The revision of EU GMP Annex 1, Manufacture of Sterile Medicinal Products was published 25 August 2022, by the European Commission.¹ The Annex has expanded from 16 to 58 pages and includes new requirements and additional details related to the requirements presented in the 2008 version of Annex 1.

The Annex comes into effect on 25 August 2023—one year from the date of publication in Eudralex Volume 4—and on 25 August 2024 for point 8.123 of the Annex pertaining to sterilization of lyophilizers—two years from the date of publication.

After August 25th of this year, manufacturers can expect to be inspected against the new Annex. While there may be some variability across EMA inspectorates in enforcement early on, the Irish Health Product Regulatory Agency (HPRA) has stated that they will inspect against the new Annex when effective.

The Annex can be viewed HERE.

Requirements

Annex 1 compliance is required for all sterile medicinal products that are licensed in the EU regardless of the country of manufacture. While the requirements are not mandated for products sold in the U.S., the FDA participated in the drafting of the new Annex 1; therefore, the FDA will be inspecting with the Annex in mind. Additionally, global harmonization will be driven through the Pharmaceutical Inspection Co-operation Scheme (PIC/s) which adopted the new Annex verbatim. PIC/s drives mutual recognition of inspections across 54 participating health authorities, including the U.S. FDA.

The document also states that it can be used for low bioburden products and biological intermediates. Manufacturers can expect inspectors to ask about some Annex 1 requirements for these items.

Implementation

Gap assessments can be effectively completed using different approaches or tools, albeit with common underlying frameworks. When preparing a gap assessment, laying out the scope for assessment may be considered the first step. While linear review through the revised Annex 1 structure may be a reasonable approach, it is important to understand the interplay between the Principle and PQS sections, and the specific Premises, Equipment, Utilities and Personnel sections and how these relate to the elements of the Production and Specific Technologies that may be relevant for the facility/assessment and the application of the Environmental and Process Monitoring and QC sections. The assessment of performance in the current state of individual and collective sections encourages consideration of a systematic approach and a tool which allows consideration and reflection of performance against each requirement and the collective picture. 

Implementation of Annex 1 requirements may, for many companies, be largely well progressed as they have for some time implemented continuous improvements based on many years of operational experience within existing frameworks of global regulations, established CAPA in response to deviations and internal audits, improved technologies, and testing assurance, and responded to external regulatory findings and citations. What may not be in place is systematic, documented and demonstrated compliance with links to continuous improvement based on assessment of current state performance and future state intent. A narrow focus on compliance may provide short term results but does not ensure a sustainable business plan and avoid the cycle of perishing quality standards, which ultimately leads to Regulatory citations, product recalls and disturbance to supply chain delivery and the consequences of negative impact to patients. For others, the window to complete assessments and establish realistic and practical plans to bring gaps into compliance by August 25, 2023, may be challenging.

Challenges

Gap assessments will reveal both common and unique challenges for individual companies to address. These may include the shortfall in design considerations and the attention to isolators or Restricted Access Barrier Systems (RABS), consideration of existing strategies for aseptic process simulation, or other technical challenges to implement Pre-Use Post sterilization integrity testing. 

As compliance may not always be binary, when approaching the gap assessment, a scored methodology allows for assessment of the range in the maturity of controls that may be in place, highlighting complete gaps, and partial and fully effective controls. This is enabling input to subsequent prioritization and risk assessment that may follow and in the development of action and mitigation plans for the closure of any gaps. 

Another important consideration is to establish targets for meeting the requirements from an immediate action to long term actions that may speak to maturity. Assessing the completeness of a Contamination Control Strategy (CCS) is a good example. The revised Annex 1 formalizes the need to have a [documented] CCS. Contamination control is referenced six times in Annex 1, half of which are included in the Principles Section. As with much of Annex 1, this is not a new consideration for many—however, ensuring the approach supports the holistic nature of the Principle and is implemented across all appropriate areas of the facility and processes. The assessment is recommended to draw upon a team of appropriate SMEs with Quality oversight. As well as the enhanced value of muti-disciplinary knowledge-based input to the assessment. This also allows for timely consideration of updates to PQS and standards that a company may want to include as part of action and mitigation plans following the assessment. 

What to expect

Manufacturers can expect some key elements of their implementation to be subject to immediate scrutiny, particularly regarding the risk assessments which were carried out to determine the specific implementation action plan and, most pertinently, the CCS. In every one of these cases, it is strongly advised that associated documentation has been subject to Quality oversight, review, and approval. Where actions will not be complete by the date of implementation and intervening actions may disrupt manufacturing operations, defined target completion dates based on robust risk assessment shared with the relevant National Competent Authority (NCA) will provide assurances regarding a site’s commitment to Annex 1 integration. A key element of this risk assessment must be consideration of potential interruption of supply of medicines to patients due to implementation headwinds.

While enforcement of all elements of the revised Annex 1 may vary from one authority to another, there is no doubt that the regulatory expectation will be that most of the revised regulation is in place and is subject to inspection on the effective date of 25 August 2023. This applies to all but one element of the revised Annex, related to the location, design, and sterilization requirements for lyophilizers. The revisions to Annex 1 have been the subject of much public discussion for years and the revised document has been official since August 2022. This makes it unlikely that manufacturers can expect wholesale extensions to the deadline as the accepted position of European Medicines Agency and the NCAs is that the timeframe to align with the regulations has been ample. In short, manufacturers who fail to implement Annex 1 within the timeframe and are unable to provide comprehensive risk assessments to address uncompleted action items can expect to see an increase in the number and severity of observational findings from NCAs during inspections.

A common question regarding Annex 1 is how much focus FDA investigators will apply when carrying out inspections in Europe. In recent months, FDA officials have made it clear in public forums that while FDA has no obligation to comply with the Annex 1 requirements, they are aligned with the principles of Annex 1 and that their inspectorate will be fully trained on the revised Annex. In fact, FDA considers Annex 1 to be analogous to the risk based CGMP approach for the manufacture of sterile medicinal products which it has been advocating for decades via the industry guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, which was issued in September 2004.²

Bringing it all together

Knowing where you are on the Annex 1 journey is a critical first step. A company cannot decide where it needs to go unless they know where they are starting. To set the path for success, it is typical to perform an assessment. However, it can be a significant mistake if a company assumes where they are or only assess what they know. Self-assessments can be useful, but for significant changes, such as Annex 1, a self-bias can creep in and create blind spots. The best assessments tend to lean toward semi qualitative or qualitative assessments, enabling continued improvement to be measurable. In cases where a company may find themselves behind in awareness and maturity of compliance to Annex 1, careful and deliberate planning is advised. Rushing through an assessment and assuming compliance status can create rework later and is always more expensive.

The golden rule is to set a baseline and create a measurable plan for demonstrable progress. Utilizing independent consultants can not only deliver the baseline faster but will eliminate any potential bias. As with any compliance initiative, setting risk-based goals and meeting achievable goals is always preferable to passive ad hoc objectives.

For this reason, it is always advisable that companies seek out consultants that utilize a consistent tool. Use of an assessment tool that provides quantitative results will not only give a company a measure of itself and set a direction, but also provide an indication of its compliance position, thus producing an instant benchmark against peers.

An industry call to action is to identify weaknesses in accordance with Annex 1 to not only create a culture of continuous improvement, but also help in identifying potential risks across a supply chain. In the end, it always has been about safe and effective products and sustainable supply at the right time. Take the time now to assess your current position and make plans for the near future, using professional consultancy can accelerate your journey.

References
1.  European Commission; The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Annex 1; Manufacture of Sterile Medicinal Products; 8 August 2022; https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
2.  FDA, Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice, September 2004, Guidance for Industry (fda.gov)

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Keith A. Lamb, Ph.D., is an executive director at Lachman Consultants and a quality and chemistry manufacturing and controls (CMC) executive with a passion for innovation and delivery of novel medicines to patients. He brings broad technical understanding and experience in biopharmaceuticals, small molecules, and cell and gene therapy (CGT). Mr. Lamb has extensive experience in design, implementation, and operation of pharmaceutical quality management systems for current good manufacturing practice (cGMP) and product quality, all while growing and developing organizations and inspiring people development.

John Darby, M.Sc., is a senior director in the compliance practice at Lachman Consultants. Mr. Darby is a goal directed, results-focused executive professional with a strong, global background in quality assurance, compliance, audits, training, and remediation. His 18+ years of experience and insight contribute to his ability to identify issues and form innovative solutions and strategies for continued success. Mr. Darby has been responsible for the management, organization, and strategic guidance of global, quality and operations-based training functions. He is proficient in sterile pharmaceutical manufacture, oral solid dose manufacture, and API manufacture.

Lachman Consultant Services, Inc. furnishes expert compliance, regulatory affairs, and technical services to clients around the world, helping avoid and resolve compliance problems, and assisting in the development of efficient and effective strategies for the submission and approval of drugs and devices. More info: Lachmanconsultants.com