Post approval changes (PAC) are vital aspect of managing the development of a pharmaceutical product. During lifecycle, Products usually having various changes. In initial condition, the substance hardly remains the same. These advanced developments are being propelling by a variety of factors, including, for example, the need to strengthen and optimize the processes and efficiency, consumer needs, and regulatory requirements that are constantly changing. There are a justifying explanations for making changes to products after they have obtained regulatory approval. This change must be closely monitored and must adhere to the jurisdiction's regulatory path. The current study examines post- approval changes in Europe & regulations, rules, and procedures for submitting post-approval changes. The company’s change management determines how modifications are measured, implemented and enforced in depth & how the change impact the continuity. Different type documentations required for monitoring the regulatory updated guidelines, and the level of regulatory monitoring required would be determined by the type of change. The regulatory framework for PAC, also known as variation filing in Europe, has been specifically established by the EMA guidelines for both pharmaceutical products and biologics.

PAC           :             Post approval changes

EMA          :             European medical agency

API           :            Active Pharmaceutical Ingredient

EU             :             European Union

FP              :            Finished Product

MAH          :            Marketing authorization holder

SmPC        :            Summary of Product Characteristics

PIL             :            Package Information Leaflet

CTD            :            Common Technical document

TSE             :            Transmissible Spongiform Encephalopathy

CEP             :           Certificate of Suitability to the European Pharmacopoeia

ATC code   :           Anatomical Therapeutic Chemical code

GMP           :           Good manufacturing practices

ASMF         :           Active Substance Master File

PMF            :           Plasma Master File

VAMF          :           Vaccine Antigen Master File

Variation as per European Commission:

According to EU, Variation in terms of a marketing authorization is an amendment to the contents of the dossier and documents to the applications submitted as per Articles 8(3), 9, 10, 10a, 10b, 10c and 11 of regulation (EC) No 1901/2006 of the European parliament in the case of finished drug products especially for human use .

Minimum Requirements for implementing the change as per EU:

• Each variation must be submitted separately; grouping of variants is permitted only where the variations are interconnected.
• Pre-Notification is required.
• A common application form for filing all the variations named as ''Application for variation to the Marketing Authorization" should be utilized.
• Applicant has to provide the details of proposed change, declaration for the variation types proposed, documents containing the details of the studies that are proposed or ongoing non- clinical studies and clinical studies.
• Variation classification is dependent on the risk level to human or health of the animal, as well as the effect on pharmaceutical product's quality, safety and efficacy.

Categorization of changes as per EU:

EMAhascategorizedthechangesintoconcerneddepartmentwiseasmentionedintheflowcharts-

Categorization of Changes as per EU

Reporting strategies as per EU in the below flow charts:

Type-ivariation:

ItisaminorchangeanditisoftwotypesnamelyType-IAandType-1Bvariation.

1.Type IA Variations:

consists of minor variations that have least or no effect on the pharmaceutical products quality or safety or efficacy, do not necessarily have to provide the approval in advance before implementation. procedure)

Thesearedividedintotwosubcategoriesbasedontheimpactontheirsubmission.

i.Variation that requires immediate notification (IAIN) Examples include:

Changes of the title or name of the as well as finished product's manufacturer/importer.

Change in imprints, bossing or others hapes and dimensions of the pharmaceutical dosage form.

ii.Variation that do NOT require immediate notification (IA) Examples include:

Inclusion of physicochemical test in specification Omission of non-significant test

Tightening of specification limits Updates to the CEP

ThebatchsizeofAPIandFPincreasesorreducesby10fold

2.Type IB Variations:

A minor change that is not a Type IA change, a Type II change, or an extension. Prior to the implementation, MAH must notify EMA (Tell, Wait and Do Procedure)

Examples include:

Therehasbeenasignificantimprovementintheacceptedandanalyticalprocess

• Significant change in acceptable and analytical method FP manufacturing site variations
• Extension of shelf life Storage condition changes
• Negligible modifications to the manufacturing methods that are accepted
• Altrations related to the finished product batch size having more than 10fold category Changes of SmPC/PIL with innovator product approved by FDA.

Type iivariations:

Changes that have the potential impact to the quality, safety or efficacy of a product. This variation necessitates the addition of an addendum, updated summaries, or a new submission of the above- mentioned changes.

Examples include:

• Inclusion of alternative/new API DMF supplier. Easing of approved specification.
• Significant changes to the manufacturing process that are of accepted composition.

Line Extension Application:

It is a major change for which requires the full assessment of the application. This takes place onlywhen there is any modification(s) to be performed for the following aspects of drug product.

Changes to the API:

The existing chemical active substance is replaced with different salt/ester complex having similar therapeutic moiety, with no noticeable change in efficacy/safety characteristics. Modifications to the strength, pharmaceutical type, and administration route:

Timelines for Variation:

• The Aim is to compare the Pharmaceutical and biologics requirements and challenges faced during filing post approval changes.
• Also, to provide an overview of CTD requirements for submitting a PAC of both Pharmaceutical products andbiologics.
• To review and compare the post submission process within EU countries with respect to type of variation.

In this cosmic symphony of discussion and interpretation, the implications of our analysis emerge not as mere footnotes but as cosmic revelations, beckoningstakeholders to partake in a collective cosmic dance. As we traversethe celestial expanse of pharmaceutical exploration, these implications serve as guiding stars, illuminating the path toward a future where stakeholders, equipped with cosmic insights, collaboratively sculpt a regulatory cosmos that harmonizeswith the aspirations of industry,the needs of patients, and the transformative potential of technology.

The study focuses on the differences between pharmaceutical products and biologics when it comes to filing for variations, vaccines has a different approach of categorizing the type of variation.

When filing out a variation application for vaccines, filing procedure of variation type plays a crucial part. Since filing a variation for pharmaceutical products will refer to and apply a variation as per the EMA variation guidance, while filing a variation for vaccine requires obtaining confirmation from EU authorities.

The confirmation process from the agency is the most difficult phase for the company and any error in the explanation of the change will result in the variation getting rejected.

Any delay in receiving a response from the agency or submitting a variation to the agency will result in the variation rejected, and the organization will have to file a new application which will be a financial loss.

To stop variation rejection, the company should be transparent and specific when filing out the type of variation and classifying it, and there should be a follow-up from the agency about confirmation.

With ever-evolving EU guidelines, expect that progress will keep on with to made toward establishing separate well-established and stringent guidelines for both pharmaceutical products and biologics in terms of filing post-approval changes with respect to changes / type of variation, which will aid in the filing process for each variation category.