Changes:

The applicants of registered generics who wish to make changes will have to follow regulations in accordance with the agency which differs from different countries. The regulation classifies the changes for drug substances and drug products.

The categories for the changes are as follows:¹

· Components and Composition

· Manufacture

· Specifications

· Container Closure System

· Stability

· Labelling Changes

The changes are then classified as:

Major Change:

The change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug substance or drug product.

Moderate Change:

The change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug substance or drug product.

Minor Change:

The change that has a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug substance or drug product.

DISCUSSION:

JAPAN:

In Japan, the legal basis for changes in a marketing approval is stipulated in the Pharmaceutical and Medical Device Act. Changes are only approved when the identity of the approved product is not affected, and the product remains the same. In case of changes with regard to the active ingredient, its content or dosage form, a new approval application is required. Two reporting categories are existing, minor change notification and partial change approval.

The holder of a marketing authorization is eligible to apply for a partial change of approved items in the approval. Partial change applications (PCA) are described in Article 14, Paragraph 9 of the Pharmaceutical and Medical Device Act (PMDA). The Japanese word for partial change means “changes in the currently approved items of the medicinal product. In other words, an application for a partial change application has to be filed in case the applicant alters the content of the current approval by the change. Also changes requiring adequate change control can be identified as partial changes. This major change needs between 12 and 18 months as a standardized timing for approval.⁽¹⁾

Changes only requiring minor change notifications (MCN) are stipulated in Article 14 Paragraph 10 of the PMDA. A minor change to an existing approval does not require an application for approval as a partial change does. The manufacturer has to notify the health authority within 30 days after the change has been implemented confirming that the change does not affect the quality of the medicinal product. Related data to the change has to be filed at the manufacturing site. GMP inspectors will confirm the appropriateness of the change procedure later on during a GMP inspection.

Minor changes are other than those specified in the following items in the approval;

· Changes in the manufacturing methods affecting the nature, properties, performance and / or safety of the product.

· Deletion of items regarding specifications and test methods as well as regarding changes in the approved specifications.

· Change in the methods used for the inactivation or elimination of pathogenic factors.

· All other changes affecting the quality, efficacy or safety of the product. ⁽¹⁾

Two types of Post Approval Changes are:

1. Partial change approved application (PCA)

2. Minor change notification (MCN)

In general, the Partial change approved application (PCA)/ Minor change notification (MCN) change classification should be based on Critical Quality Attributes (CQA) and Critical Process Parameter which may affect the CQAs, on development data, prior knowledge and the overall control strategy.

Partial change application is also called as major change, which requires prior approval before implementation because these kinds of changes have direct effect on the safety, efficacy, purity, potency and quality of the drug product.

A minor change notification can be reported soon after the implementation and it does not require any prior approval from the agency.¹

· The differences between a partial change application and a minor change notification can be explained as follows: a change in the principle of an unit operation of a critical process or a change in a process control criteria as quality endpoint criteria is filed as a partial change application whereas a process parameter to only control the quality endpoint criteria is filed as a minor change notification.²

Standard Periods and procedures for a PCA and a MCN:

In the event that it is discovered in the GMP inspection that, a MCN had been submitted concerning changes in manufacturing process that should not have originally been addressed in the MCN, the MCN becomes invalid, and there may be the possibility that the manufacturer may be accused of violating the Pharmaceutical Affairs Law.³

What change is addressed in a PCA and an MCN?:

· Change of manufacturing procedures that affect quality, characteristics, efficacy and safety of the final products

· Deletions or changes of the item of specifications and test methods

· Change of the manufacturing processes concerns inactivation or elimination of pathogens

· Additions, changes or deletion of Dosage and administration, and Indications

· Any other change fear of being affected quality, efficacy or safety of the final products⁴

· Change of manufacturing sites :

Since change in manufacturing sites requires adequate change control, they shall be, in principle, addressed in a PCA for matters that have been approved. However, for changes that are related to facilities for inspection and testing, it shall be addressed in an MCN.⁵

· Specifications and test methods:

Changing strictly an acceptance criterion without changing the substance of the item of specifications is addressed in an MCN.

· Changes in manufacturing method:

For changes in the manufacturing method of drugs, etc., adequate validation and change control, etc. shall be conducted as a prerequisite for changes in either a PCA or an MCN, regardless of the magnitude of the impact on quality. That is, a change shall be made based on the judgment that the change imposes no obvious impact on the quality though change control as performed under GMP.⁶

Necessary data for a PCA:

1. Manufacturing Sites

Process validation data and lot analysis data at a new manufacturing site, comparability data, etc.

2. Specifications and test methods

Validation data, comparability data, etc.

3. Period of Validity

A real-time/real-temperature stability data

4. Manufacturing procedures

Process validation data, comparability data (characteristics, specifications, stability etc.)⁷

CANADA:

In April 1994, Health Canada released the policy entitled “Changes to Marketed New Drug Products”. This helped the sponsors who intended to make changes to new drugs that have already received a NoC, this includes pharmaceuticals, biologics, radiopharmaceuticals for human use and pharmaceutical, radiopharmaceuticals and certain biotechnological products for veterinary use.⁸

New Drug Submission:

This pathway applies to the registration of new drugs only. At the completion of the review, if Health Canada has approved the drug product, it issues a Notice of Compliance (NOC) which permits the drug to be marketed in Canada.⁹

Abbreviated New Drug Submission:

Abbreviated New Drug Submission (ANDS) sets out all data establishing the quality, safety and efficacy of the drug with that of innovator drug Canadian Reference Product (CRP). At the completion of the review, if Health Canada has approved the drug product, it issues a Notice of Compliance (NOC) which permits the drug to be marketed in Canada. The current study focuses on the changes in the Abbreviated New Drug Submission (Post-Notice of Compliance).¹⁰

Handling of Variations in Canada:

Changes to an Approved ANDS:

Changes to an approved drug product in Canada fall into one of four risk-based categories with Level I being the highest level of risk and Level IV being the lowest.

The classification of changes for drug substances and drug products are discussed which are reflected in module 3 of CTD.

Recommendations are provided for post approval changes in

A. General Information

B. Pharmaceutical Development

C. Manufacture

D. Control of Drug Substance, Excipients and Drug product

E. Container Closure System

F. Stability

The changes are classified as major, moderate, and minor quality changes.

For the ease of understanding the changes for drug Substance and drug Product are classified separately.¹¹

LEVEL I - SUPPLEMENTS (MAJOR QUALITY CHANGES):

· Level I - Supplements (Major Quality Changes) are changes that have a 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

· This allows Health Canada the opportunity to apply the principles of risk management by having the necessary time for an appropriate assessment of the documentation

· The changes included in this reporting category shall be filed, along with the recommended supporting data, to Health Canada as a Supplemental Abbreviated New Drug Submission (SANDS)

· The change may not be implemented by the sponsor until a NOC has been issued¹²

LEVEL II-NOTIFIABLE CHANGES (MODERATE QUALITY CHANGES):

· Level II - Notifiable Changes (Moderate Quality Changes) are changes that have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product

· But notifiable changes are not applicable to Human Pharmaceuticals but applicable to Veterinary products only

· The changes included in this reporting category should be filed, along with the recommended supporting data, to Health Canada as a notifiable change

· All Level II changes should not be implemented by the sponsor until a No Objection Letter (NOL) has been issued¹²

LEVEL III - ANNUAL NOTIFICATION (MINOR QUALITY CHANGES):

· Level III - Annual Notification (Minor Quality Changes) are changes that have minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.¹³

· The changes included in this reporting category may be implemented by the sponsor without the prior review by Health Canada of the data supporting such a change.¹⁴

· Supporting data for the Level III changes should not be submitted; however, the data should be available to Health Canada within thirty (30) calendar days, if requested at any time

· Annual Notifications should be submitted in the month of august every year for the approved products if there are any changes.¹⁵

LEVEL IV CHANGES - RECORD OF CHANGES:

· Level IV (Quality only) changes are changes to approved drugs that are not Level I, Level II or Level III and are not expected to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product

· The changes included in this reporting category may be implemented by the sponsor without prior review by Health Canada. The changes should be retained as part of the drug product’s record by either the sponsor or the manufacturer and comply with GMP requirements the Food and Drug Regulations¹⁵

Table 2: Reporting Categories of Changes in Canada

Change	Major Change	Minor Change
Reporting Category	Level I (Tell, wait and Do after getting Approval)	Level III (Do and Tell)	Level IV (Tell)
To be filed as	SANDS*	Annual Notification	Record of changes
When to Notify to Agency	Before implementing the change	Must be notified within 12 months following the implementation.	The list of all changes should be recorded and maintained.
Fees	$20,910	NA	NA
Estimated timeline for Approval	Approx. 12-18 months	NA	NA

*Supplemental Abbreviated New Drug Submission, NA-Not Applicable

Note: Level II has not been included in the table considering its applicability for veterinary products only which falls outside scope of this dissertation.

MALAYSIA:

Throughout the life of a pharmaceutical product; the product registration holder is responsible for the product that is placed in the market and is also required to take into account technical and scientific progress, and to make any amendments that may be required to enable the pharmaceutical products to be manufactured and checked by means of generally accepted scientific methods. Such amendments have to be approved by National Pharmaceutical Control Bureau (NPCB).¹⁶

Variation applications are categorized into major variation, minor variation (prior approval) and minor variation (notification).

Major variation (MaV):

Variation to a registered pharmaceutical finished product that may affect significantly and/or directly the aspects of quality, safety and efficacy and it does not fall within the definition of minor variation and new registration.

Minor Variation (MiV-N & MiV-PA):

Variation to a registered pharmaceutical finished product in terms of administrative data and/or changes with minimal/no significant impact on the aspects of efficacy, quality, and safety.¹⁶

Procedure and Timeline:

Table 3: Minor Variation – Notification

Type of variation

Minor variation (Notification) MiV-N

Procedure

Notification “Do & Tell”

If the notification fulfils the requirements (conditions and supporting documents) as per described under MiV-N, product registration holder must notify NPCB. NPCB shall acknowledge receipt of a notification.

Timeline for NPCB to acknowledge the variation notification

Within 20 working days following receipt of a notification.

A MiV-N application may be rejected in specific circumstances with the consequence that the product registration holder must cease to apply the already implemented variation. Product registration holder must ensure validity of the manufacturer’s license prior to implementation of MiV-N.

Table 4: Minor Variation –Prior Approval and Major Variation

Type of variation	Minor variation(Prior approval) MiV-PA	Major variation MaV
Procedure	Prior approval If the application fulfils the requirements (conditions and supporting documents) as per described under MiV-PA, NPCB shall issue an approval for the proposed change.	Prior approval If the application fulfils the requirements (conditions and supporting documents) as per described under MaV, NPCB shall issue an approval for the proposed change.
Timeline for NPCB to evaluate the variation Application	Within 45 working days following receipt of an application	Within 60 working days following receipt of an application
Approval or correspondence	Approval or first correspondence shall be issued to product registration holder within 45 working days, provided all conditions and supporting documents are fulfilled. Subsequent correspondences which fulfil the requirements will be granted approval within 20 working days. After third correspondence, application may be rejected if still does not fulfil requirements	Approval or first correspondence shall be issued to product registration holder within 60 working days, provided all conditions and supporting documents are fulfilled. Subsequent correspondences which fulfil the requirements will be granted approval within 30 working days. After third correspondence, application may be rejected if still does not fulfil requirements
Timeline for product registration holder to reply	Within 20 working days failing which application will be rejected. Auto- reminder will be sent 10 working days before the deadline.	Within 30 working days failing which application will be rejected. Auto- reminder will be sent 15 working days before the deadline.
Implementation of the variation	Within 6 months after the product registration holder has been informed of the approved variations.

Additional notes to product registration holder prior to submission:

- NPCB reserves the right to re-categorize the application type, where deemed appropriate. Re-categorization may require the product registration holder to withdraw the original application and resubmit a new application according to the correct category.

- Variation application is submitted along with declaration letter which is undersigned by the product registration holder that declares:

l There is no other change except for the proposed variation

l The change will not adversely affect the quality, efficacy and safety of the product

l All conditions for the variation concerned are fulfilled

l The required supporting documents as specified for the variation have been submitted; and

l The proposed change has been checked in reference with the currently approved data in the system

- Submission of revised draft of package insert and labelling is subject to current regulatory requirements as per latest Drug Registration Guidance Document and Circulars from NPCB.

- NPCB reserves the right to request for additional information, when deemed necessary or reject the application when the submission is incomplete.¹⁶

CONCLUSION:

Post approval activities are important throughout the lifecycle management of a product. After approval of ANDA, a product needs to go through processes like submission of final content of labelling, electronic drug registration and listing, pharmacovigilance activities like Adverse drug event reporting, Field alert report, prior approval supplement for any changes in the approved drug product for undisturbed and smooth commercial distribution of product.

Changes are very important in pharmaceutical industry for the continuous quality improvement of the product. By the help of guidance documents and other relevant regulatory requirements the applicant should be making necessary changes to the already approved product in a country. The applicant should also consider the impact of the change on the Quality attributes of the final product and have to report the changes to the regulatory authorities in a timely manner. This will ultimately help in providing the best quality Medicines to the patient.

ACKNOWLEDGEMENT:

The authors thank JSS Academy of Higher Education and Research and JSS College of Pharmacy, Mysuru for providing the support and necessary facilities for carrying out this work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest for this work.

AUTHOR CONTRIBUTIONS:

Ms. Thaikadan Soorya Sukumaran:

Has compiled and collated information from various sources, prepared the preliminary draft of the manuscript.

Dr. M. P. Venkatesh:

Provided inputs and guided for the gathering relevant information, scientific writing of the manuscript; editing of the manuscript and the final proof reading and follow-up.

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Received on 17.05.2019 Modified on 01.07.2019

Research J. Pharm. and Tech 2020; 13(6):2585-2590.

DOI: 10.5958/0974-360X.2020.00460.6

Changes	Partial change approved application (PCA)	Minor change notification (MCN)
Reporting category	PCA · A significant impact on the Quality, Safety or Efficacy of a medicinal product. · Prior Approval Procedure.	MCN · A minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product concerned. · Notification Procedure. · 30 days.
When to notify to the agency	Must be notified to the agency and can be implemented after approving the change.	Must be notified within 30 days of implementation.
Time period for assessment by agency	1 year followed by six months GMP inspection.	30 days from starting of ‘Day 0’ if there is no query from the authority.
Fees	Not Mentioned	NA
Estimated time for approval	18 months	30 days