What is your understanding of CCS?

the first impression leads us to say that CCS involves the creation of a document that describes the production process, identifies contamination risks and the associated control measures in place to prevent contamination (microbial, pyrogenic and particulate).
This answer is not entirely false, but is not reflecting all dimensions that should the CCS have, as it focuses exclusively
on the way the CCS is documented and misses the holistic approach, leading to the following assumption:
“Besides the documentary aspect, the purpose of setting up a CCS in a company is to develop a continuous oversight of contamination state of control during the manufacturing process of sterile and low bioburden products“. What does this mean in concrete terms?
We need to explore more to have the response….

Do you expect CCS to fit into the PQS (Pharmaceutical Quality System) and how does it interact with existing processes?

Let’s look at GMP Annex 1 requirements that are emphasizing CCS:
Section 2.3: “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 organizational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods. Its effectiveness should form part of the periodic management review. Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood”
Section 2.4: “Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together”
Section 3.1: “The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products”

From sections 2.3 & 2.4, in particular, in the highlighted statements, we can understand that the regulation does not require to create new control systems or measures if they are already existing and well managed, but CCS is coming connecting the dots between these existing control systems, measures and events in order to have a holistic view of the contamination control state in the company.
In the section 2.3, a very important element of PQS is pointed out: “Periodic management review”, so we can understand that CCS should be integrated in the PQS and should interact with all PQS elements.
Finally, the section 3.1 clearly mentions that the manufacturer’s PQS should embrace the specific requirements of sterile product manufacturing with the objective of identifying process and control vulnerabilities and the appropriate continuous improvement pathways. So, we can say that:
The CCS is coming to strengthen the PQS with a contamination control dimension (Figure 1)

Key concerns to ensure a meaningful adaptation of the existing PQS with the contamination control dimension.

Considering contamination control requirements at early stages of projects and the product life cycle, implementing a high level of awareness of contamination risks, an efficient quality culture in the company and defining clear roles and responsibilities at all levels of the organization and during the entire life cycle of the product are key elements for CCS sustainability.

1. Consider CCS since the early stages of projects and product development 

Designing premises, facilities, equipment, utilities and processes is crucial to guarantee a good level of contamination control since the beginning and during the entire product lifecycle.
The building of a robust User’s Requirement Specification (URS) is a Cornerstone in Pharmaceutical Qualification. For sterile processes, this document should capture all aseptic processing needs (Barrier Technology, RTP ports, easy set-up without opening the doors, CIP/
SIP, quality oversight feasibility from windows…) and should set the stage for compliant, robust, and fit-for-purpose systems before any design or procurement begins.
Whatever the system or equipment to be qualified, a well-developed URS is the first line of protection against design weakness, regulatory issues and operational failures.
Design qualification is the key step in verifying that contamination control requirements have been met, for example:
– Suitability of the equipment for the specific characteristics of the sterile or low bioburden product and process.
– Positioning instruments and accessibility for periodic metrology testing without compromising product quality.
– Cleanability and hygienic design with easy disassembly for autoclaving.
– CIP/SIP possibility.
– Possibility and accessibility of requalification testing (ex: clean room reclassification, smoke studies exercises…).
– Accessibility for maintenance without compromising product quality.
– Contamination prevention for sterile or multi-product facilities (e.g., backflow prevention, unidirectional flows, physical barriers, closed systems).
– Design minimizing interventions and, if necessary, interventions thought out carefully in advance, without breaking first air.
– Digital Traceability and Connectivity: equipment should allow automatic data collection for real-time monitoring, deviation detection, and integration into quality systems (e.g.: ERP, SCADA…) to facilitate investigations, trending and CCS effectiveness review.

Challenging engineers and suppliers is
highly expected:
– To meet users’ needs
– To propose innovative design to meet technical and operational expectations of GMP Annex 1 and other current regulations (ISO, USP…)
– To learn from manufacturing and inspection experience and difficulties ( see role of suppliers part)
Every change or upgrade of the premise, facility or equipment must be an opportunity to improve contamination control and to introduce innovative solutions.
Using Quality by Design (QbD) approach is essential for designing processes and the associated control strategies Contamination control of a new process/product needs to be assessed at various stages of the project: during product & process development, during technology transfer, validation and commercial manufacturing by using adapted risk assessment tools. The purpose of this contamination risk assessment is to
improve the process continuously during the project life cycle, if some weakness or risks are identified.
Product specifications (except for compendial testing) and sampling plan during the process should be representative and well-designed according to the identified contamination risks (eg. risk of endotoxin contamination, risk of particle and/or microbial contamination… product microbial proliferation properties) to maximize the detectability of any contamination issue and reinforce CCS.
Meeting high level design expectations for premises, facilities, utilities, equipment coupled with an optimized process design and specifications using a risk approach, will strongly reinforce CCS during product development and the entire project phases leading to a high
CCS performance for routine activities and consequently, a high level of industrial performance.
In the diagram below (Figure 2), contamination control requirements are represented as a V Model to provide a global understanding of existing interactions between product/process design and systems/equipment design. This customized CCS V Model works like an immune antibody to prevent and control contamination in the pharmaceutical industry.

Role of suppliers
For suppliers, at a time of increasing demand for innovative and accurate treatments, it’s essential to have skilled process engineers who understand the complexity of sterile pharmaceutical manufacturing and manufacturer’s needs.
The role of process engineering has never been more critical. Whether improving manufacturing efficiency or ensuring compliance with stringent regulatory standards, Supplier’s process engineers play a key role in transforming complex processes into rationalized, cost-effective and innovative solutions (e.g. RMM, SUS, AI and digital solutions…)
It is strongly recommended that suppliers and stakeholders work closely together to facilitate understanding of regulatory concerns and challenges. We can emphasize the potential of networking and innovation as an effective mean of improving suppliers’ consideration of user needs.

Management of internal activities
Within pharmaceutical companies, CCS implementation at all levels requires the orchestration of all the impacted resources around a single objective and enables strong collaboration between different professions that previously did not work closely together (e.g. sterility
Assurance, project leaders, production, QC, technical services…. quality assurance). The creation of a multi-disciplinary group of different business experts, who work together over the long term. is essential for success.
To create the favorable conditions in which these new challenges can be applied, it is essential to identify opportunities for adjusting the organization, the roles and responsibilities, ways of working and defining clear pathways of escalation.
Once a favorable organizational model has been identified, it must be validated by top management, clearly documented and communicated to all stakeholders.
For such a reorganization, the involvement of top management and stakeholders is fundamental
In fact, team engagement depends on top management’s commitment to the strategy: budget available, resources allocated, inter-sector collaboration, all supported by a strong communication on the benefits/risks of implementing a CCS approach, as well as the commitment of the entire management team.
Management of outsourced activities
Contamination control can also be affected by several outsourced activities (e.g. QC testing, cleaning of classified area, sterilization of materials…) which underlines the importance of subcontractor/ service provider management that should include for a minimum:
– Assessment of the quality system of the subcontractor/ service provider (e.g., change control, change notification of customers, deviation management, good documentation practice).
– In the quality agreement between the customer and the subcontractor/service provider, consider URS requirements (related to contamination control).
– In the quality agreement between the customer and the subcontractor/service provider, specify the expectation to have a CCS and its related effectiveness review.
– Regular on-site audits performed by the customer.
When using a CMO or CDMO for manufacturing pharmaceutical products, the implementation of CCS is the responsibility of the CMO or CDMO and should be specified in the quality agreement between the two parts. The customer should have a quality oversight of the CCS.

The elements specified in Figure 1 are the main pillars of the PQS model. They are intended to be used appropriately and consistently throughout the product lifecycle. They should facilitate acknowledgement of opportunities for identifying continuous improvement pathways for contamination control. How can this be achieved using standard PQS elements?
Changes, deviations and CAPA Management
If we include the CCS in the PQS, the CCS becomes an integral part of the product lifecycle and can evolve as new knowledge is acquired or changes occur. This may involve the modification/adjustment of certain control measures which are an integral part of the CCS. PQS components such as deviation and CAPA management, as well as change management, are triggers for any revision of the CCS.
Therefore, introducing a systematic assessment of the impact on the CCS when dealing with deviations, changes and defining CAPAs (e.g. Change in cleaning & disinfection program, change in personal gowning for a specific operation, CAPA adding a new control measure…) is very useful for having a contamination control strategy that is permanently up to date and under control, acting proactively to prevent deviations and recurrences.
This encourages us to place even greater importance on the accurate definition of root causes, the definition of immediate actions when possible and appropriate CAPA to reduce the risk of contamination and eliminate recurrences. The definition of suitable effectiveness reviews is extremely important.
Some adjustments may be necessary to facilitate data collection, which is very important for the holistic analysis carried out when reviewing the effectiveness of the CCS (for example, categorizing deviations according to CCS elements to facilitate follow-up.eg. glove test integrity failures, EM excursions, sterility testing failures, product leakage…. failure in GXP equipment requalification, APS failure, critical alarm occurrence, repeat and recurrent significant events).

Process performance & Product Quality monitoring system and Management Review
Giving a particular importance to contamination control in all quality management processes is very helpful:
– In starting the reflection about contamination risks at each stage and being able to alert and escalade as early as possible.
– In preparing the needed data for CCS effectiveness review.
The type of monitoring can also be adjusted (in type, number and frequency) using adapted risk management tools to be able of detecting any drift in the level of control. A well-designed monitoring programs (EM program, cleaning program, utility monitoring, deviations, complaints…. QC testing trending, alarm trending) will help to select the adapted Metrics for the CCS effectiveness review.
The purpose of performing the CCS effectiveness review at a regular basis is to evaluate CCS performance during the life cycle of the product and identify any improvement or remediation actions. This CCS effectiveness review should form part of the periodic management review (Section 2.3 of GMP annex 1) already in place (eg. PQR, APR, CPV….)
In order to better understand the functioning of all these existing quality reviews and product monitoring, their relationship should be clarified to make sense and take benefit of the outcome of each exercise for performing the holistic review of CCS performance.
And you, has your company redesigned its existing PQS systems to include a contamination control dimension?
4. PQS Enablers:
As illustrated in Figure 1, two key enablers are identified in the PQS model:
– Product and process expertise
– Quality & risk culture
Let’s make a focus on contamination control applicability
Product and process expertise:
For manufacturers of sterile products, developing skills and competencies in product knowledge, contamination control, microbiological fundamentals, investigation tools and root cause analysis is required for key positions participating in the steps of design, qualification/validation, contamination risk assessment, routine manufacturing according to well-designed procedures, maintenance in clean area, trending analysis, investigations, CAPA definitions, Quality Assurance and Quality Control.

This expertise grows over time and during the product life cycle (changes, process adaptations, regulatory evolution…), underlining the importance of a longterm organization with the identification of SMEs in critical fields.
An individual and collective development plans should be in place for each employee according to the needs of his function. A special focus should be done on contamination control risk identification, proactive evaluation before the problems occur, continuous improvement actions and escalation paths.
Networking with peers and potential suppliers as well as attending conferences on regulatory evolutions, microbiology days and aseptic production is highly recommended and should not be limited to quality employees.
All these elements will impact positively shaping the pharmaceutical future with innovative technologies and optimized design
Quality & risk culture
Embracing an efficient quality culture in our day-to-day activities is a real challenge nowadays for pharmaceutical companies, with the increasing expectations of sterile product manufacturing.Agile and innovative solutions should be implemented at all levels of the organization to give sense and should use a variety of smart educational tools adapted to each audience. Practical and interactive case studies have a real added value for developing the mindset of employees to better understand risks and act appropriately.
Companies’ top management and the quality department are the essential actors for promoting quality culture. It is essential that managers lead by example, incarnating quality values in their daily actions, decisions and orientations. Their awareness about the added value that a sustainable quality culture can have on our way of working, on our performance and on the company’s brand image will help for settingstrategic orientations and objectives of the company every year.
Close collaboration between operational stakeholders (e.g. the production department, engineering and technical services….) and human resources is crucial for defining the targeted agile initiatives to promote these principles: regular culture talks (about : risk management, continuous improvement and contamination control management) , continuous campaign of awareness on contamination control , agile projects focused on continuous improvement, new working methods, dedicated quality weeks, quality podcasts, targeted training, ongoing collaboration with operational staff and creative ways of engaging teams in this important subject.
Implementing a strong quality culture is not only a matter of compliance or the only business of the quality department but the business of all the company from the top management to the operationals directly involved in manufacturing, packaging operations and distribution.
As required by GMP annex 1(section 3.1): “the risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk”.
This clear requirement emphasizes the importance of risk culture and the use of QRM for supporting a robust CCS in the company. Other regulations such as, The CFR – Code of Federal Regulations, ICH, PIC/S have in recent years incorporated in their guidance’s, the requirements for using QRM during the entire product life cycle. The added value of using QRM principles is to identify our existing risks, to cote their criticality, mitigate them by proposing continuous improvement actions. Embracing a proactive risk approach is a key element for preventing and reducing contamination.
As precised for quality culture, risk culture is also a prerequisite for CCS implementation and should be promoted by the company’s leadership. It’s useful not only for risk assessments redaction but also useful for everyone to embrace a risk behavior. It means that every employee should be able:
– To identify quality and contamination risks,
– To assess the risk with relevant bodies contribution,
– To act appropriately according to defined procedures,
– And to escalade if it is assessed critical for patient safety and/or product quality and/or business continuity