Notes on Annex-1 Part two
A new revision of EU-GMP Annex-1 is in the process of being implemented including new requirements that could have serious impact on your quality management system. One of the new requirements in this GMP annex considers the need to have a Contamination Control Strategy.
Final consultation on this document ended on 20 July 2020 and implementation is expected in 2022. Progress has the expertise to translate this new version of the annex-1 to your specific situation.
Earlier this year we published a first note on the new Annex-1 and an article on disinfectant validation. In the first part of our Notes on Annex-1 and the article published via Linkedin emphasis was laid on the selection and validation of disinfectants as part of a Contamination Control Strategy (CCS). In the current publication we will consider the CCS in a broader perspective and discuss what CCS is and what it should encompass.
With the revised version of Annex-1 the requirement for a CCS has been formalised and made mandatory. In the past parts of such risk based strategy were actually already expected to be in place, but requirements for CCS were not clearly laid down in the guidelines and the concept was not discussed in the holistic manner it is now in the new annex-1.
In a comment PIC/s inspectors already expressed that to their opinion there is nothing new in this respect.
What is CCS:
The Contamination Control Strategy should be a comprehensive strategy laid down in a policy document and underlying procedure and instructions. The CCS policy should be based on risk management principles and discuss successively linked events and procedural instructions that define critical control points, monitors such controls and evaluate their effectiveness to manage the risks associated with any form of potential contamination of the manufactured products from raw material up to distribution of the final product.
What is the purpose of the CCS:
The purpose of the contamination control strategy is to provide assurance in all aspects of operation that could lead to any form of contamination. And that could impact on the safety of the medicinal products manufactured in the facility.
The CCS shall assure that final products are intrinsically safe to use and free from microbial, particulate, chemical, or other forms of contamination.
Although the requirement for a CCS is not entirely new, with the newly drafted Annex-1 it is the first time it is described as an all-encompassing and overarching concept in a regulatory document. Because the full description of the concept is new it will be good to study and apply this concept well. There is a serious chance that this will be one of the major inspection themes for companies manufacturing parenteral medicinal products in the near future. And actually the new annex-1 defines that application of the concept of risk-based CCS should also be considered for non-parenteral products and for non-aseptic process steps in the manufacture of sterile products.
What does CCS encompass:
As stated in the chapter “what is CCS”; the CCS shall be a risk management driven program that touches upon all aspects of processing and the facility. It considers not only the manufacturing processes, but also includes all ancillary processes, utilities and materials potentially impacting microbial, particulate and other potential contamination of the products in these facilities.
A proper CCS shall at least encompass documented evaluation of the following points for potential risk on contamination of intermediate and final products:
- Facility design, qualification and validation,
- Process design and validation, consider risks in all process steps,
- Personnel Training and Qualification (including requirements for disqualification),
- Management of Equipment and Systems including qualification and where necessary validation,
- Management of Utilities, including qualification and validation,
- Raw material selection, qualification and control, including supplier selection and qualification, with special emphasis to excipients,
- Product containers and closures, design, qualification and validation,
- Management of outsourced activities,
- Process risk assessment,
- Process monitoring and ongoing evaluation/ trend analysis,
- Validation and revalidation policies to processes,
- Maintenance and (re-)Calibration programs,
- Cleaning and Disinfection processes, design, qualification and validation,
- Environmental monitoring system, design, qualification, validation and ongoing evaluation/ trend analysis,
- Monitoring of wear and tear of clean room garments,
- Product reviews; recognition of trends in manufacturing processes,
- Management reviews; recognition of trends in quality and management systems and potential for continuous improvement,
If you do not have a Contamination Control Strategy yet, then it is highly advisable to start working on a policy document for your contamination control strategy as soon as possible.
When defining a CCS policy consider the implication of implementation of such policy and underlying procedures to ensure the strategy is implemented and alive within your company. This should be applied not only for the production of sterile final products, but also include at least all other processes and process steps where (very) low levels of microbial, pyrogenic and particulate contamination are deemed necessary.
The Contamination Control Strategy should preferably be laid down as a policy document, describing principles of prevention, reduction and other forms of assurance by which products shall be protected from extraneous sources of contamination. Such policy document should refer and relate to underlying procedures in which the processes for execution of contamination control and monitoring on their efficacy are laid down for all above mentioned attention points.
Important to understand is that a single terminal event or testing alone does never provide a sufficient level of contamination control. The CCS should be a document encompassing a total program, including measures of containment and confinement constraining the possibility of entry of contamination, measures in the form of cleaning and disinfection, measures in environmental controls and measures in process controls. Some shall be shielding the product, creating a clean environment and minimising the potential contaminants in the direct vicinity of the product, whereas others are aimed at cleaning and disinfecting or sterilising the surfaces by which the product can be contacted.
Where tests and measurements are performed the results shall be evaluated and trended over time to show continuous control over the conditions. The trend results shall be included in a program for continuous improvement.
CCS, as all-encompassing and overarching concept, shall exist of an extensive series of successively linked events and measures. The evaluation of these events and measures should not only include evaluation of individual points, but also an assessment of collective effectiveness of the CCS program, including evaluation over longer periods of time. Such collective assessment could best be included in the regular Management reviews.
It is furthermore important to understand that the new Annex-1 explicitly states that the scope of the document includes areas other than sterile products, where the general principles of contamination control as laid down in the guidance document should be applied. The scope of the Annex-1 document therefore is extended to the manufacture of non-sterile products, especially where these are vulnerable to contamination by microbial, particulate, pyrogenic, or other substances.
In addition to the above stated points; it is important to consider that FDA has recently issued guidance for non-sterile medicinal products that is very similar in its intentions to what is defined for non-sterile products in the new annex-1. (Microbiological Quality Considerations in non-sterile Drug Manufacturing; September 2021). This guidance discusses considerations with regard to product development, risk assessments, manufacturing process design and analytics. Like the new annex-1 this guidance emphasizes the prevention of contamination and performance of risk assessments in order to assure the safety, quality, identity, purity and efficacy of medicinal products. The new guidance furthermore emphasizes the need to design risk based prevention of contamination into each aspect of development, manufacture and analysis of drug products.
FDA does not use the phrase Contamination Control Strategy, but actually the intention of the new guidance is similar to what is written in the new Annex-1; it will be important to have such strategy implemented as soon as possible.
We plan to write a series of articles on the new annex-1 and the new FDA guidance, a next article will discuss the requirements for the manufacture of non-parenteral products in more detail.
All pharmaceutical companies manufacturing medicinal products that could be adversely affected by microbial, particulate or pyrogenic contamination shall be expected to develop, document and apply a Contamination Control Strategy for their products. Expectation is that this will become an important theme in upcoming regulatory inspections.
Such CCS shall define the critical control points and controls in the operations and be based on Quality Risk Management and consider all aspects of contamination control.
Design and development of a CCS requires thorough technical and process knowledge, as well as thorough understanding of the effective regulatory requirements and guidance.
Preferably the CCS shall be documented as a high level company policy, comparable to a Validation Master Plan, with details relating and referring to the CCS defined in the site master file, the VMP and underlying procedures and instructions.
As discussed in the article above a new version of the EU-GMP Annex-1 is currently in review and expected to be effectuated relatively soon. An important concept discussed in detail in this document concerns the requirement to develop, document and apply a Contamination Control Strategy.
The requirement for the CCS shall mean that companies will have to design and implement a strong Contamination Control Strategy, document this in an overarching policy, perform Risk Assessments on their operations, define the critical control points in their processes and assure the required level of control. The created situation should than be able to withstand any inspection or audit.
Progress can help you in all aspects of assessing your operations and developing a suitable CCS for both Active Pharmaceutical Ingredients and Medicinal Products that may be vulnerable to contamination.
Progress consultants can help you to assess your operations, perform risk assessments, perform critical control point assessments and develop and set up a suitable Contamination Control Strategy.