If you are in the business of Sterile Medicinal Products, you surely are following the revision of EudraLex Volume 4 Annex 1. It might be the most discussed regulatory guideline revision in years. Also, you might have heard this, it is a ‘re-write’ rather than a ‘revision’. However, is there anything in the current draft that is absolutely new to you, and new to the industry? The revised Annex 1 to me is more a reflection of the technologies advanced through the years and a collection of industry best practices. As we say all the time, ‘Quality Beyond Compliance’. When all the necessaries are in place to assure the product quality, compliance will be achieved.
Indeed, the revised Annex 1 significantly expands the content – the document will very likely grow from the current 16 pages to somewhere around 50 pages. New sections will be introduced and will be structured in a more logical flow. However, most of these are intended to provide more clarity rather than to impose new requirements.
Contamination Control Strategy
One may argue that there’s a new concept introduced, stated in the Draft Annex 1:
A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks associated with contamination.
Though the concept is introduced in Annex 1 for sterile products, it is established that all medicinal products, sterile or non-sterile, should be free of contaminants – nothing really new here. Then ‘Control Strategy’, defined in ICH Q10 as..
A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
So put them together, a CCS is a set of controls to ensure product is consistently manufactured to the controlled contamination level. In my opinion, it’d be best to form a CCS for all medicinal products, and of course for sterile product the stakes are much higher, hence the controls are more stringent.
As mentioned, the new Annex 1 intends to provide more clarity, hence it explicitly specified:
Elements to be considered within a documented CCS should include (but are not limited to):
- Design of both the plant and process.
- Equipment and facilities.
- Raw materials controls – including in-process controls.
- Product containers and closures.
- Vendor approval – such as key components suppliers, sterilization of components and single use systems and services.
- For outsourced services, such as sterilization, sufficient evidence should be provided to the contract giver to ensure the process is operating correctly.
- Process risk assessment.
- Process validation.
- Preventive maintenance – maintaining equipment and premises (planned and unplanned maintenance) to a standard that will not add significant risk of contamination.
- Cleaning and disinfection
- Monitoring systems – including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination.
- Prevention – Trending, investigation, corrective and preventive actions (CAPA), root cause determination and the need for more robust investigational tools.
- Continuous Improvement based on information derived from the above.
The above paints a complete picture – what to be assessed and included in a CCS. So now, where do we start to write one? A CCS, in my opinion, intends to summarize the current status of control and to address any CAPA or continuous improvement required. It is a summary based on a series of comprehensive Risk Assessment on the elements listed above. I know it looks like a long and exhaustive list, but give it a closer look and you’ll most likely (hopefully!) identify many (if not all) of them have been addressed in various format of Risk Assessment during the product lifecycle (from Process Design to Continued Process Verification). Hence CCS is more an overarching document pointing to the specific risk assessments, rather than a completely new document to be prepared from scratch. The purpose of requiring a CCS is to force the companies to assess and manage the risks in a rather proactive manner.
Certainly, it would be good practice to formalise the procedure of CCS in an SOP. The major aspects to address in the procedure could cover:
- Purpose and Scope: elements to be assessed.
- Responsibilities: Quality might have an oversight of the execution and implementation of CCS, however the assessment of each element should be led by the respective function and performed with a multidisciplinary team. The accuracy of each assessment is significantly dependent on the understanding of the business process of each element, hence SME in each area should be involved.
- Template: if any risk assessment method (e.g. FMEA) or template is available, with risk classifications defined.
- Review cycle: the CCS should be periodically reviewed to ensure the current controls are effective. Between the reviews, Change Controls and/or Deviations could also trigger the revision of CCS.
There’s nothing new or mysterious about the above points discussed around CCS. They are all the fundamental principle of our Pharmaceutical Quality System (PQS), especially the application of Quality Risk Management (QRM) principle, which is truly the enabler of PQS and it will also be introduced in the new Annex 1.
I hope with this brief overview of CCS, a clearer picture is outlined. I’d be more than happy to discuss further on the topic, please do not hesitate to reach out.
Also to build the QRM foundation, ISPE Singapore is organising a training with NSF – a well recognised education and certification organisation in the industry, on 29 Apr 2021. Details can be found here.
With 15 years of experience in the global pharmaceutical industry, predominantly in Process, CQV, Process Automation and Project Management, Shanshan has held both Consultant and End User roles. With increasing involvement in the GMP remediation and GMP audit projects, she has been building in-depth compliance knowledge as well as interaction with authorities globally.