Comparison of EU and US variation requirements

 Key points in regulatory management of variations

• Lifecycle management of pharmaceutical products varies between the EU and US in terms of different submission requirements and assessment timelines. However, similarities do exist in regional approaches to a general categorization of post-approval changes (variations) and in many cases also the principles of implementation.

• Post-approval variations in the EU and US can be administrative in nature, simple changes requiring minor review, or major changes that are often complex.

• Administrative: EU regulators go as far as to define “administrative” as a category in their classification guideline, whereas in other regions they fall into the lowest variation category and have significant crossover with minor variations, e.g. new addresses. Many agencies accept that these changes can be implemented without the need for approval. Prior approval of administrative changes is time-consuming for agencies and costly for industry. Additionally, in certain cases such as a marketing authorization holder (MAH) moving address, the change would actually need to take place prior to submission.

• Minor: Minor variations are generally considered to have either no impact on the quality of the product or have a very low chance of impact; and hence lower risk. Consequently, the level of agency review, and hence the time required is reduced. As regulatory frameworks have developed, agencies have introduced means to allow the most minor of variations to be implemented before review. For example, in the EU, when a Type IA variation is submitted the MAH must state which of a pre-defined list of conditions applies to its change, thereby reducing the amount of review required. With minor variations, many agencies have documentation requirements that are well-established and must be met before variations are submitted. This ensures that MAHs know what is expected before a submission and can prepare sufficient supporting data. This leads to faster review times as assessors have less need to request further data from applicants.

• Major: Where notable alterations to product registration are required, these are expected to have an impact on a product’s quality and efficacy and as such are tightly controlled, requiring in-depth assessment and review. The MAH must demonstrate that the product will retain the same level of quality and efficacy. Comparative data is a significant requirement for such changes and must reliably show the proposed changes do not impair product quality. Assessment times for such variations are often much longer, as agencies carefully review submissions and frequently make requests for additional data and answers to questions and concerns.

Table 1: Summary of variations and anticipated implementation dates in Europe and US.
Europe				US
Variation	Type	Anticipated implementation time	Guideline approval timeline	Type	Anticipated implementation time	Guideline approval timeline
Admin	Type IAIN	14 days before submission	N/A	AR	Up to 1 year before submission	N/A
	Type IA	Up to 1 year before submission	N/A
Minor	Type IB	Up to 3 months after submission*	30 days	CBE-0	On receipt of submission by FDA	N/A
				CBE-30	30 days after receipt of submission	6 months
Major	Type II	Up to 6 months after submission*	30 days	PAS	Up to 6 months after submission*	4 months
*The noted anticipated dates are based on experience with submitting variations to the relevant agencies and incorporate the time taken for validation, application assessment, applicant’s response to questions (clock stop) and assessment of responses.

European (EU) Variation Requirements

What is Variation:

Variation means any amendment to the terms of the decision granting the marketing authorization as well as any change to the summary of product characteristics and the documents forming the basis for an authorization to market a medicinal product.

European Commission has classified the variation type as type IA/IAIN, type IB and type II.

Type IA/IAIN (do and tell):

Changes that fall under this category are commonly referred to as “do and tell” variations because the applicant is required to implement the change and then notify the agency of the details.

This level of variation is reserved for administrative changes that are anticipated to have no impact on the quality, safety or efficacy of a product.

Variations that can be submitted as Type IA must be implemented and then the required submission made within 12 months of the implementation date.

 For changes that are categorized as Type IAIN the applicant must notify the agency within 14 days of implementation and for a single product multiples variation can be made at the same time, as long as all of them fall within the required submission deadline.

Type IB (tell, wait and do):

Minor variations that require assessment of supporting data and are anticipated to potentially have an impact on product quality, safety or efficacy are classified as Type IB and these are also referred to as “tell, wait and do” variations.

Type IB variations are minor variations, which are neither a type IA variation, a type II variation nor an extension.

The applicant must make the submission, including all required supporting data, and await agency approval before implementing the change.

The process follows a defined assessment period of 30 days, but with agency questions it can often take up to 03 months.

Classification of Impurities as per ICH guidelines

Impurities can be classified into the following categories:

·         Organic impurities (process- and drug-related)

·         Inorganic impurities

·         Residual solvents

Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:

·         Starting materials

·         By-products

·         Intermediates

·         Degradation products

·         Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process.

They are normally known and identified and include:

·         Reagents, ligands and catalysts

·         Heavy metals or other residual metals

·         Inorganic salts

·         Other materials (e.g., filter aids, charcoal)

Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished.

Classification of Residual Solvents by Risk Assessment

Class 1 solvents: Solvents to be avoided

Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.