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Contamination Control

Strategy

Greg McGurk

GMP Conference

12th November 2014

Microbiological, Pyrogen / Endotoxin & Particulate

Scope

• Introduction

• Control strategy

Understand sources of contamination

Specific considerations for the design of a control strategy - Process / facility design, people, process, equipment, environment, raw materials etc

• Examples of deficiencies

212th November 2014

Introduction

Minimisation of the risks of contamination in the manufacture of sterile & biological medicinal products is fundamental

• The principle of Annex 1 (‘Manufacture of Sterile Medicinal Products’) to the EU GMP Guide states ‘The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination.’

• Need to assess risks – Execution of a process risk assessment

12th November 2014 3

Introduction

• Paragraph 125 of Annex 1 specifies that

‘The sterility test applied to the finished

product should only be regarded as the last

in a series of control measures by which

sterility is assured.’

• These control measures form the

foundation for the contamination control

strategy


Introduction

• The principle of Annex 2 (‘Manufacture of

Biological Active Substances and Medicinal

Products for Human Use’) states ‘…quality risk

management (QRM) principles are particularly

important for this class of materials and should

be used to develop the control strategy across

all stages of manufacture so as to minimise

variability and to reduce the opportunity for

contamination..’


Introduction

• Over recent years the HPRA has highlighted

concerns related to risks associated with

biofilms and contamination from

environmental sources, including

microbiological, pyrogen and particulate

sources


Introduction

• In order to minimise the risk of

microbiological and particulate

contamination, the HPRA is taking a

proactive approach and, if not already in

place, is seeking the development of

appropriate process risk assessments and

control strategies by manufacturers of

sterile medicinal products.


Understanding source of Contamination -

Microbiological

Typical Sources

• Water - Gram –ve rods & as below

• Environment -Staphylococcus, Micrococcus & Bacillus species

• L-forms - lack cell walls and consist of highly pleomorphic elements ranging in size from 100nm to 800nm.


Microbiological

L-Forms - Form and grow as biofilm in interstitial spaces such as found in filters and membranes.

Filters and membranes form a focal point for concentration of metabolites and L-Forms of bacteria.

L-Forms can pass through 0.2 micron filters with ease and have been proved to cause disease.


Microbiological

• Cellular Debris – Endotoxin, exotoxin

• Metabolites – e.g. Bacteriocins: pyocins, megacins and colicins

Quorum sensing is the basis of chemical communication between bacteria. It involves secretion of signaling molecules and receptor mediated response to these molecules

There are potentially many thousands of signalling molecules released in a biofilm and their toxicology is relatively unknown


1112th November 2014

Microbiological

Perception

-Easy to detect / easy to kill

-Planktonic – free living organisms

If a control strategy is developed using this

model it will not be effective

Current monitoring programmes are

developed based on the above assumption

Microbiological

• Micro-organisms exist in complex densely

populated structures.

• Biofilm – preferred mode of growth

• Organisms are typically sessile and occupy

a complex mixture in a densely populated

microbial environment

• Adequate system for determination of shift

change in the expected flora


Microbiological

• The development of biofilms on otherwise

clean surfaces (i.e., surfaces that are free of

organic and inorganic contaminants)

proceeds through a 4-step process:

1. Sorption of trace organic and inorganic

compounds to form a conditioning film, which

may serve as an organism recognition factor in the

initial phases of attachment.


Microbiological

2. A reversible primary attachment, mediated by

advective transport processes and/or

chemotaxis , which is the movement of an

organism in response to a chemical gradient.

3. Surface-division, also referred to as colonization.

4. Synthesis of EPS, which stabilizes the sessile

population.


Microbiological

Why do biofilms go undetected?

• Biofilm mass contain only 1 to 15% micro-organisms and so the underestimate by traditional tests is significant.

• Recovery from water samples is in the region of only about 0.25%.

• On inspection, it is not unusual to see some TNTC results for water samples. This is usually put down to:

– Sampling error

– Analyst error

– Accidental contamination


Microbiological

Consideration should be given to whether such TNTC results are in fact true results and could be as a result of the presence of biofilm

• The introduction and use of more modern and accurate methods for microbiological testing should be considered.

• Companies should execute a feasibility study to assess current technologies available and determine most appropriate and compatible technology



Understanding sources of contamination -

Particulate contamination

• Annex 1 states ‘Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eye-sight checks, with spectacles if worn, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals.


Particulate contamination

• Typical sources – glass, plastic, raw materials, process related, environmental

• System for 100% inspection of all filled parenteral products required.

– Manual or automated

– Appropriately evaluated and qualified for identification and rejection of defective units

– Routine assessment of effectiveness of these systems

– Analysis of defect data / trending

– See Denise Coakley’s presentation


Contamination Control Strategy

The development of such a strategy requires thorough process knowledge. It includes should include consideration of several elements:

•Design

•People

•Process

•Equipment

•Environment

•Raw materials


Contamination Control Strategy - Design

considerations

• Must facilitate contamination control

• Design tailored to the dosage form

• Understand the facility location and background contamination risk

• Optimized layout to minimise risk of cross contamination / contamination ingress

• Optimisation of utilities to minimise risk of contamination


Contamination Control Strategy - Process /

Equipment Considerations

• Method of manufacture

• Sterilisation / aseptic

• Automation Vs manual

• Equipment – cleaning, sanitisation, sterilisation – use of CIP / COP systems

• Fundamentally the process should be designed with a contamination control strategy

• Process Risk Assessment


Contamination Control Strategy - Personnel

Considerations

• Training to gain basic understanding of the risks personnel represent to the product and process

• Iterative training programme – asepsis (consider incorporation of off line training in performance of certain more complex, more intricate and high risk aseptic manipulations, cleanroom behaviour, process simulations)

• Continuously assess adequacy of training provided


Contamination Control Strategy -

Environmental Considerations

• Adequate environmental controls

• Appropriate classification based on the risks involved and in line with Annex 1

• Determination of a process related environmental monitoring programme based on observation of the process

• Appropriate trending and assessment of trends (assess actual counts as well as % alert and action limits exceeded). Include species trend assessment


Environmental Considerations

• Ongoing assessment of the adequacy

of environmental monitoring

programme

• Inclusion of additional targeted

monitoring – GMP areas, Fungi, Facility

monitoring, for example, during

building work


Contamination Control Strategy - Raw material

Considerations

• Robust supplier qualification programme

• Robust supplier audit programme

• Appropriate microbiological controls in

place at the raw material manufacturing

site

• Adequate assessment of the

manufacturing process and controls with

respect to control of contamination.

• Routine testing and trend assessment



Additional elements to be considered within such a control strategy should include:

(Note: this is not an exhaustive list)

• Utilities

• Preventative maintenance – Maintaining equipment and premises to a standard that will not add significant risk from a contamination viewpoint. Consider regular inspection of utilities, process equipment and transfer lines for obvious signs of deterioration – O-rings, gaskets, seals –regular inspection and replacement



• Process qualification

• Cleaning / sanitisation – Frequent, rotation of disinfectants & detergents and inclusion of sporocidal agents

• Monitoring systems - include an assessment of the feasibility of the introduction of more modern and sensitive methods of detection & introduce where deemed necessary

• Prevention – Investigations / CAPA / Root cause determination and the need for more robust investigational tools



• Contamination control and steps taken to minimise the risk of contamination are a series of successive linked events / measures. These are typically assessed, controlled and monitored in isolation.

• A contamination control strategy would integrate all of these measures to ensure a comprehensive approach is taken with respect to prevention and control of microbiological and particulate contamination.



The strategy should take into

consideration all aspects of

contamination control and its life cycle.


Thank you

Thanks to Centre for Biofilm Engineering, Montana State University

for permitting use of the pictures representing biofilm formation

Additional references: PDA technical report on Biofilm control

(Draft – pending publication)

PHSS – White paper on control strategies

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