Contamination Control Strategy: practices & a case study

of a CCS implementation.
As a result of the successive revisions to the draft EU GMP Annex 1 (1), the term
“Contamination Control Strategy (CCS)” has become as well known as the term “Quality
Risk Management (QRM),” which is intriguing because the CCS foundation is built on QRM
principles.

Since the release of the first EU GMP Annex 1 draft, many questions have been raised by
manufacturers and industry associations to the Inspectors Working Group (IWG) regarding
the CCS expectations:

 What is the CCS scope – viable and non-viable particulates from any origin (product
residue, viruses, disinfectant residues, etc.)?”
 Should the CCS be a document, for example, a “sterility assurance quality manual”
that includes an exhaustive list of expectations listed in the latest draft?
 Should manufacturers create a standalone document per site or per production
buildings that describes how the strategy is applied and how the performance is
measured and evaluated?

These types of questions have led the IWG to include the CCS definition in the glossary of
the draft Annex 1 version 12, released in February 2020. “A planned set of controls for
microorganisms, pyrogens, and particulates, derived from current product and process
understanding that assures process performance and product quality. The controls can include
parameters and attributes related to the 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”(1).

Despite the second revision of the draft Annex 1 v12 by IWG, it appears that the need for
additional practical guidance for establishing and documenting an appropriate CCS is
considered necessary by our industry. Therefore, many technical and scientific industry
associations (such as PHSS/A3P, ECA, PDA, ISPE) are working actively to publish CCS
practical guideline to assist the industry.

This article is part of a series of articles that will cover CCS practices, development,
implementation and evaluation. This first article will discuss CCS practices and a case study
of a CCS implementation. The first section presents the results of a survey conducted by
STERIS to assess the scope, implementation status, and implementation needs of CCS. The
second section provides a real-world example of the key elements of an existing
contamination control program, and how this program was upgraded to a CCS based on a gap
assessment of the existing program versus the expectations laid out in the latest EU GMP
Annex 1 draft v12.

1. Contamination Control Strategy Implementation Status and

Practices
In April 2021, a survey was initiated during a STERIS hosted webinar titled “Contamination
Control Strategy: Implementation Roadmap” to understand the (bio)pharmaceutical CCS
implementation status, practices, and needs. One hundred ninety-one attendees located across
the globe participated in the webinar (Figure 1- top and bottom). Only responses from
pharmaceutical industry (i.e.: pharmaceutical, biopharmaceutical, medical, industrial,
research, consumer) who responded to the survey were considered for the purpose of this
analysis; the responses rate varied between 42 to 52% of the total participant.

The majority of respondents work downstream (e.g., formulation, filling, and packaging) and
medical devices. The remaining respondents work in upstream (e.g., bulk, drug substance
manufacturing) , small molecules, and cell & gene therapy or advanced therapeutic medicinal
products (Figure 2).
40% of the respondents see that the biggest challenge in designing a CCS is identifying all
the critical controls. In comparison, 22% consider as challenging to identify the interlink
between controls (Figure 3 – top). Some (18%) believe that the significant challenge is to
define the CCS scope. The challenges expressed by the respondents seem to be the same
across the different types of manufacturers.

60% of the respondents are implementing a CCS, despite various challenges identified and
Annex 1 being a draft. However, 29% are still in the information-gathering stage or waiting
for Annex 1 to go into effect (Figure 4).
Most respondents (81% or 77) would apply the CCS to the manufacturing processes and
facilities. In comparison, 7% (or 7) have also included the distribution processes where
contamination may occur. The rest (12% or 11) have not defined where the CCS would be
applied. It should be noted that the distribution includes transportation of intermediate or
finish products between affiliates’ sites or to a contract manufacturer before or after release of
the final medicinal product.

71% (or 77) have already defined the scope of their CCS, while the rest, 19% (or 18), have
not yet defined it. of those who have already defined the CCS scope, 55% focus on
contaminants from microorganisms, particulates, and pyrogens, while 26% focus only on
microorganisms and particulates (Figure 5).

The contamination definition in the draft Annex 1 version 12 seems not to include viruses or
other types of contaminations (e.g., TSE/BSE under the EMA note for guidance
EMA/410/01). However, suppose viruses are identified as a source of contamination, the
CCS scope should at least address this risk of contamination and how to prevent
contamination.

The term particulate with respect to the CCS scope is currently subject of intense debate as
some have included product residue as per EU Annex 15 in their “particulates’ ‘ definition.
Therefore, they have included the concept of cross-contamination in their CCS scope. On the
other hand, others argue that the definition of “contamination” in the draft Annex 1 glossary
deals with foreign particulate matter (e.g visible, or sub-visible particles contamination) as
expressed in the United States Pharmacopeia (USP<790>, USP<788>) or European
Pharmacopeia (E.P. 2.9.20, E.P. 2.9.19). Exogeneous and environmental particulates should
be included in the CCS scope. It is acceptable to have a separate document dealing with
product residue or cleaning agent contamination regulated by the EU Annex 15 and Chapter
3. This last document (cross-contamination program) can be part of the genealogy of the CCS
documentation. 58% (56) of respondents have included product residue in their definition of
particulate, while 19% (18) have only referred to particulate as exogenous (visible and sub-
visible particulates) and environmental particulates. The rest did not yet define the term
particulate.

59% have or plan to have a gap assessment of their current documentation (e.g., process map,
risk assessment, procedure, and organizational measures) and practices against the CCS
requirements. In comparison, 10% will not perform a gap assessment (Figure 6).

Ensuring that existing documentation and practices align with the CCS requirements and
scope may help identify the critical controls. These critical controls must reflect the
effectiveness of all the various controls (design, procedural, technical, and organizational)
and monitoring measures employed to prevent the contamination risk. 62% of the
respondents recognize the challenges in identifying all critical controls, while 11% do not
think it will be a challenge. 18% of the respondents have already identified all their critical
controls (Figure 7).

The CCS should consider all aspects of contamination control and its life cycle with ongoing
and periodic review, resulting in appropriate quality system updates (1, 2). The periodic
review is generally set at a defined period. However, some indicators or threshold values
(e.g., Residual Risk Priority Number (RPN), quality performance indicator, Key performance
indicator) suggesting an increase in the contamination risk or trend should trigger the review
of the CCS to identify corrective actions(2). 39% have not defined the threshold that would
trigger the CCS review, while 25% have defined it (Figure 8). Some of the respondents have
not (5%) or do not think (4%) it is required to determine a threshold value; they might
consider that their Pharmaceutical Quality System will trigger the corrective action to manage
risks associated with contamination.

The CCS calls for a holistic view of all the critical controls involved in managing risk
associated with contamination (1,2,3). This holistic view should encompass an end-to-end
supply chain that includes starting material (e.g., raw material, excipient) until the final
product, the facilities, and the surrounding environment (e.g., facilities, equipment). We can
quickly imagine how complicated this could be with complex supply chains involving
multiple entities across the globe. However, despite this complexity, 55% of respondents plan
to have a holistic and unique document to present their CCS, while only 9% will not (Figure
9).

There are various ways to implement a CCS. However, a thorough understanding of the
manufacturing processes and surrounding environment is required to adequately define the
CCS scope and the documentation structure that fits a pharmaceutical manufacturer’s process
and its supply chain complexity (2).

2. Case study of the implementation of the CCS by updating an

existing Product Protection and Control Strategy (PPCS):
Disclaimer for the case study : “the gap assessment summarized in table 2 represents
documentation gaps between an overarching existing PPCS approach in line with the current
GMPs and applicable guidances and a newly possible CCS aligned with the requirements of
the Revision 12 draft of the EU GMP Annex 1”.

Implementing a CCS requires a cross-functional team of Subject Matter Experts (SME) who
have a holistic understanding of the process, facility, and product contamination risks and
regulations.
The survey presented in the first section demonstrates that CCS development is a difficult
exercise. It is more than just establishing a “sterility assurance quality manual.” It is about
creating a strategy that includes holistic contamination risk management and ongoing
evaluation of the improvement implemented to prevent contamination (1).

3. Case Study
The case study presents the update of an existing strategy called “product protection and
control strategy” (PPCS) , created several years ago, that:

 Includes microbiological and particulates contamination, product residue cross-

contamination, chemical containment, and product degradation. During product
technology transfer to a production site, a depth risk assessment is performed to
identify all critical control points at the facility and process level, followed by
documentation and implementation of the PPCS.
 Is already entirely integrated into the current Product Quality Management System
and part of the Site Validation Master Plan. This step provides the strategic
framework that assures that the manufacturing operates in a validated state and
appropriate governance to enable balanced continuous improvements and investment
plans.

Step 1: verify alignment with CCS scope and documentation structure expectations
versus the existing PPCS

The scope of the CCS is clarified in the definition provided in the glossary of the EU GMP
Annex 1 Feb 2020 revision draft v12. In addition, in point 2.1 and point 2.5, we have the
following key expectations that identify the scope further: “minimize risks of microbial,
particulate, and pyrogen contamination,” and “potential sources of contamination are
attributable to microbial and cellular debris (e.g., pyrogen, endotoxins) as well as particulate
matter (e.g., glass and other visible and sub-visible particulates).” In terms of the CCS
document structure, the latest Annex 1 revision draft does not contain any special
expectation.

Therefore, based on the proposed definition and elements in the Annex 1 revision draft, the
following decision has been taken as summarized in Table 1.
In conclusion of step 1: the site decided to change the name of the PPCS to CCS to align with
the expected terminology while keeping the PPCS structure.

Step 2: identify the gaps between the PPCS with the new CCS requirements while
maintaining the PPCS structure.

The existing PPCS considers all the aspects of the contamination control from prevention by
design, control per qualification and operations, to monitoring at critical control points,
sterility assurance metrics performance evaluation, and continuous improvement. This
process is in good alignment with the current drafted expectations at point 2.1, 2.2, and 2.3.

The current PPCS is based on six central pillars that include several key elements that need to
be described in terms of contribution to the overall contamination risk management:

A. People

 Aseptic Gown design and cleaning/sterilization qualification, related supplier

qualification
 Theoretical Training and Qualification of personnel which includes in the scope:
hygiene, basics elements of microbiology (contamination sources and contamination
prevention measures)
 Practical qualification to gowning in aseptic areas, to sterile manufacturing operations
(general cleanroom practices, aseptic techniques, product process design, disinfection)
 Participation in Aseptic Process validation

B. Facilities, Equipment, Utilities & Infrastructures Design, Qualification, Maintenance,

and Control Measures

 The design sub-elements are the facility layout, cleanroom design and classification,
cross-contamination management where appropriate, and people and material flow
 Airborne Contamination Control measures HEPA filtration, airflow, and pressure
cascades, localized unidirectional airflow protection, airflow Pattern qualification,
continuous total particulates monitoring systems where appropriate
  Biocontamination control measures any associated equipment such as cleaning,
disinfection, sterilization systems/processes, and related validations
 Cleanroom’s classification, qualification, and monitoring
 HVAC, pressure cascade, utilities, and production equipment systems alarms setting
and qualification – Pest control programs
 Preventive and corrective maintenance programs
 Good housekeeping programs

C. Process Design, Validation, and Control Measures

 State of the art design: using closed systems, barrier technologies, single-use systems,
highly automated and integrated systems facilitating data integrity expectations,
cleaning and sterilization in place, online filter integrity testing, automated
decontamination systems
 Cleaning and sterilization of all equipment and primary product components
 Product sterilization by filtration validation
 Clean, dirty, aseptic, and sterile hold times qualification
 Process Control Parameters qualification and Process validation
 Manufacturing and aseptic operation activities practices qualification and monitoring

D. Product and Container Closures Design, Validation, and Control Measures

 Critical Quality Attributes determination, qualification, control, and performance

monitoring
 Raw materials, excipients, container closure systems, single-use systems used in
production, selection and qualification, related suppliers’ qualification, and
management
 Ready to Use or Ready to Sterilize Components when more appropriate
 Container Closure Integrity Validation
 Pre-filtration Bioburden, endotoxins and other In-process Control’s validation and
implementation

E. Sterility Assurance Performance Metrics and Monitoring Program

 Cleanroom Environmental monitoring data, utilities monitoring data assessment and

trending
 Facility and process alarms management and trending
 Product analytical controls management, assessment, and trending (in-process,
release, and stability testing data) – Raw materials, excipients, and primary products
containers control and monitoring data
 Product visual inspections data (defects classification, defects levels, trending)
 Process monitoring data
 Operators’ performance monitoring and trending (personnel monitoring and
qualification data)
 Aseptic Process Simulations data
 Assets Qualification Monitoring data
 Housekeeping evaluation, fit ad finish program in classified areas
 Pest control data

F. Ongoing overall Quality Oversight and Continuous Improvement

  Deviation, complaints management
 Change Management
 Site self-inspection program, quality and sterility assurance field observation, global
quality audits
 Supplier management and audit program
 Management review of the quality systems and process/product performance and
quality metrics
 Regulatory inspections trends and observations
 Regulatory expectations and Technological evolutions survey

The decision was made to keep the six pillars structure, as they remain aligned with the
current drafted Annex 1 expectations for the CCS documentation. Potential gaps or
improvements needs were identified for each key element listed in each pillar with the latest
draft EU GMP Annex 1 revision text. The potential gaps identified can be improvements in
procedures, processes, or points/rationale that need further clarification.

This gap assessment was performed following these steps:

 Deep line per line, word by word analysis between the newly revised draft Annex 1
v12 and the current site strategy
 A search in the regulatory framework using the following keywords: CCS,
Contamination Control, Contamination.
 A benchmark of practices through external workshop, training, or seminars (e.g.,
A3P, ISPE, ECA, PDA workshop/training on CCS) to identify if additional elements
or best practices needed to be included.

Then the new elements based on the gap assessment have been included in a template table
(table 2) to facilitate the update of the existing strategy.
Step 3: reference all key site strategies, rationales, reports, risk assessments, procedures,
plans, etc., capturing the rationale for the site’s contamination control and sterility
assurance risk management program.

As described at point 3.1 of the draft Annex 1: the Pharmaceutical Quality System “PQS for
sterile product manufacture should also ensure that: An effective risk management system is
integrated into all areas of the product life cycle with the aim to minimize microbial
contamination and to ensure the quality of the products manufactured. 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. […] The risk management outcome should be reviewed regularly
as part of ongoing quality management, during change control, and during the periodic
product quality review.“

So far, all essential procedures were already referenced directly in the text of the documented
current strategy. Still, based on the outlined new requirements, the decision was taken to
collect and reference in addition the relevant key site strategies, supporting rationales,
reports, risk assessments, plans, etc… to capture the justification underlining the site’s
contamination control and sterility assurance risk management program. As for step 2, these
new elements have to be included in the table 2 to facilitate the update section while re-using
the pillars structure as presented previously.

Step 4: Update of the different sections of the CCS by the site’s Subject Matter Experts

Each site SME was involved in the gap assessment for its area of expertise and
responsibilities. After the gap assessment was made, each SME had to:

 Update existing sections or create new sections to fill the gap between current
procedures and regulatory/future requirements.
 Reference the adequate strategic documents, rationales, risk assessments, etc.

At the end of the four steps, the final CCS is a standalone comprehensive document with
three major parts:

 The core text describes the CCS and the six pillars structure as described in step 2.
 The Table 2 records all relevant key CCS supporting strategies and assessments by
the pillar as outlined in steps 3 and 4.
 A list of all Products/Production areas specific appendixes for chemical cross-
contamination and product containment controls.

Step 5: Final holistic review by the CCS owner and approval by the senior management

As with any key strategic document (e.g., the site validation master plan), the CCS had to be
approved by the senior management. The approvers formally commit to the described
contamination risk management strategy and associated governance process to ensure product
quality, patient safety, and continuous improvements by approving this CCS.
It is clear that this CCS document will become a major expected deliverable of a sterile
products manufacturing site during future regulatory inspections. This document includes a
complete overview of contamination control management. It can directly be used as a support
for the inspectors to verify the effective application of the described process and controls and
to assess the robustness of the referenced supporting rationales and risks assessments.

It must be acknowledged that the creation (and even the update) of such a comprehensive
document represents a challenge and necessitates an excellent transverse knowledge of the
process and facility control elements. On the other hand, once finalized and approved, this
CCS is also an excellent training tool for all employees who must be aware of their role in the
holistic contamination control picture.
One of the biggest challenges foreseen is defining an effective transversal performance
dashboard and governance decision-making as suggested by the draft Annex 1 at point 2.4.

4. Conclusion
The CCS is a key strategic document/plan that describes the contamination risk management
strategy and associated governance to decide the continuous improvements and investment
plans to prevent contamination. Therefore, developing such a document requires a cross-
functional team of experts with good production, QRM, and regulatory knowledge. This
work will undoubtedly require extensive hours of meetings and teamwork.

Despite the second revision of the draft Annex 1 by Inspector Working Group (IWG) and
several industry conferences and workshops around the CCS topic, need for additional
practical guidance for establishing and documentation of an appropriate CCS is considered
necessary by our industry.

It is logical to encounter different CCS understanding and implementation practices as

suggested by the survey presented. This phenomenon may explain why the CCS scope may
be different between manufacturers based on:

 the type of processes (e.g., downstream, upstream, medical device),

 type of product manufactured (sterile, non-sterile),
 manufacturer process knowledge and expertise,
 understanding of the draft Annex 1 version 12,
 the existing contamination control program in place.

Consequently, the implementation and the evaluation of the CCS will also differ between
manufacturers. The practice difference is acceptable when the manufacturer can justify that
the CCS will comply with regulatory requirements.
This article shared one example of defining the CCS scope and implementing a CCS by
updating an existing contamination control program.

However, it is up to the manufacturer to decide the scope and the elements (also called
“points to consider” in draft Annex 1) being part of the CCS to create a strategy that includes
a holistic contamination risk management and ongoing evaluation of the improvement
implemented to prevent contamination.

The survey and the case study shed light on the industry challenges in:

 Agreeing on the CCS scope,

 Identifying all the critical controls,
  Organizing people roles and the PQS around the CCS, e.g., creating a new role,
creating new governance bodies, or integrate it within the existing organization,
 Defining the threshold that would require review/evaluation of the CCS,
 Developing an effective transversal quality performance CCS dashboard.

This article is part of a series of articles. The second article will focus on the challenges of
developing and implementing a CCS during the early design phase of a new project. The
third article will present an example of an evaluation program to assess the performance of
the CCS and how an efficient continuous improvement plan is identified.

References
[1] : Second targeted stakeholders’ consultation on the draft revision 12 of Annex 1, on
manufacturing of sterile medicinal products, of Eudralex volume 4 – Public Health –
European Commission.
https://ec.europa.eu/health/medicinal_products/consultations/2020_sterile_medicinal_product
s_en (accessed Jun 10, 2020)

[2] : Walid El Azab, Contamination Control Strategy: Implementation Roadmap, PDA

Journal of Pharmaceutical Science and Technology, Volume 75, Number 5,
September/October, 2021.

[3] : Johnson, L.; Hansy, C. Establishing a Contamination Control Strategy/Program: From

Global Development to Site Implementation.
https://www.americanpharmaceuticalreview.com/Featured-Articles/564173- Establishing-a-
Contamination-Control-Strategy-Program-From-Global-Development-to-Site-
Implementation/?catid=6262 (accessed Jun 10, 2020).