In the demanding world of the pharmaceutical industry, guaranteeing drug quality, safety and efficacy is vital. An essential aspect of guaranteeing this is managing contamination. In the 2015 update, the European Good Manufacturing Practices (GMP) set out in chapter 3 “Premises and Equipment” and chapter 5 “Production” the regulatory requirements imposed to minimize contamination risks. In 2023 the publication of the revised version of Annex 1 of the European GMP, which covers GMP for sterile drugs, further reinforced these requirements by focusing on preventing contamination. 

The term contamination often refers to microbial contamination. However, this contamination in the pharmaceutical industry can take many forms, including microbial, particulate, and chemical, and can stem from a range of sources such as raw materials, equipment, actual manufacturing processes, and personnel. The consequences of uncontrolled contamination can be significant, ranging from loss of expensive production batches to patient health risks, including regulatory consequences for manufacturers. Faced with these issues, manufacturing of pharmaceutical products, particularly sterile products, requires special attention to avoid any form of contamination. It is in this context that Annex 1 was revised and provides details of the regulatory expectations for aseptic manufacturing, underlining the importance of a robust and well-designed Contamination Control Strategy (CCS). 

The CCS is a comprehensive document explaining the means put in place to demonstrate that contamination risks are under control and enable prevention, detection, and elimination of contamination risks at all stages of pharmaceutical production to guarantee product quality. 

It covers various aspects, ranging from design of facilities and equipment to training of personnel, plus operating procedures and environmental monitoring. For manufacturers, complying with Annex 1 is not only a question of abiding by laws; it is an essential process to guarantee product quality and protect patient health. 

In this article, we are going to examine how to draw up this CCS. We will start by briefly studying the issue of contamination to understand the expectations of the CCS. Then we will provide details of the different approaches suggested by the ECA Foundation and Parenteral Drug Association (PDA), as well as the 5M-based approach and summarize the practices to be used. The goal is to implement an effective CCS, guiding professionals through the writing process and implementation of this strategy. 

1. Understanding contamination in the pharmaceutical industry

Contamination is the introduction of foreign agents or substances into a pharmaceutical product, which can affect its quality, safety, or efficacy. In the pharmaceutical industry, contamination is classified into several categories (microbial, particulate, and chemical) each featuring points requiring special attention in terms of production and product quality. 

Microbial contamination is caused by bacteria, viruses, yeasts, or molds. These micro-organisms can be introduced into the pharmaceutical product from the environment, raw materials, equipment, or personnel. This microbial contamination is particularly concerning for sterile products, where the presence of any microbes can have consequences for the patient. 

Particulate contamination is caused by the presence of foreign inorganic or organic particles, such as dust, fibers, metal particles, or leftover product. These particles can stem from equipment wear, material handling, or breakdown of components of the actual product. 

Chemical contamination or cross-contamination occurs when chemical or biological substances in one product are transferred to another, potentially due to inadequate cleaning practices or poor separation of production lines. 

The potential sources of all these contaminations will be studied and monitored via this CCS. The production environment including air, air renewal systems, water and water treatment systems, surfaces, and the general state of cleanliness of facilities in production zones can be vectors of contamination. Likewise, the general state of equipment and machines, their state of cleanliness, residues from previous production, machine wear and lack of upkeep can also contribute to contamination. And raw materials used to manufacture pharmaceutical products can be contaminated at the source or during storage and transport. Finally, personnel can introduce contaminants themselves via direct or indirect contact with product or product contact surfaces. 

The number of potential sources of contamination is long but each one is important and must be considered and controlled. Every failure can cause contamination with consequences, ranging from therapeutic inefficacy and side effects to patient safety incidents, such as infections or toxic reactions. 

2. The CCS in Annex 1

This underlines the importance of a CCS to protect all stages of pharmaceutical production against risks of contamination. The definition of the CCS according to Annex 1 is “A planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient 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.” 

Annex 1 provides information on the content of the CCS. It lists the issues to cover including all potential sources of contamination to analyze in this support document. However, it does not state how to construct and structure this document in case of a new facility to put in place or for a facility in operation with preexisting documentation. 

The 16 points featured in Annex 1 cover the following concepts: 

1. Design of both the facility and process
2. Premises and equipment
3. Personnel
4. Utilities
5. Raw material controls – IPC
6. Product containers and closures
7. Vendor approval
8. Outsourced service management
9. Process risk management
10. Process validation
11. Sterilization process validation
12. Preventative maintenance
13. Cleaning and disinfection
14. Monitoring systems
15. Prevention – trending, investigation, and CAPA 16. Continuous improvement.

Drawing up a CCS is an exercise that can be complicated for manufacturers and several reasons can combine to turn the exercise into a difficult challenge. Indeed, pharmaceutical product manufacturing processes can be extremely complex, involving a range of equipment, technologies, and stages. Identifying and assessing contamination risks at every stage requires technical expertise and understanding of interactions between these different components of the manufacturing process. Validation of contamination control measures can accordingly be a long and arduous process to demonstrate its necessity and be accepted by each department involved. 

For new facilities or businesses launching new products, there can be a lack of historical data to use to assess contamination risks. Furthermore, putting in place an effective CCS can require significant resources in terms of time, personnel, and financing. Coordinating these efforts across different departments (e.g., production, quality assurance, engineering, etc.) and getting all stakeholders to commit can be difficult while also ensuring the continuity of daily business. 

Several approaches have been suggested to pharmaceutical manufacturers by associations assisting businesses to help to draw up a CCS and to assist them with putting in place and writing this document. 

3. Drawing up the CCS according to ECA Foundation

ECA Foundation, a non-profit organization assisting the European pharmaceutical industry, provides help to develop a CCS. Via the ECA Task Force of Contamination Control Strategy, in 2022 it published a document to help respective managers to draw up a CCS: “How to Develop and Document a Contamination Control Strategy”? 

This document provides a description of the way to develop and document an effective strategy. It provides details of a three-phase approach: CCS development or review, CCS document compilation, and finally CCS assessment. These three phases are based on the same approach as the three process validation stages set out by the FDA. 

To develop the CCS, this organization identifies an approach either for a new facility or for an existing facility based on the level of understanding of processes. For a new facility, it will be necessary to start by getting to grips with, understanding and mapping the process to identify potential sources of contamination. Assessment of these potential sources via a risk analysis will enable classification of possible dangers of contamination and identification of preventative measures to put in place. These controls mentioned in the CCS must be described in the documentation. For an existing facility or otherwise with in-depth knowledge of the process, the CCS will compile and summarize preexisting controls and analyze any discrepancies. The risk analysis will be an update to or otherwise supplement documentation already in force and enable identification of any additional measures that need to be put in place. 

This organization describes a three-stage working method covering what must be done about each issue affecting contamination control as defined in Annex 1. 

Phase 1 describes all the documentation, risk analysis, rationale, and control measures in place that can be described or used to guarantee contamination control. All these analyses are conducted based on the list of sixteen elements that must be included in the CCS as described in Annex 1. Links are included with Annex 1 to explain and highlight points requiring special attention in terms of control practices to put in place. 

Phase 2 describes how to compile all these documents into a single CCS document legibly and understandably featuring all previously identified documentation. A summary and basic outline of the CCS are provided in the annexes of this document. 

Phase 3 describes the cycle and conditions for review of this document to keep it updated and in line with the appropriate level of control to guarantee the facility’s contamination control. 

The advantage of this support document to draw up a CCS is to properly highlight all existing documentation and risk analyses to provide reasons for all the controls and therefore documentation compiled to explain the contamination control. 

4. Drawing up the CCS according to PDA

The PDA non-profit supplies guides to facilitate improvement of the development and manufacturing of parenteral pharmaceutical products, and published PDA technical report 90: “Contamination control strategy development” (TR-90) in February 2023. This report provides advice on the way to draw up an effective CCS and describes governance to put in place featuring three interdependent quality system levels to guarantee successful proper contamination control. 

The first level includes individual elements and describes expectations to minimize contamination risks. This includes fundamental elements such as design and construction of production facilities, design of air flows, selection of construction materials, layout of equipment, choice of materials, consumables and suppliers, cleaning or sterilization methods, and training courses defined for personnel. 

The second level includes quality processes put in place for classification and validation of these individual elements, and enables demonstration that each individual element selected can reasonably achieve the appropriate level of control. The goal is to create a controlled environment that prevents introduction, generation, and retention of contaminants. 

The third level includes monitoring put in place such as monitoring of air, surfaces, water, personnel, and other critical parameters to quickly detect any deviation from established standards. Monitoring put in place can for example include trend analyses, or alarms. Data collected is used to assess the effectiveness of environmental controls and to take corrective measures if necessary. A basic outline is provided in the annexes of the technical report to help draw up this CCS. 

The advantage of this document is its structure that enables organization and tracking of each section individually across the different levels. 

It must be demonstrated for each individual element what critical data has been identified and that it is properly representative of a contamination risk. It must then be tracked over time to keep this element under control. To ensure the effectiveness of the document, each individual element must be considered holistically because they are interdependent of each other. For example, a well-thought-out facility design can be compromised by poor operating practices, and even the best operating practices cannot make up for inadequate facility design. 

5. Drawing up the CCS according to 5M

The writing of a CCS can also be structured via a risk analysis of sources of contamination conducted based on a 5M diagram (or Ishikawa diagram). The 5M diagram enables identification of potential sources of risk of contamination based on each category: Raw Material, Machine, Manpower, Medium, Method. 

The Raw Material branch enables identification of contamination risks based on the quality of the material, its supplier, its storage, and flow of materials entering the production zone until they are used. 

The Machine section covering equipment used directly or indirectly in production will enable identification of contamination risks stemming from activities such as cleaning and maintenance but also their assembly in aseptic connections. 

The Manpower branch will enable identification of contamination risks stemming from personnel including, for example, hygiene, training, and traceability of personnel working in aseptic zones, plus gowning practices. 

The Medium branch covering production premises will enable the identification of contamination risks stemming, for example, from cleaning and disinfection of these premises including white zones of all grades D to A, or the controlled air input system. 

Finally, the Method branch will enable identification of contamination risks during the actual production process including for example mixing, filtration, and final filtration. 

The rating of each of these risks identified by 5M branch will enable definition of critical risks. Based on this rating and with reasoning, controls will be established to get under control, reduce or eliminate risks. 

The main advantage of this method is that it provides a structured approach to examine the different dimensions that can influence product quality or process performance. 

Branch-by-branch analysis encourages examination of all the aspects of the production process, which enables identification of the causes of issues that could be neglected. It is also relatively simple to understand and implement, which makes it accessible to all levels of the organization. 

6. Structure of the CCS

The goal of the CCS is to document in a comprehensive approach the organizational, technical, and procedural control measures put in place and to guarantee that all risks of contamination by micro-organisms, endotoxins/pyrogens and particles are appropriately identified, assessed, and mitigated.  

The goal of drawing up this CCS is to be able to answer “why,” i.e., understanding not only how the contamination occurs, but above all why it occurs in a process, and consequently in the product. Why can a contamination occur, why here, why can it proliferate, in the equipment, process, facility, etc. 

Answering all these “why’s” will enable an understanding of root causes and therefore the definition of the optimal mitigation tool to reduce or even eliminate the risk of contamination, and to put in place sustainable solutions. 

This CCS can be structured, either as a comprehensive main document including all aspects of the control strategy put in place, or a master document referring to separate connected documents covering all the topics to address and that must be linked together. It must not be a simple list of documents existing at the facility or a list of documents covering the points mentioned in Annex 1. It is a comprehensive document that highlights the risk and reasoning for the controls put in place with a view to demonstrating that all dangers of contamination are controlled; it enables linking of different aspects and related support measures. 

Whatever the selected approach, whatever the history of the facility, the first stage of drawing up a CCS will be risk assessment. This involves systematic analysis of all production processes to identify, classify and manage potential risks of contamination based on the probability and severity of different contamination scenarios. It will be necessary to properly define the relevant process(es) or facility as well as the sterile products and/or any product or ingredient requiring bioburden control. Risk analysis of process(es) must not be confused with risk analysis of sources of contamination; the former enabling identification of potential risks with an impact on product quality and the latter enabling identification of potential sources of contamination of the facility. This activity must be conducted with a multidisciplinary team featuring members of different departments such as production, quality assurance, and engineering. Risk analyses conducted or identified if existing, and preventative measures will then be put in place to control and monitor these identified critical points. This process enables guaranteeing that control measures put in place are both adequate and proportional to the nature and gravity of risks identified. Based on this(-ese) risk analysis(-es), the CCS must describe this strategy clearly and in detail. It will cover how each risk will be managed or mitigated and provide details of the reasoning for the choices made, descriptions of controls put in place, and procedures for monitoring and revising the strategy. This can include changes to design, Standard Operating Procedures (SOP), training programs, improved cleaning practices, and environmental monitoring systems. 

The strategy put in place must enable a proactive approach, enabling detection of any trend or any anomaly upstream from the event and prioritizing prevention over reaction to contamination incidents. 

7. Conclusion

As we have explored in this article, an effective CCS relies on meticulous risk assessment, smart facility design, rigorous environmental control, standard operating procedures, and in-depth training of personnel. By following the stages described for putting in place this strategy and drawing up this document, the CCS will meet contamination risk management quality and support expectations to maintain consistent pharmaceutical product quality. It guarantees that critical contamination control points are identified, and contamination control measures integrated into the manufacturing process. Furthermore, it will enable identification and proactive management of contamination risks, which can reduce the frequency of contamination incidents, product recalls, and related financial losses. 

As the pharmaceutical industry continues to evolve and tackle new challenges, the CCS is becoming a vital pharmaceutical quality document. Businesses that invest in robust contamination control strategies and adopt the latest innovations are better equipped to protect their patients, products, and reputation. Implementation of the CCS according to Annex 1 provides this exhaustive framework to guarantee production of safe and efficacious sterile drugs.