25.03.2026
What are the GMP Requirements for Biotechnological Products?
[中譯] 生物技術產品的 GMP 要求為何？

Biotechnologically manufactured medicinal products (often referred to as "biologics" or "biopharmaceuticals") are medicinal products that are manufactured using biological systems. Biotechnology refers to the targeted use of cells, microorganisms or biological molecules to produce defined active substances. This is not an entirely novel principle: Traditional antibiotics are also produced using microorganisms. However, the key difference in modern biotechnology lies in the targeted genetic modification of production organisms, for example through recombinant DNA technology, in order to produce specific proteins such as monoclonal antibodies, hormones or enzymes. The most important biotechnologically produced drugs include recombinant proteins (e.g. insulin, growth hormones), monoclonal antibodies (mAbs), fusion proteins, vaccines, blood and plasma products, biosimilars and, in a broader sense, ATMPs.
[中譯] 生物技術製造的藥品（通常稱為「生物製品」或「生物製藥」）是使用生物系統製造的藥物。生物技術是指有目的地使用細胞、微生物或生物分子來生產特定的活性物質。這並非全新原理：傳統抗生素也是利用微生物生產的。然而，現代生物技術的主要差異在於對生產生物進行定向基因改造（例如透過重組 DNA 技術），以生產特定蛋白質，如單株抗體、荷爾蒙或酵素。最重要的生物技術藥品包括重組蛋白（如胰島素、生長激素）、單株抗體 (mAbs)、融合蛋白、疫苗、血液及血漿製品、生物相似藥，以及廣義上的先進治療開發藥品 (ATMPs)。

Biologics are characterised by their high molecular complexity, post-translational modifications (e.g. glycosylation), their production in living cells and inherent batch-to-batch variability. Unlike chemically synthesised drugs, identical copies are virtually impossible to produce. Even minor process changes can affect the structure, activity or immunogenicity. These special characteristics are directly reflected in the GMP requirements.
[中譯] 生物製品的特徵在於其高度的分子複雜性、轉譯後修飾（如醣基化）、在活細胞中生產以及本質上的批次間變異性。與化學合成藥物不同，生物製品幾乎不可能生產出完全相同的副本。即使是微小的製程變更也可能影響結構、活性或免疫原性。這些特殊性質直接反映在 GMP 的要求中。

Regulatory framework in Europe
[中譯] 歐洲法規架構

The legal basis in Europe is provided by the relevant EU regulations and directives, particularly Directive 2001/83/EC on medicinal products for human use, as well as national implementations, e.g. in the German Medicines Act (AMG). The binding GMP requirements are summarised in EudraLex Volume 4 (EU GMP Guidelines). These consist of:
[中譯] 歐洲的法律依據是由相關歐盟規章與指令提供，特別是關於人用藥品的 Directive 2001/83/EC，以及各國的施行法，例如德國藥品法 (AMG)。具強制性的 GMP 要求彙整於 EudraLex 第 4 冊 (EU GMP 指南)，包含：

• Part I: Basic requirements for medicinal products
  [中譯] 第一部分：藥品基本要求
• Part II: GMP for active substances (API)
  [中譯] 第二部分：原料藥 (API) 的 GMP
• Part III: GMP-related documents
  [中譯] 第三部分：GMP 相關文件
• Annexes (product-specific requirements)
  [中譯] 附錄（特定產品要求）
• Part IV on ATMPs
  [中譯] 第四部分：關於先進治療開發藥品 (ATMPs)

EU GMP Part II, which is based on ICH Q7, is particularly relevant for biotechnologically manufactured active ingredients. Chapter 18 ("Biotech Chapter") contains specific requirements for APIs derived from cell culture or fermentation. For the finished medicinal product (drug product, DP), Part I also applies. Specific requirements for biological medicinal products are regulated in Annex 2 ("Manufacture of Biological Medicinal Substances and Products for Human Use"), and requirements for sterile active substances and drugs in Annex 1. For investigational medicinal products, Annex 13, Regulation (EU) 536/2014 and Delegated Regulation (EU) 2017/1569 also apply. The EMA "Guideline on quality, non-clinical and clinical requirements for investigational ATMPs" from 2022 describes the data required for an investigational medicinal product (IMP).
[中譯] 基於 ICH Q7 的 EU GMP Part II 與生物技術製造的活性成分特別相關。第 18 章（「生物技術章節」）包含對源自細胞培養或發酵之 API 的特定要求。對於成品藥 (DP)，Part I 同樣適用。生物藥品的特定要求規範於 Annex 2（「人用生物藥品物質與產品之製造」），而無菌原料藥與藥品的要求則規範於 Annex 1。對於臨床試驗用藥，Annex 13、歐盟規章 (EU) 536/2014 及授權規章 (EU) 2017/1569 亦適用。2022 年 EMA 之「臨床試驗用 ATMPs 之品質、非臨床與臨床要求指南」描述了臨床試驗用藥 (IMP) 所需的數據。

Internationally, ICH guidelines are also central, specifically for biologics: ICH Q5A (virus safety), ICH Q5C (stability), ICH Q5D (cell banking systems), ICH Q6B (specifications for biotechnology products) and ICH Q8-Q11 (QbD, risk management, pharmaceutical quality system).
[中譯] 在國際上，ICH 指南也是核心，特別是針對生物製品：ICH Q5A（病毒安全）、ICH Q5C（安定性試驗）、ICH Q5D（細胞庫系統）、ICH Q6B（生物技術產品規格）以及 ICH Q8-Q11（品質設計 QbD、風險管理、藥品品質系統）。

The production of biotechnological APIs typically begins with a cell bank system. Annex 2 and ICH Q5D require clear characterisation, documentation and control of master and working cell banks. The cell bank must be established in a controlled environment. Its history, genetic stability and freedom from adventitious agents must be demonstrated. Details on the quality of cell banks can also be found in the European Pharmacopoeia.
[中譯] 生物技術 API 的生產通常始於細胞庫系統。Annex 2 與 ICH Q5D 要求對原始細胞庫與工作細胞庫進行明確的鑑定、文件化與管控。細胞庫必須在受控環境中建立。其歷史紀錄、遺傳穩定性以及無外源因子污染必須得到證實。關於細胞庫品質的細節亦可參閱歐洲藥典。

A key GMP issue is virus safety. Biotechnological products, especially those derived from animal or human cell lines, carry the risk of viral contamination. Therefore, ICH Q5A requires validation of virus inactivation or virus removal steps with demonstrable reduction performance. Annex 2 also emphasises the need to systematically avoid cross-contamination and microbiological contamination.
[中譯] GMP 的一個核心議題是病毒安全。生物技術產品，特別是源自動物或人類細胞株者，帶有病毒污染的風險。因此，ICH Q5A 要求對病毒去活化或病毒清除步驟進行確效，並具備可證明的降低係數效能。Annex 2 亦強調必須系統性地避免交叉污染與微生物污染。

Part II Chapter 18 describes requirements for fermentation, harvesting, purification, and viral inactivation and removal steps. The focus here is on process control: Parameters such as pH, temperature, oxygen supply and feed strategies are considered critical process parameters (CPPs) because they directly affect critical quality attributes (CQAs). CQAs include, for example, potency, purity, aggregation behaviour, glycosylation patterns and immunogenicity.
[中譯] Part II 第 18 章描述了發酵、收穫、純化以及病毒去活化與清除步驟的要求。此處的重點在於製程管制：pH 值、溫度、溶氧量與補料策略等參數被視為關鍵製程參數 (CPPs)，因其直接影響關鍵品質屬性 (CQAs)。CQAs 包括例如效價、純度、聚合行為、醣基化圖譜與免疫原性。

Analytical characterisation is particularly extensive. According to ICH Q6B, identity, purity, content, biological activity and process- and product-related impurities must be assessed. Host cell proteins, host cell DNA, media components or chromatography ligands are typical process-related impurities that must be minimised and controlled. The development and validation of analytical methods follows ICH Q14 and ICH Q2.
[中譯] 分析鑑定特別廣泛。根據 ICH Q6B，必須評估鑑別、純度、含量、生物活性以及製程相關與產品相關雜質。宿主細胞蛋白質 (HCP)、宿主細胞 DNA、培養基成分或層析配體是典型的製程相關雜質，必須予以最小化並管控。分析方法的開發與確效遵循 ICH Q14 與 ICH Q2。

Biotechnological processes are often microbial or cell culture-based and therefore highly susceptible to contamination. Annex 2 therefore requires a risk assessment of contamination hazards throughout the entire process, including a risk-based definition of hygiene areas and cleanroom classifications, which in turn are described in Annex 1. There are no rigid cleanroom classification requirements for active ingredient manufacturing (API); rather, the classification must be appropriate for the respective process stage and microbiological risk. For the manufacturing steps involved in obtaining sterile active ingredients, reference is made to Annex 1. This concerns cleanroom classes (A/B for aseptic filling), environmental monitoring, media fills (APS), contamination control strategy and quality risk management.
[中譯] 生物技術製程通常基於微生物或細胞培養，因此極易受污染。Annex 2 要求對整個製程中的污染危害進行風險評估，包括基於風險定義衛生區域與無塵室等級（此部分則於 Annex 1 中描述）。對於原料藥 (API) 製造並無僵化的無塵室等級要求；相反地，等級必須適合各別製程階段與微生物風險。對於涉及取得無菌原料藥的製造步驟，應參考 Annex 1。這涉及無塵室等級（無菌分裝為 A/B 級）、環境監測、培養基填充試驗 (APS)、污染管制策略 (CCS) 與品質風險管理。

Biotechnological APIs are typically transferred to sterile filling with low bioburden. A clear separation between the API and DP areas is essential. Annex 2 requires the implementation of appropriate measures to prevent cross-contamination. This usually involves the use of separate HVAC systems for fermentation (upstream) and purification (downstream), as well as a clear separation of pre- and post-viral process steps.
[中譯] 生物技術 API 通常在低生物負荷量 (Bioburden) 的情況下移交至無菌充填。API 與 DP 區域之間的明確區隔至關重要。Annex 2 要求執行適當措施以防止交叉污染。這通常涉及在上游發酵 (Upstream) 與下游純化 (Downstream) 使用獨立的空調系統 (HVAC)，以及對病毒處理前後製程步驟進行明確區隔。

Closed systems and single-use technologies are becoming increasingly important. These also require a formal risk analysis, especially with regard to extractables/leachables, biocompatibility and microbiological quality.
[中譯] 封閉系統與單次使用技術 (Single-use technologies) 正變得日益重要。這些技術同樣需要正式的風險分析，特別是針對萃取物/滲出物 (E&L)、生物相容性與微生物品質。

Cleaning validation is mandatory for multi-product systems. In addition to Part II, Annex 15 and the HBEL/PDE guideline for deriving health-based limit values also apply here. Special considerations apply to proteins, as they can denature at extreme pH values or temperatures and are then difficult to clean.
[中譯] 多產品系統必須進行清潔確效。除了 Part II，Annex 15 以及用於推導健康基礎暴露限值的 HBEL/PDE 指南亦適用於此。蛋白質需經過特殊考量，因為它們在極端的 pH 值或溫度下會變性，進而變得難以清潔。

Due to the natural variability of biological systems, the "state of the art" is not static, but is constantly evolving. The German AMG specifically requires that manufacturing and quality control comply with the latest scientific and technical standards.
[中譯] 由於生物系統的自然變異性，「最新技術水準」並非靜態，而是不斷演進。德國 AMG 特別要求製造與品質管制必須符合最新的科學與技術標準。

Conclusion
[中譯] 結論

The GMP requirements for biotechnological medicinal products are more complex and scientifically demanding than those for chemically synthetic products. They are based on a dense network of European and international regulations (in particular EU GMP Part II, Annex 2, Annex 1 and ICH Q5A-Q6B). The focus is on process understanding, virus safety, control of biological variability, comprehensive analytical characterisation and a risk-based quality system. Biotechnological GMP is therefore not so much a rigid set of rules as it is a scientifically sound, risk-based control system with the aim of providing reproducible, safe and effective medicinal products despite inherent variability.
[中譯] 生物技術藥品的 GMP 要求比化學合成產品更為複雜且具科學挑戰性。它們建立在密集的歐洲與國際法規網絡之上（特別是 EU GMP Part II, Annex 2, Annex 1 以及 ICH Q5A-Q6B）。其核心在於製程理解、病毒安全、生物變異性控制、全面的分析鑑定以及基於風險的品質系統。因此，生物技術 GMP 並非僵化的規則集，而是一套具科學實證、基於風險的管制系統，旨在克服固有變異性，提供具再現性、安全且有效的藥品。

Source: https://www.gmp-compliance.org/gmp-news/what-are-the-gmp-requirements-for-biotechnological-products