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The examples describe the relevant reporting categories for changes to the ranges of the manufacturing process parameters, controls or equipment referenced in the tables

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ICH HARMONISED ANNEX

TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL PRODUCT LIFECYCLE

MANAGEMENT

ICH Q12 指引之意見彙整表

段落 標題 內文 相關建議及意見

(請提供中英文內容) p. 1-8

ANNEX I: ECS – ILLUSTRATIVE

EXAMPLES

Identification of Established Conditions for the Manufacturing Process

The examples provided below are intended for illustrative purposes and only suggest how the EC concept could be applied using the development approaches described in ICH Q12 Guideline Chapter 3.2.3.1.

The examples describe the relevant reporting categories for changes to the ranges of the manufacturing process parameters, controls or equipment referenced in the tables.

This demonstrates that increased knowledge and understanding (e.g., enhanced development approaches) leads to reduction of uncertainty and improved management of risk. As a result, ECs could become less

extensive and reporting categories more flexible.

For example,

- Enhanced knowledge may lead to a reduction in uncertainty demonstrating that an initially determined CPP does not have a direct impact on a CQA. Therefore, it could be classified as either a KPP (impact on process consistency) or a process parameter (PP).

- Risk management activities could lead to downgraded reporting

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categories e.g., change to CPP could be downgraded from prior approval to notification.

- Where the performance based approach is used, some process parameters may not be classified as ECs due to assurance of quality being provided by online monitoring. In this circumstance the typical operating conditions for process parameters is provided as supportive information. During manufacture, the process

parameters may be adjusted to deliver the expected outcome. The risks related to the inline PAT (Process Analytical Technology) tests, e.g., NIR, should be appropriately managed throughout the

lifecycle. The inline PAT tests are considered ECs.

For the parameter based approach where there is limited process understanding, if specific ECs were not proposed by the MAH then regional regulations would be followed for managing post-approval changes. This is illustrated in the examples for comparative purposes.

A holistic view of the manufacturing process and overall control strategy is necessary when considering ECs as the output of one-unit operation is the input for a subsequent operation.

Change Reporting Categories:

Prior Approval (PA) – PAS, Type II, PCA, etc.

Notification Moderate (NM) – CBE 30, Type IB, MCN, etc.

Notification Low (NL) –AR, Type IA, MCN etc.

Not Reported (NR)

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Annex I A: Chemical Product Process Flow

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Annex I B: Biological Product

EXAMPLE FOR BIOLOGICAL PRODUCT

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p. 9-14

ANNEX II: PACMP- ILLUSTRATIVE

EXAMPLES

The examples provided below are intended to illustrate the range of PACMPs that are possible for a given type of change. They are not intended to serve as a binding template and other approaches may also be acceptable. The first example below outlines a protocol for a single change (a manufacturing site change) to a single product. The second example outlines a protocol for multiple changes (multiple manufacturing site changes) that could be implemented for multiple products. These examples are not intended to suggest that the only type of change appropriate for inclusion in a PACMP is a manufacturing site change. As described in ICH Q12 Guideline Chapter 4, in order to meet expectations regarding continuous improvement of the product and process, many other quality-related changes may be suitable for inclusion in a PACMP.

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Annex II A: PACMP Example 1

Alternative manufacturing site for a small molecule drug substance Outline for Step 1 Submission

1. Introduction and Scope

This PACMP is intended to allow for the addition of an alternative manufacturing site for the manufacture, testing, and release of the drug substance for a small molecule solid oral drug product.

Based on the risk management activities described below, the

implementation of this change in Step 2 is proposed to be reported in a submission type that is a lower category than currently provided for in existing regulations or guidance, or a submission type eligible for accelerated review timelines, depending on regional requirements.

2. Quality Risk Management (QRM) Activities

QRM is conducted for the proposed alternative site and includes:

 Identification and assessment of the potential risks associated with the proposed change, as well as the activities proposed to mitigate each risk;

 Accounting for known elements of the process, such as

robustness, existing controls, and potential impact on product quality; and

 Incorporating prior knowledge gained from development and commercial manufacturing experience.

3. Acceptance criteria

Based on the risk assessment, the following acceptance criteria should be

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met:

 In a comparative batch analysis, three consecutive batches of drug substance manufactured at the alternative manufacturing site should meet approved specification to demonstrate equivalence to batches manufactured at the currently approved site

Other conditions to be met prior to implementation:

 Stability studies will be initiated immediately on a suitable number of commercial scale batches of drug substance manufactured at the alternate manufacturing site and drug product manufactured with drug substance produced at the alternate manufacturing site.

Stability data are to be reported to the regulatory authority

subsequent to implementation of the new site according to regional requirements.

 Alternative manufacturing site to have acceptable compliance status for small molecule drug substance manufacturing; depending on the region, this may be indicated by the last GMP inspection with

acceptable outcome, through a valid GMP certificate, or other appropriate documentation (e.g., Qualified Person declaration)

 Alternative manufacturing site to use similar manufacturing equipment or equipment with the same type of material of construction

 Technology transfer and process qualification to be completed

 No change to synthetic route, control strategy, impurity profile, or physicochemical properties

 No change to any specification or analytical method for starting material or intermediates

 No change in analytical methods or specification for release and

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stability testing for drug substance manufactured at the alternative site

 Any additional regional requirements.

Summary of Step 1 and Step 2 Submissions

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Annex II B: PACMP Example 2

Manufacturing Site Transfers of Biotech Drug Substances Proposed Outline for Step 1 Submission

1. Introduction and Scope

The primary objective of this expanded PACMP is to support the mobility across biologic drug substance manufacturing sites, i.e., the transfer of one or multiple products from one donor site to one or more recipient site(s) including CMOs (sites already licensed with appropriate inspection record) thereby reducing the number of regulatory submissions of similar content and driving consistency. The expanded PACMP effectively

leverages concepts of Quality Risk Management and ICH Q9. Typical process adaptations linked to scale and equipment differences at the donor and recipient site(s) are in scope of the protocol (e.g., change in raw material sourcing) whereas the scope excludes opportunistic significant process changes (e.g., changes to increase productivity/yield).

2. Quality Risk Management (QRM)

QRM is performed for each individual site transfer, and includes:

 Identification, scoring, and documentation of the potential hazard and harm associated with each manufacturing unit operation and process change, as well as the prevention and detection controls

 Accounting for known elements of the process, such as

robustness, existing controls, and potential impact on product quality

3. Comparability/ Acceptance Criteria

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The overall comparability plan in line with ICH Q5E comprises the following elements:

 The drug substance meets all release and in-process

specifications, as well as comparability acceptance criteria (e.g., tolerance intervals [TI, 95/99]) derived from the entire

manufacturing history

 Analytical profiles from selected characterization tests of

post-change material are consistent with pre-change material in side-by-side comparison

 Process performance attributes, e.g., cell culture performance, purification process yields, and impurities levels are comparable between donor and recipient site

 Planned process validation at the recipient site

 Drug Substance degradation studies consistent with pre-change material

4. Site specific Considerations a) Site Risk

A risk assessment for the receiving site will be conducted by the MAH at the time of implementation. The risk assessment includes the GMP compliance status and should also include factors such as facility

experience, process knowledge, and any additional regional assessments such as QP declaration. The outcome of the risk assessment will indicate

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to the MAH whether a site inspection by the competent regulatory authority may be needed and whether additional data to support the change should be generated (e.g., site-specific stability data).

b) Process Validation

An overview of the process validation project plan and validation master plan for the site transfer in accordance to the current PQS system should be provided (at step 1). A summary of validation studies performed to support the site transfers, e.g., studies adopted from donor site and new studies at the recipient site are part of the step 2 implementation

submission.

The number of proposed validation batches should be based on the variability of the process, the complexity of the process/product, process knowledge gained during development, supportive data at commercial scale during the technology transfer and the overall experience of the MAH.

c) Stability

Stability studies are traditionally rate-limiting to site transfer timelines;

following successful demonstration of comparability by analytical characterization methods, including accelerated and/ or stress stability studies (see ICH Q12 Guideline Chapter 8.2.) can leverage tiered regulatory submission reporting categories and commitments.

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Summary Expanded PACMP Step 1 submission and proposed outline for Step 2 submission

p. 15-18

ANNEX III:

PRODUCT LIFECYCLE MANAGEMENT

DOCUMENT - ILLUSTRATIVE

EXAMPLE

Example for a Solid Dosage Form Tablet X (small molecule)

The following example for drug product illustrates how MAH can present the elements of ICH Q12 Chapter 5 in the PLCM document. Other

approaches and formats can be used as appropriate.

Figure 1 presents the current Flow Diagram the drug product

Manufacturing Process for Tablet X. For purposes of this example, the flow diagram is limited to the dry blending and roller compaction operations

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within the manufacturing process using an enhanced approach. The table elaborates the details of the specific established conditions for these operations, the change reporting categories, and associated PACMPs and commitments.

Note: This example is not intended to describe the EC identification process.

Summary of Product Control Strategy

Tablet X is an immediate release, film coated tablet containing 100 mg of API Y, manufactured via a standard batch manufacturing process.

Description of Manufacturing Process and Process Controls is typically described in section P.3.3 of Module 3.

The drug product has been developed following an enhanced development approach, using the science- and risk-based principles described in ICH Q8(R2), Q9, and Q10.

Figure 1 Partial Flow Diagram of the Manufacturing Process for Tablet X

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數據

Figure 1 presents the current Flow Diagram the drug product
Figure 1 Partial Flow Diagram of the Manufacturing Process for Tablet X

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