International Journal of Drug Development and Research

Keywords

Post Approval Changes, Non-Compliance, ICH

INTRODUCTION:

Change is defined as “A change to any aspect of a pharmaceutical product, including but not limited to a change to formulation, method and site of manufacture, specifications for the finished product and ingredients, container and container labeling and product information”.[1] Changes to approved products should be evaluated to assess their impact on product quality, safety and efficacy/effectiveness. These changes should be documented properly. Depending on the degree of impact, some changes may simply need the company to document the change being evaluated. Different mechanisms exist in different jurisdictions for reporting these changes and these can vary from an annual report to an amendment/variation application to a new license application. Manufacturers should consult the guidance documents specific to the jurisdiction in order to follow the proper compliance procedures.

Post Approval Change Management:

A post-approval change management describes specific changes that a company would like to implement during the lifecycle of the product and how these would be prepared and verified. Such a stepwise approach is expected to lead to faster and more predictable implementation of changes post-approval, since the Marketing Authorization Holder will have obtained agreement from the Regulatory Authorities about the proposed strategy and tests to verify the effect of the change on product quality [2].

In US, EU, Saudi Arabia, Singapore and India Post approval changes are designated as:

US Scale Up and Post Approval Changes EU Variations Saudi Arabia Variations Singapore Variations India Post Approval Changes

Grading the Changes:[3]

According to the area of consideration (e.g. approval conformity or validation status), it may be necessary to use different change procedures as a base. This is the way many companies deal with changes to printed packaging material (information for use, folding cartons, and labels) in accordance with a special change control procedure, because these changes occur relatively frequently in practice and the process sequences can be standardized easily. In these cases, the sequences and the criteria used are not independent, but are carefully matched to suit and coordinate with each other.

MATERIAL AND METHODS:

Regulatory guidelines are the backbone of the present study; the complete study is based on the guidelines and/or regulations which are published by Regulatory Agencies of each country.

Pharmaceutical Regulatory Agencies: Regulatory authority and organizations are responsible in operational drug regulation essential to ensure the safety, efficacy and quality of drug products and/or substances. Regulatory bodies provide strategic and operational direction and support for working within regulations to expedite the development and delivery of safe and effective healthcare products to individuals around the world.

Guidance documents for Post Approval Changes in US, EU, India, Saudi Arabia and Saudi:

DISCUSSION:

Post Approval Changes – European Union[5]: Types of Variation:

Type IA Variations:

Do not require immediate notification. May be submitted by the marketing authorization holder (MAH) within 12 months after implementation, or may be submitted earlier should this facilitate dossier life-cycle maintenance. The 12 months deadline to notify minor variations of Type IA allows for an ‘annual reporting’ for these variations

Type IAIN Variations: Type IAIN variations must be notified (submitted) immediately to the National Competent Authorities/European Medicines Agency (‘the Agency’) following implementation

Type IB Variations: Variation which is neither a Type IA variation nor a Type II variation nor an Extension; such minor variations must be notified to the National Competent Authority/European Medicines Agency (‘the Agency’) by the Marketing Authorization Holder (MAH) before implementation. MAH must wait a period of 30 days to ensure that the notification is deemed acceptable by the National Competent Authority/the Agency before implementing the change

Type II Variations: Any change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation.

Type II Extension: Change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation.

Changes requiring an extension application

Changes to the active substance(s)

Changes to strength, pharmaceutical form and route of administration

Post Approval Changes – US[4]

In US post approval changes are designated as Scale Up and Post Approval Changes, the changes are categorized into three level:

Post Approval Changes – Saudi Arabia [7]

Minor Variations:

Type IA: Minor Changes that does not require prior approval before implementation but require notification submitted by the MAH within 60days after implementation.

Type IB: Minor variations that must be notified to the SFDA by the MAH before implementation, but do not require formal approval; however MAH must wait for period of 120 days to ensure that the application is denied acceptable by the SFDA before implementing the change.

Major Variations:

Type II:Major variations in which there might be a significant impact on the Quality, Safety or Efficacy of a medicinal product and require prior approval before implementation;

Variation Review Process:

1. Validation

2. Product Licensing

3. Assessment

4. Testing

5. Inspection

6. Pricing

7. Variation Approval

8. Appeal Process

Timelines for Approval of Variation Application As per SFDA guidelines:

Post Approval Changes – Singapore [8]q

Major Variations (MAV):

MAV – 1: Any variation to the approved indication(s), dosing regimen(s), patient group(s), and/or inclusion of clinical information extending the usage of the product (e.g. clinical trial information related to an unapproved indication, dosing regimen and/or patient population; recommendation for concomitant administration of vaccines; additional bacterial strains to expand the indication(s) for antimicrobial products).

MAV – 2: A change in current approved forensic classification, also known as reclassification

Minor Variations (MIV):

MIV-1: A minor variation, which requires regulatory approval. MIV-2: A minor variation or an administrative change.

Timelines:

Post Approval Changes: India[6]

Classification of Changes:

Level I: Changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a biological product as these factors may relate to the safety or effectiveness of the product. Level II: Changes that have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the biological product as these factors may relate to the safety or effectiveness of the product.

Level III: Changes that have minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the biological product as these factors may relate to the safety or effectiveness of the product;

Timelines:

With an ever evolving industry such as the pharmaceutical industry, we can hope that advances will always be made, technology improved but this process will also probably result in an ever changing set of marketing authorization applications and legal guidelines.The present study provides a detailed analysis of the current EU, US, India, Saudi Arabia and Singapore regulations and/or guidelines for post approval application submission and approval process in both GMP.

European Medical Agency provides detailed guidance for submission of application including established timelines where as in US FDA has limited guidance for the process of submissionand related aspects. Saudi Arabia classification of variation is quite similar to EU but there minor changes in terms of classification and timelines

for approval of application, Saudi Arabia have various levels of parallel evaluation procedures which include pricing, Inspection, Assessment, Testing and Product Licensing. HSA process of submission of all type of variation is relatively similar, only modifications in the format of the application and evaluation timelines. Indian guidelines are not much established, it’s restricted only to biologics, only timelines have been clearly published and process is not clearly defined.

Tables at a glance

Table 1 Table 2 Table 3 Table 4 Table 5 Table 6

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12

References

1. 1) Comment DFOR. WHO General Guidance On Variations To Multisource Pharmaceutical Products Development of draft based on WHO Expert Committee. 2014;(April):1–24. Available from: https://www.who.int/medicines/areas/quality_saf ety/quality_assurance/VariationsMultisourcePhar maceuticalProducts_QAS14-575_24022014.pdf accessed on 12th December 2014
2. 2) Wharf C, Kingdom U. Questions and answers on post approval change management protocols Use of Post Approval Change Management Protocols. 2012;44(October):1–6. Available from: https://www.ema.europa.eu/docs/en_GB/docu ment_library/Scientific_guideline/2012/04/WC50 0125400.pdf accessed on 14th December 2014
3. 3) Implementation C. Pharma Change Control. Available from: https://www.fdanews.com/ext/resources/files/Th e_Food_And_Drug_Letter/2013/Pharma- Change-Control-Peither-ExecSeries.pdf accessed on 12th December 2014
4. 4) Services H. Guidance for Industry Changes to an Approved NDA or ANDA Guidance for Industry Changes to an Approved. 2004;(April). Available from: https://www.fda.gov/downloads/Drugs/Guidanc eComplianceRegulatoryInformation/Guidances /UCM077097.pdf accessed on 13th December 2014
5. 5) Protection PH. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure. 2014;2(June). Available from: https://www.ema.europa.eu/docs/en_GB/docu ment_library/Regulatory_and_procedural_guideline/2009/10/WC500003981.pdf accessed on 20th December 2014
6. 6) Safety E, Documents E. Guidance for Industry Submission of Clinical Trial. Available from: https://www.cdsco.nic.in/writereaddata/CDSCO -GuidanceForIndustry.pdf accessed on 21st December 2014
7. 7) Regulatory Framework for Drug Approvals. 2014; Available from: https://www.sfda.gov.sa/en/drug/drug_reg/Reg ulations/Regulatory_Framework_for_Drug_Appro vals_v_5 0.pdf accessed on 12th December 2014
8. 8) GUIDANCE ON MEDICINAL PRODUCT. 2011;(April). Available from: https://www.hsa.gov.sg/publish/etc/medialib/hs a_library/health_products_regulation/western_medicines/files_guidelines.Par.22361.File.dat/Guidance on Medicinal Product Registration in Singapore 2011 (COMPLETE).pdf accessed on 18th December 2014