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Contamination Control Strategy

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What you need to know about Phar­ma­ceu­tical water systems

ccs

And BWT solu­tions regarding your Cont­a­m­i­na­tion Control Strategy.

With the release of the EU GMP Annex 1 in August 2022, an imple­men­ta­tion of a Cont­a­m­i­na­tion Control Strategy (CCS) has become manda­tory. The scope of the CCS has changed as well. It includes not only the testing of final product, for the release rele­vant para­me­ters such as conduc­tivity, TOC and bioburden, but also the moni­toring of the overall process. Based on a cont­a­m­i­na­tion risk manage­ment (CRM), measures and activ­i­ties must be imple­mented to guar­antee the spec­i­fied func­tion­al­i­ties of each indi­vidual process step of the water purifi­ca­tion system, in partic­ular cold water systems.

Plant with Focus on Water Systems
Plant with Focus on Water Systems
Overview of Production Plant with a Focus Point on Water Systems
With BWT solu­tions, you are prepared for the imple­men­ta­tion of a CCS.
We are here to assist you.


CCS: a holistic concept

As stated in the EU GMP Annex I: "...Appro­priate design of the facility, equip­ment and processes, followed by the imple­men­ta­tion of well-​designed proce­dures, and finally appli­ca­tion of moni­toring systems as the element that demon­strates that the design and proce­dures have been correctly imple­mented and continue to perform in line with expec­ta­tions..."
Annex 1, C (2022) 5983 final, Chapter 2.2
Pyramid Scheme CCS
Pyramid Scheme CCS

The CCS can be broken down to four elements

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Prevent

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monitor icon

Control

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Combat

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Document

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Contamination Risk Management

The foundation of a successful Contamination Control Strategy is a Contamination Risk Management (CRM) which requires a deep understanding of the individual process steps and their contribution to the contamination risk. Based on the CRM, which is required to identify all risks in your water system, a CCS can be implemented.

RAW WATER AND PRE-​TREAT­MENT

The most crit­ical path for micro­bial cont­a­m­i­na­tion is through the raw water. Depending on the source of the raw water, e.g. munic­ipal water, spring water or well water the quality can be very different, and it may have serious seasonal changes. Para­me­ters like total hard­ness, chlo­ri­na­tion, dissolved inor­ganic substances like nitrate, sili­cate are crucial for the design of a water purifi­ca­tion plant. For PW and WFI it is impor­tant that the source water quality is according to drinking water stan­dards.

In terms of micro­bi­ology this means that e.g. the limit for CFU for aerobic mesophilic microor­gan­isms is in the range of 300/ml. Under these condi­tions, the real number of microor­gan­isms is in the range of 15,000 to 200,000 TCC  (Total Cell count)1. This means that there is a signif­i­cant under­es­ti­ma­tion of the bioburden by just consid­ering the CFU.

1Trinkwasserqualität

 

Raw Water and Pre Treatment

POINT OF USE

Whereever a water system is connected to an opening, microor­gan­isms can enter. Sampling points that are not main­tained and ster­il­ized prop­erly, connec­tions to other processes that may be cont­a­m­i­nated bear a high risk of back­wards cont­a­m­i­na­tion of the water loop.
Glass Bottle Pharma

MAIN­TE­NANCE

When­ever main­te­nance or repair of a water gener­a­tion or distri­b­u­tion system is needed there is a high risk to cont­a­m­i­nate the instru­ment with microor­gan­isms. Even if you exer­cise the utmost care when replacing compo­nents like valve membranes, RO or EDI membranes, or any other compo­nent, there is still a risk of cont­a­m­i­na­tion with microor­gan­isms. After restart of the plant sani­ti­za­tion and moni­toring of the bioburden is crucial for a safe use of the system. It should also be consid­ered that after opening of the plant, the popu­la­tion of microor­gan­isms may change since new organ­isms may enter the system.
Maintenance Pharma

INAD­E­QUATE SANI­TI­ZA­TION CONCEPT

Finding the ideal sani­ti­za­tion proce­dures is always a compro­mise between risk, effort, cost and tech­nical limi­ta­tions like heat or chem­ical resis­tance of the plant. Sani­ti­za­tion should be performed as less as possible but as much as required.

Insuf­fi­cient sani­ti­za­tion of a water gener­a­tion or distri­b­u­tion systems is one of the most impor­tant sources of micro­bial cont­a­m­i­na­tion. The sani­ti­za­tion process needs to be opti­mized for the indi­vidual gener­a­tion / distri­b­u­tion system. Dead legs, or pipes with small flow rates, filters or membranes e.t.c. need special atten­tion. Moni­toring that the spec­i­fied sani­ti­za­tion condi­tions (temper­a­ture, ozone concen­tra­tion …) are reached at any point of the system is crucial. Insuf­fi­cient sani­ti­za­tion can even result in forma­tion of a more resis­tant microor­ganism popu­la­tion by inducing persister cells that may survive sani­ti­za­tion processes and are able to repop­u­late biofilm.



The four main elements of CCS

Prevent

The preven­tion of a micro­bial cont­a­m­i­na­tion is crucial within the water gener­a­tion for the phar­ma­ceu­tical industry. But how can we persis­tently prevent such? By under­standing the process and thus being able to esti­mate the contri­bu­tion of the risk for a micro­bial cont­a­m­i­na­tion for each indi­vidual process step.
The design of the plant and the main­te­nance proce­dures are the two crucial aspects. We need to under­stand where the germs come from, there­fore it is crucial to know how the entire water gener­a­tion process is struc­tured.

prevent
prevent

microbiological monitoring
microbiological monitoring

Control

Heterotrophic Plate Count (HPC) is the only compen­dial method for micro­bial cont­a­m­i­na­tion moni­toring today. A serious concern for imple­menting a CCS as described in Annex I, is the fact that HPC does not detect all microor­gan­isms in a sample. Only colony forming units (CFU) are visible.
Studies have shown that the number of CFU does not reflect the number of microor­gan­isms in a system. To grasp the real micro­bial situ­a­tion in a water purifi­ca­tion system, rapid methods have to be consid­ered to gain more control.


Combat

There is no PW or WFI water gener­a­tion and distri­b­u­tion system that is sterile over the whole life­cycle. Microor­gan­isms always find a way into the plant. Either through the raw water, back contamination through user points or during main­te­nance activ­i­ties. Sterility is tech­ni­cally hard to achieve and would generate a high effort and cost and the ster­il­iza­tion proce­dures exert enor­mous stress to the equip­ment.

combat
combat

document
document

Docu­ment

A key success factor for a CCS is a gapless docu­men­ta­tion. Just talking about 21 CFR Part 11 or audit trail is not suffi­cient anymore. It’s more about data generated during the system lifecycle, raw data, meta data et cetera. Due to the increasing demands in data manage­ment and data integrity e.g., ALCOA or ALCOA+ prin­ciple and other regu­la­tions, the effort for compliant docu­men­ta­tion is perma­nently increasing. A serious number of concerns and warning letters from the FDA are related to data integrity viola­tions.



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