Annex 1 and GMP: Key Differences Across Manufacturing Scales in Sterile Drug Production

Overview 

Annex 1 of the EU Guidelines for Good Manufacturing Practice (GMP) provides a unified framework for sterile medicinal product manufacture across the European Union and United Kingdom, and for products imported into these regions. 

This article offers a UK-centric perspective on how Annex 1 is applied in practice, particularly under the UK’s regulatory frameworks such as Section 10 and the “Specials” licence (a UK-specific category for unlicensed medicines made to meet individual patient needs). While terminology and implementation may vary across EU member states and other regions, the core principles of Annex 1 remain widely relevant to any sterile manufacturing setting. 

Its primary aim is to minimise microbial, particulate, and pyrogenic contamination, with terminal sterilisation as the preferred method. Aseptic processing is permissible only where terminal sterilisation would compromise product quality (RSSL, 2022). 

Manufacturing Scale Classifications 

Environmental Monitoring in Aseptic Manufacturing: Tailoring Strategies by Scale 

Environmental monitoring (EM) is a core component of contamination control in aseptic manufacturing, but the tools, regulatory obligations and practical approaches can vary significantly, depending on the size and maturity of the operation. Whether you're working within a large-scale licensed manufacturing facility, a small-scale "Specials" unit, or a start-up navigating pre-licence challenges, understanding the specific regulatory landscape and quality expectations is essential. 

In this post, we explore how EM requirements differ across three key manufacturing contexts: 

• Large-scale manufacturing, where complex quality systems and automation support high-volume production under full GMP. 

• Small-scale manufacturing, where leaner operations and patient-specific output demand risk-based strategies under the UK "Specials" framework. 

• Start-up manufacturing, where flexible infrastructure and outsourced functions must still align with Annex 1 during scale-up and transition.
  
  Each environment presents unique challenges andes, and calls for an EM approach tailored to its operational model, licence type, and regulatory obligations. 

1. Large-Scale Manufacturing

In large-scale aseptic manufacturing, operations are governed by a Manufacturer’s/Importer’s Authorisation (MIA), and subject to rigorous regulatory oversight. These facilities require comprehensive quality systems, dedicated Qualified Persons (QPs), and robust environmental monitoring programmed to ensure GMP compliance and product sterility at scale. 

• License Type: Manufacturer’s/Importer’s Authorisation (MIA) 

• Issued By: MHRA or relevant EU authority 

Key Requirements: 

• Qualified Person (QP): legally responsible for ensuring that each batch meets GMP standards before release 

• Robust Pharmaceutical Quality System (PQS): includes documentation, risk management, and continuous improvement

• Full documentation, sterility assurance, environmental monitoring (EM) trending, and Annual Product Quality Review (APQR)

Features: 

• Advanced automation and contamination control
• Integrated container closure integrity testing (CCIT), EM trending, and stability testing 

Environmental Monitoring Tools: 

• Active air sampling 
• Passive air sampling (settle plates) 
• Surface contact sampling
   

2. Small-Scale Manufacturing

Small-scale manufacturing under the UK "Specials" framework focuses on producing unlicensed medicines to meet specific patient needs when no licensed alternative exists. While operating on a smaller scale, these facilities are still subject to Annex 1 requirements and must maintain robust aseptic controls, stability data, and effective environmental monitoring within lean, risk-based frameworks. 

• Licence Type: MS (Specials): for unlicensed medicines made to meet specific patient needs 

• Legal Basis: UK “Specials” framework 

• Use Case: production for unmet clinical needs where no licensed alternative exists 
  
  

Key Requirements: 

• Heads of Production and QC 

• Aseptic controls per Annex 1 

• Stability testing and documentation 

Features: 

• Isolator-based, typically in Grade C cleanrooms 

• Lean teams; risk-based strategies 

Environmental Monitoring Tools: 

• Active/passive air sampling 

• Surface contact monitoring 

Note: The UK “Specials” framework does not have a direct EU equivalent; however, similar risk-based approaches may apply to unlicensed medicines under national exemptions within the EU. 

3. Start-Up Manufacturing

Start-ups such as emerging or pre-licensed manufacturing environments are often in a pre-licence phase, working towards MS or MIA approval. With limited resources, flexible infrastructure and no in-house QP, these facilities typically outsource key functions while aligning with Annex 1 expectations during scale-up. 

Manufacturers outside the UK preparing for Annex 1 compliance may operate under different transitional frameworks depending on national regulations, but the principle of aligning with Annex 1 during scale-up applies universally. 

• Licence Type: often pre-licence; transitioning to MS or MIA 

Challenges: 

• No in-house QP 

• Resource limitations 

• Modular or flexible cleanroom infrastructure 

Features: 

• Seeks Annex 1 alignment during scale-up 

• Outsourcing of EM and QA functions is common 

Case Studies: Applying Annex 1 Across Manufacturing Scales 

The following examples illustrate Annex 1 application across varying production scales. These scenarios are inspired by the PHSS Aseptic Processing Workshop (March 2025), particularly the session presented by Alex Boseley of Torbay Pharmaceuticals Ltd. 

Scenario 1: Hospital Pharmacy Aseptic Preparation of Morphine Sulphate 10 micrograms/ml Injection 

This case study focuses on a hospital pharmacy preparing morphine sulphate 10 micrograms/mL injection under the section 10 exemption of the UK Human Medicines Regulations. The preparation is carried out aseptically for a named patient, typically within an isolator-based setup, without the requirement for batch release testing. This scenario is specific to the UK Section 10 exemption. EU hospital pharmacy operations may follow national guidelines informed by Annex 1, but requirements for batch testing and licensure vary. 

While operating at a reduced scale, the environment still demands stringent control. Key quality considerations include validated aseptic technique, clear documentation, robust isolator monitoring, and clinical risk assessments for every dose prepared—ensuring patient safety remains the priority even outside a traditional GMP setting. 

• Legal Framework: section 10 exemption (UK Human Medicines Regulations 2012) 

• Preparation: by a pharmacist or under their supervision for a named patient 

• Shelf Life: typically, no more than 7 days, unless supported by risk-based extension 

• Sterilisation: aseptic preparation only, in a closed system 

• Premises: often isolator-based in a non-classified background 

• QC Focus: immediate-use sterility; batch testing not required 

Key Considerations (QAAPS, 2022): 

• Validated procedures to ensure concentration accuracy and patient safety 

• Aseptic technique validation and operator competency checks 

• Validated airflow and pressure monitoring within isolators 

• Full documentation with clear audit trails 

• Appropriate labelling and traceability 

• Clinical and quality risk assessments for every preparation 

• Validated cleaning and sanitisation, even at reduced scale 

Scenario 2: Specials-Licence Batch Manufacture of 30 Units 

This scenario outlines the manufacture of unlicensed medicines under an MS (Specials) licence, where products are prepared in advance of clinical need, based on prescriber specifications. Production typically takes place in isolators within a Grade C cleanroom, with shelf life extended up to 84 days when supported by validated stability data. 

Although operating at a smaller scale than licensed manufacturing, MS facilities are held to rigorous quality standards. Key QA considerations include a defined PQS, validated formulations, sterility and stability testing, operator competency, and active environmental monitoring — ensuring that quality, traceability, and patient safety remain at the heart of every batch. 

• Licence Type: MS (Specials) 

• Preparation: for anticipated need, based on prescriber specification 

• Shelf Life: up to 84 days with validated stability data 

• Facilities: isolator in a Grade C background 

QA/QC Requirements: 

• Qualified Head of Production and QC 

• Sterility and stability testing 

• Documentation standards 

Key QAAPS Considerations (QAAPS, 2022) 

• Validated formulation and supported shelf life 

• Cleanroom infrastructure and equipment 

• PQS: SOPs, deviation handling, audit processes 

• Aseptic technique training and periodic assessments 

• Environmental monitoring and data trending 

• Validated cleaning/sanitisation regimes 

Scenario 3: Licensed Commercial Manufacture of 10,000 Units 

This case study focuses on a fully licensed manufacturing facility operating under a Manufacturer’s/Importer’s Authorisation (MIA). Production takes place in Grade A aseptic zones with high levels of automation, and terminal sterilisation is typically preferred to maximise sterility assurance. Shelf life is determined through both long-term and accelerated stability studies. 

With a named QP responsible for batch certification, these facilities maintain a comprehensive QA/QC infrastructure. This includes container closure integrity testing (CCIT), environmental monitoring, extractables and leachables testing, and regular product quality reviews — all forming part of a mature Pharmaceutical Quality System that supports compliant, large-scale sterile manufacturing. 

• Licence Type: MIA 

• Production Environment: grade A aseptic zones with automation 

• Sterilisation: terminal sterilisation preferred 

• Shelf Life: based on long-term and accelerated stability studies 

QA/QC Infrastructure: 

• Named QP for batch certification 

• Full CCIT, EM, and extractables/leachables testing 

• Annual Product Quality Reviews (APQR) 

Table 1 highlights the key differences in quality and operational requirements across Section 10, MS (Specials), and MIA-licensed manufacturing. While all three settings involve aseptic preparation, the level of regulatory oversight, QA/QC infrastructure, and process complexity increases significantly with each licence type. From sterilisation methods and shelf-life justification to water quality, container closure integrity testing, and quality system expectations, the table clearly illustrates how manufacturing scale and licence type influence the controls required to ensure product safety and compliance. 

Table 1: Comparative Analysis of the Three Manufacturing Scales 

Different container types used in aseptic manufacturing bring distinct technical and regulatory considerations. Table 2 outlines the key features and challenges associated with syringes, vials, and ampoules—including requirements for container closure integrity testing (CCIT), extractables and leachables profiles, and transfer validation. Selecting the appropriate container involves balancing factors such as product stability, sterility assurance, cost, and operational complexity. 

Table 2: Considerations for Container Closure Systems  

Global Relevance 

While this article focuses on the application of Annex 1 within the UK regulatory landscape—including Section 10 exemptions and MS (Specials) licences—the underlying principles are widely applicable across sterile manufacturing environments globally. 

Whether operating under the MHRA, EMA, FDA, or another national authority, manufacturers face similar expectations around contamination control, environmental monitoring, and aseptic assurance. Annex 1 provides a shared benchmark, with core tenets that should be interpreted and implemented in line with local regulatory frameworks, product risk profiles, and operational realities. 

Conclusion 

Annex 1 sets a unified benchmark for contamination control and sterility assurance—but these are minimum standards, not endpoints. Manufacturers must go beyond compliance through risk- and scale-appropriate enhancements, tailored to product type, patient safety, and operational realities (RSSL, 2022). 

• Large-scale manufacturers rely on automation, QP oversight, and full-spectrum QA/QC. 

• Small-scale and hospital pharmacy operations must comply with isolator-based aseptic technique, robust documentation, and environmental controls. 

• Start-ups can adopt validated, scalable strategies that enable safe growth within Annex 1 expectations. 

Redipor®: Supporting Your Contamination Control Strategy 

From single-dose compounding to full-scale production, Redipor supports your sterility assurance needs. In addition to off-the-shelf products, we offer tailored formulations and packaging solutions to suit your specific environment.  

Our Redipor brand offers: 

• Pre-validated plates for cleanrooms and isolators 

• Scalable EM kits, including the versatile UOBT for hospital pharmacies, start-ups, and GMP facilities 

• Bagged media for APS and media fill studies 

• Bottled media for microbiological testing 

• Custom solutions tailored to your environmental monitoring programs 

• Expert guidance for Annex 1–aligned monitoring 

For more information or to discuss your specific Redipor requirements, contact our team.

References 

QAAPS (2022). Quality Assurance of Aseptic Preparation Services: Standards Handbook (5th ed.). London: Royal Pharmaceutical Society. 

RSSL (2022). EU Annex 1: Manufacture of Sterile Medicinal Products – A White Paper. Reading Scientific Services Ltd. Available at: https://www.rssl.com/media/4pka2zry/rssl-white-paper-eu-annex-1-manufacture-of-sterile-medicinal-products-online-version.pdf