筆記目錄
一、前言
希望本筆記可幫助在歐盟販賣醫療器材的廠商去了解，過渡期間的上市後 (Be placed on the market or put into service) 的設計變更 (aka 工程變更)，是否會影響歐盟的銷售許可。
| 本筆記適用於「已取得 90/385/EEC (AIMDD) 或 93/42/EEC (MDD)」 的產品 (MDD/AIMDD compliant devices)。 本筆記不適用於「已取得 MDR 上市許可」產品的上市後變更評估。 |
另外，若想了解上市後變更對美國 510(k)、台灣查驗登記的影響，可參考〈上市後醫材的設計 (工程) 變更多大會影響到許可證？ 關於美國 FDA、台灣食藥署 TFDA 的規定，本篇文章整理給你！〉
二、背景介紹
在 MDR (2017/745) 四年寬限期 (2020/05/26 ~ 2024/05/26) 間，廠商仍然可以拿著遵循 AIMDD (90/385/EEC) 或 MDD (93/42/EEC) 上市的產品 (MDD/AIMDD compliant devices)，在歐盟合法販售 (有人稱此類產品為 Legacy devices)，但須遵循下面規定：
By way of derogation…a device with a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC…may only be placed on the market … provided there are no significant changes in the design and intended purpose…
MDR 2017/745 | Article 120 Transitional provisions, Paragraph 3
總的來說，若要在四年寬限期間持續販 Legacy devices，
- 須確保「設計 (Design)」或「預期用途 (Intended purpose)」沒有重大變更 (Non-Significant change)；
- 若有重大變更，則現有的 (AI)MDD，就算在四年寬限期內，也不可依照 MDR Article (3) 繼續販賣相關產品。
但什麼是「重大」變更呢？
〈MDCG 2020-3〉就是為了使廠商、主管機關 (Competent authority, CA) 及第三方驗證機構 (Notified body, NB) 針對「重大變更」有一致的評估標準而誕生的，此指引也是本筆記的主角。
三、權責區分
廠商的責任
廠商必須
- 於品質系統中建立評估、通報變更的程序 (It is expected that manufacturers adjust their change notification procedures)；
- (不確定、或認為有可能是重大變更時) 提交變更內容的文件給 NB 審查；
- 留存 NB 發出的 Non-significant change 證明 (編碼，並與相關 MDD/AIMDD 證書放在一起)；
- 提供變更確實沒有重大影響設計或預期用途的證據 (Providing evidence that all the above-mentioned changes do indeed neither affect the design nor the intended purpose)。
依照上面第 2、3 點要求，難道所有大大小小變更都要給 NB 評估是否為重大變更？
我認為，不用，只須提供廠商判定為重大變更、或懷疑可能是重大變更的內容給 NB。因為：
[原因一]
雖然〈NBOG’s Best Practice Guide 2014-3〉規定，「變更的實施時機要依 NB 審查結束的時間而定」，但下一步規定「提交任何關於重大變更的資訊給 NB」。以下節錄相關原文：
Step 5. Determination whether the change is substantial or not
Step 6. Decision to implement the change taken and the timing of implementation (dependent on Notified Body review)
Step 7. Information given to the Notified Body about any substantial change
Step 8. Final implementation of the change.
[原因二]
另外，〈NBOG’s Best Practice Guide 2014-3〉也規定「廠商須盡速通知 NB 任何預計進行重大變更」：
The manufacturer shall inform the Notified Body of the planned substantial changes as soon as possible without delay.
[原因三]
並且，在顧問公司 Decomplix 的〈Guidance on medical device significant changes〉一文中說明，NB 會在「稽核」或「收到廠商的變更通知」時，確認是否會為重大變更 (Verified by the Notified Body at audits or upon change notification submissions)。
綜合上面三個原因，我認為，廠商應該只有在下述兩情況須通知 NB：
- 廠內自行評估是重大變更，及
- 不確定是否為重大變更時。
Notified body (NB) 的責任
依照 MDR ANNEX VII 以下描述，NB 須確保已取得 CE 認證產品的品質系統、設計、宣稱的預期用途 (Intended use of or claims made for the device) 在變更後仍符合要求：
The notified body in question shall:
1. ensure that manufacturers submit for prior approval plans for changes as referred to in the first paragraph and relevant information relating to such changes,
2. assess the changes proposed and verify whether, after these changes, the quality management system, or the design of a device or type of a device, still meets the requirements of this Regulation, and
3. notify the manufacturer of its decision and provide a report or as applicable a supplementary report, which shall contain the justified conclusions of its assessment.
MDR 2017/745 | ANNEX VII REQUIREMENTS TO BE MET BY NOTIFIED BODIES
The notified body that issued the AIMDD or MDD certificate may confirm in writing (after having reviewed manufacturer’s description of the (proposed) change) that the implementation of the change does not represent a significant change in design or intended purpose under MDR Article 120(3) and that the related AIMDD or MDD certificate remains valid.
MDCG 2020-3 | Section 4 Assessment of changes’ significance in accordance with MDR Article 120(3)
四、哪些變更可能是 Significant change？哪些不是？
Significant change
如同 FDA〈Design Control Guidance For Medical Device Manufacturers〉，在歐盟〈MDCG 2020-3〉中，歐盟也提供了一個主表、五個次表供廠商與 NB 評估變更程度。
主表
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| M1 | Change of the Intended Purpose? | Go to 表 A | Go to M2 |
| M2 | Design change related to corrective actions, and has been assessed and accepted by the relevant competent authority? | Non-significant change | Go to M3 |
| M3 | Change of the design or performance specification? | Go to 表 B | Go to M4 |
| M4 | Software change? | Go to 表 C | Go to M5 |
| M5 | Change of a Material? | Go to 表 D | Go to M6 |
| M6 | Change of terminal sterilization method of device or packaging design with impact to the sterilization? | Go to 表 E | Non-significant change |
| 為何針對 Corrective actions 的變更 (M2) 可判定為 Non-significant change 呢？ 依照 CAMD FAQ no 17 規定，下面兩項變更不屬於 Significant change： 1. Limitations of the intended purpose. 2. Design changes related to corrective actions assessed and accepted by the Competent Authority (CA). 其中第二項針對 Corrective actions 執行的變更，因為已經被 CA 評估且接受了 (Assessed and accepted)，代表對安全與功效沒有負面影響，可特例讓廠商於寬限期變更。因此， 1. 這邊說的「Corrective actions」不是廠內 CAPA，而是針對嚴重不良事故發起的 Field Safety Corrective Action (FSCA) 的矯正措施。 2. 我微調指引原本的 M2，加上「須被 CA 評估且接受」的但書。 |
表 A – Change of the Intended Purpose
須評估變更 Labeling (例如，Contraindications 或 Warnings) 對預期用途的影響。
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| A1 | Limitation of the Intended Purpose? | Go to M2 | Go to A2 |
| A2 | Extension or change of the Intended Purpose? | The change is considered significant | Go to A3 |
| A3 | New user or patient population? | The change is considered significant | Go to A4 |
| A4 | Change of clinical use? (例如，變更應用的身體部位 (Anatomical sites)、進入位置 (Access site)、或實施方式 (Deployment methods)。) | The change is considered significant | Go to M2 |
表 B – Change of the Design or Performance Specification
| 任何種類的變更 (軟體、硬體…) 都可能造成下面 B1 ~ B3 的影響。 |
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| B1 | Does the change require further clinical or usability data to support safety and performance? | The change is considered significant | Go to B2 |
| B2 | Do new risks require control measures or are existing risks negatively affected? | The change is considered significant | o to B3 |
| B3 | Change of built-in control mechanism, operating principles, source of energy, or alarms? | The change is considered significant | Go to M4 |
表 C – Software Change
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| C1 | New or major change of operating system or any component? | The change is considered significant | Go to C2 |
| C2 | New or modified architecture or database structure, change of an algorithm? | The change is considered significant | Go to C3 |
| C3 | Required user input replaced by closed-loop algorithm? | The change is considered significant | Go to C4 |
| C4 | New diagnostic or therapeutic feature, or new channel of inter-operability? | The change is considered significant | Go to C5 |
| C5 | New user interface or presentation of data? | The change is considered significant | Go to C6 |
| C6 | Minor Change? | Go to M5 | The change is considered significant |
| C5 提到的「New presentation of data」是什麼呢？ 〈MDCG 2020-3〉在文中解釋：「It is connected to medical data which are presented in a new format or by a new dimension or measuring unit.」 |
| 什麼是 C6 的「Minor Change」？ 此類變更不可影響診斷 (Diagnosis) 或治療 (Treatment)，〈MDCG 2020-3〉舉例如下： 1) Correction of an error which does not pose a safety risk (bug fixes), 第一項變更和 FDA Guidance 中下述類型的變更類似，因此都屬於 Minor change 也不意外：「Is the change made solely to return the system into specification of the most recently cleared device and does not have any other impact on the software or device?」 2) Security update (e.g., cyber-security enhancements, longevity calculations), 和下面的 FDA Guidance 變更類型一樣都屬於 Minor change：「Is the change made solely to strengthen cybersecurity and does not have any other impact on the software or device?」 3) Appearance of the user interface, operating efficiencies, 4) Changes to enhance the user interface without changes in performance. 關於 FDA 的變更評估，可參考〈上市後醫材的設計 (工程) 變更多大會影響到許可證？〉。 |
| C5 和 C6 的第 3、4 項是不是有「既生瑜，何生亮」的關係呀？ 當評估到 C5 時，任何「User interface」都會被判定為「Yes，重大變更」。畢竟，C5 只問「有無新使用者介面」，若有，就直接判定為重大變更。如此一來，不可能走到 C6，再依循 C6 第 3、4 項判定為非重大變更呀。 |
| 對 MDCG 很嗆的顧問公司 Johner Institute 在〈Design Changes: Examples and Requirements〉第四部份有詳列出他們覺得軟體變更要 / 不要通報的例子，可搭配表 C 一起評估。以下摘錄部份重點： 關於 C2 的「Change of an algorithm」須通報時機 The developers change a central algorithm, e.g., algorithms for calculating medicine doses, for radiation treatment planning, or for image processing 關於 C5 的「New user interface」須通報時機 You change the user-device interface (except for insubstantial changes such as the correction of spelling mistakes). This particularly applies if you (1) add, change or remove warning messages (2) add new safety-related use scenarios and (3) change critical UI elements (formerly main operating functions). |
表 D – Change of a Material
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| D1 | Change to the material of human/animal origin including addition of new materials? | The change is considered significant | Go to D2 |
| D2 | Change to a material containing a MS (Medicinal Substance) or to the MS itself or, a change which may impact the quality, safety, or efficacy of a MS? | The change is considered significant | Go to D3 |
| D3 | Changed ingredient or material from existing supplier meets existing specification? | Go to M6 | Go to D4 |
| D4 | Ingredient or material from new supplier meets existing specification? | Go to 表B | The change is considered significant |
表 E – Change of terminal sterilization method of device or packaging design with impact to the sterilization
| 編號 | 評估項目 | Yes | No |
|---|---|---|---|
| E1 | Change of terminal sterilization method? (Non-sterile 改成 Sterile 或變更滅菌方式，均屬此類變更。但若在品質系統管制下變更循環參數 (Cycle parameters) 即不屬於 Significant change.) | The change is considered significant | Go to E2 |
| E2 | Design Change which affects or changes the sterility assurance? (不同的滅菌方式參考個別的指引，以正確評估變更對製程的影響：EN ISO 11135 (Ethylene Oxide), EN ISO 11137-1 ( Radiation), EN ISO 17665-1 (Moist Heat), EN ISO 13408-1 (Aseptic Process)) | The change is considered significant | Go to E3 |
| E3 | Change in a packaging design which affects functionality, safety, stability, or seal integrity? | The change is considered significant | Go to E4 |
| E4 | Shelf-life change validated by protocols approved by the notified body? (增加 Shelf-life 通常視為 Non-significant change，但要完成真實老化試驗，且結果被 NB 確認無誤才行。) | Non-significant change | The change is considered significant |
Significant change 範例
在 Oriel STAT A MATRIX 的網站中，提供以下二則重大變更的範例：
Example 1. Changing the floorplan of a manufacturing facility, especially for processes considered “special” or critical to the product. This could be considered a significant change, and it may require that the change be implemented in compliance with the regulations.
Example 2. A manufacturer consolidates or centralizes a key system of their QMS (e.g., design control) across multiple sites.
Non-Significant change
只要變更不會影響到「設計 (Design)」或「預期用途 (Intended purpose)」，通常就不會被判定為 Significant change。〈MDCG 2020-3〉舉例下列行政變更 (Administrative change) 通常是 Non-Significant change：
- 廠商名稱 (Manufacturer’s name)
- 法人型態(Legal form，例如從 GmbH 換成 GmbH & Co. KG)
- 地址 (Manufacturer’s address)
- 歐體代表 (Authorised representative)
- 承包商 (Subcontractors) 或供應商 (Suppliers)
節錄〈MDCG 2020-3〉相關描述如下：
For instance, administrative changes of organisations are considered in principle as non-significant. This includes changes of the manufacturer’s name, address or legal form (legal entity remains) or changes of the authorised representative.
Furthermore, all changes not having an impact on the design or the intended purpose of the device can be regarded as not significant in the meaning of MDR Article 120(3). This is the case for example of relocation or addition of new manufacturing sites, including when it affects subcontractors or suppliers, or of certain changes of the quality management system, provided that the conditions for which the conformity assessment certification was granted are maintained.
但是！上面的說法只是「一般來說」。
或者問說，只要透過上面六個流程判定為 Non-Significant change，就一定不是 Significant change 嗎？
好像也不是這樣，因為六個流程中沒有評估到某些情境變更 (例如，六個流程中，難道只有滅菌製程的變更須要評估？)。舉例來說，SIDLEY 引用 2017 年 6 月 IAF 所發行的文件 (IAF MD 9:2017) 中就提到下列的變更，雖不是「設計」或「預期用途」的變更 (而是品質系統變更)，仍可能會被 NB 判定為 Significant change：
- New ownership: 「A change in legal manufacturer (to a different legal entity) would not be considered an administrative change.」Decomplix 如是說。
- Extension to manufacturing and/or design control
- New facility, site change: Modification of the site operation involved in the manufacturing activity (e.g. relocation of the manufacturing operation to a new site or centralizing the design and/or development functions for several manufacturing sites)
| 但〈MDCG 2020-3〉把「Relocation or addition of new manufacturing sites」歸類為 Non-significant change。 |
- New processes, process changes: Significant modifications to special processes (e.g. change in production from sterilization through a supplier to an on-site facility or a change in the method of sterilization)
- QM management, personnel: Modifications to the defined authority of the management representative that impact i) quality management system effectiveness or regulatory compliance or ii) the capability and authority to assure that only safe and effective medical devices are released
- Post-market surveillance, vigilance
