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Pharmaceutical
Microbiology: Current and
Future Challenges
Dr. Tim Sandle
Pharmaceutical Microbiologist
http://www.pharmamicroresources.com/
Delivered to PDA Microbiology Europe, 15th
October 2018
Introduction
• The changing environment for pharmaceutical microbiology
• Limitations of methods
• Need for new (rapid) methods
• Separating people form processes
• Single-use technologies
• Environmental monitoring programme
• Best practices
• Rapid methods
• Contamination control strategy
• Objectionable organisms
• Burkholderia cepacia complex
The changing environment
for pharmaceutical
microbiology
Origins of pharmaceutical microbiology
• 1960s and 1970s – Pharmacy
schools, focus on sterilisation and
medicinal formulation.
• 1990 – The Pharmaceutical
Microbiology Forum in the U.S.
• 1991 - Pharmaceutical
Microbiology Interest Group
(Pharmig).
• 2000s - Pharmaceutical
microbiology courses
• 2006 – First Pharmaceutical
microbiology Master’s degree
Changing environment
• Range of activities associated with
pharmaceutical microbiology has
extended from the laboratory and
into the production environment.
• Also:
• Microbiological audits
• Rapid microbiological methods
• Conducting risk assessments
• Both proactive in terms of minimizing
contamination and reactive, in terms
of addressing microbial data
deviations;
• Ensuring that processes meet ‘quality
by design’ principles.
New understanding
• Knowledge
• Today’s pharmaceutical
microbiologist needs to have an
understanding of engineering,
regulation, the R&D process, and
production workflows.
• The microbiologist is expected to
understand industrial processes,
cleanrooms, and how to
effectively evaluate microbial risks
to products from people and
processes.
Limitations of monitoring methods
• Recognising the uncertainty with
environmental monitoring
methods
• Sample size
• Monitoring times
• Accuracy of methods
• ABNC phenomenon
• Some of these issues are greater
in ‘cleaner’ environments e.g.
Grade A / ISO class 5
Method limitations #1
• The classic techniques:
• Active air-sampling: volumetric
air-sampler
• Passive air-sampling: settle plates
• Surface samples: contact (RODAC)
plates and swabs
• Personnel samples: Finger plates
and gown plates
• New generation of ‘real time’
viable air samplers.
Method limitations #2
• Settle plates
• Position in relation to air currents
• Desiccation
• Meaningfulness of one CFU
• Attempt to quantify by Whyte’s
deposition rate
• Active air samplers
• Particle size cut-off (D50 value)
• Recovery ~50%
• Different instruments
Method limitations #3
• Contact plates
• Tidswell’s work on organism
recovery (~50%)
• Disinfectant residues on surfaces
and neutraliser selection
• Disinfectant rotation and
neutralisers
• Swabs
• Plain swabs ~10-20% recovery
• Flocked swabs 40-60% recovery
Ways to separate people from product
• Quality by design
• Control sterilisation
• Removing people from Grade A
environments
• Strengthening barriers between
people and product
• Such as: RABS, isolators or closed
systems for aseptic processing.
Single-use technologies #1
• Traditional technologies:
• Time-consuming,
• Expensive,
• Energy hungry,
• Require a large footprint,
• Prone to occasional control
breakdowns,
• Sterility assurance concerns.
• Single-use technologies:
• Reduce concerns around time,
• Can reduce costs,
• More security in avoiding non-
sterility
Single-use technologies #2
• Examples: tubing, capsule filters, ion exchange membrane
chromatography devices, mixers, bioreactors, product holding sterile
bags in place of stainless steel vessels (sterile fluid containment bags),
connection devices and sampling receptacles
• Need to assess:
• Leachables
• Extractables
• Method of sterilisation
• Robustness in relation to contamination e.g. aseptic connector
• Inhibition of microbial growth e.g. biocontainer bag
Environmental
monitoring programme
Environmental monitoring programme
• Forms part of the overall contamination control strategy.
• Purpose:
• To assess cleanrooms and controlled environments using viable and
particulate counting methods.
• To verify environmental control (how well is the cleanroom working?)
• To assess impact of staff behaviours
• To help evaluate risk in relation to excursions (location and event dependent)
• To assess event specific incidents e.g. HVAC losing power or maintenance
works
• Needs to be a written programme, with justifications.
Environmental monitoring programme
• Where monitoring takes place?
• Types of rooms and sample locations
• How often monitoring is performed?
• Pre-set sampling frequencies
• Types of samples required
• Methods describing how samples are taken and
how they are handled
• Who takes the samples?
• Data analysis and trending
• Level of microbial identification
• Investigating out of limits events
• CAPA for problems e.g. Cleaning and disinfection
• Types of culture media and incubation strategies
Importance of trending
• A good environmental monitoring programme will seek to show
consistent, high quality environmental conditions at any given time.
• The programme will seek to detect changes in the contamination
recovery rate that may be indicative of changes in the state-of-
control within the environment.
• This is achieved though a well-designed programme and an emphasis
upon trending.
• Trends are important:
• As counts
• As frequency of incidents
• As microflora
Rapid microbiological methods
• Rapid microbiological method technologies aim to provide more
sensitive, accurate, precise, and reproducible test results when
compared with conventional, growth-based methods.
• They normally involve some form of automation.
• They normal capture data electronically.
• Can support the contamination control strategy
Rapid microbiological methods
• Time
• To prepare the test
• Conduct the test
• Sample throughout
• Time to result
• Reduction in the time taken to conduct complimentary tests
• Less time for data analysis
• Simpler results reporting
Rapid microbiological methods
• Accuracy
• Reduction in human error
• Reduction in subjectivity
• To detect more accurately in comparison to a conventional method e.g. a
cultural method?
• To detect what a cultural method cannot?
Rapid microbiological methods
• Other areas:
• Real time data capture
• Electronic capture of data
• Automation
• Connecting apparatus
• Example - Real-time continuous
monitoring systems, based on
optical spectroscopy.
Contamination control
strategy
Holistic contamination control strategy
• Each facility - steriles and non-
steriles - should have a detailed,
facility-specific contamination
control strategy.
• To be effective, this needs to be an
approach that can assess
seemingly isolated contamination
events holistically.
• The process must be capable of
putting appropriate corrective and
preventive actions.
• The proposed revision to EU GMP
Annex 1 provides a working model.
Key points for a contamination control
strategy
• Understanding the design of both the plant and process.
• The quality of the design is important for controlling contamination.
• Detail of equipment and facilities,
• What is the equipment used?
• How does it work?
• How is it repaired?
• When is it calibrated?
• Are the best available technologies used?
Key points for a contamination control
strategy
• Training and control of personnel
• How well do personnel behave, especially in cleanrooms?
• Are staff trained in hygiene, cleanroom practices, contamination control,
aseptic techniques, loss of product sterility and in the basic elements of
microbiology?
• Control of utilities
• Utilities need to be controlled and operated within their design parameters.
• Compressed gasses, HVAC and water.
• Raw Materials Control
• Control of raw materials is not only a factor of testing and with controls in
place when containers are opened e.g. what safeguards are in place to
ensure containers are stored in dry environments?
Key points for a contamination control
strategy
• In-process controls
• Appropriate points in the production process need to be selected for
monitoring and appropriate limits set.
• Product containers and closures
• Aseptic processing requires a review of Grade A containment of vials; setting
maximum exposure time of sterilised containers and closures prior to closure
and ensuring crimping is conducted expediently; and establishing a robust
container closure integrity qualification.
• Vendor approval
• Understanding where materials come from, whether they have been
prepared and processed properly, and whether they remain the same as
those components used in previous validation.
Key points for a contamination control
strategy
• Outsourced services
• Cannot simply outsource services and accept certification when items are
delivered, especially with items that have undergone a sterilisation step.
Requires audit and expert review of the sterilisation process.
• Process risk assessment
• A formal risk assessment should be in place for each process step, beginning
with the start of the manufacturing process, capturing all processing steps
through to final packaging.
• Extend to good Distribution Practice.
Key points for a contamination control
strategy
• Process validation
• Process validation is an ongoing process and it should be frequently reviewed
and adapted as manufacturing feedback is gathered.
• An essential part of this is knowledge of microbial contamination rates,
particularly in relation to in-process bioburden and to the supporting
manufacturing environment.
• Preventative maintenance
• Control of the regular maintenance of equipment and premises, as either
planned and unplanned maintenance, is of importance to ensure product
quality and for a consistent process.
Key points for a contamination control
strategy
• Cleaning and disinfection
• Cleaning and disinfection are important steps for maintaining control. There
should be a rationale in place justifying the use of each disinfectant agent,
together with supporting data to show efficacy in terms of microcidal kill on
surfaces of a similar type used within the manufacturing area.
• Monitoring systems
• To assess whether cleanrooms and utilities are functioning as designed,
regular checks are required, such as checks of airflows or pressure
differentials. To be effective, the monitoring methods need to be continuous
so that data can be trended, and equipped with audible alarms.
Key points for a contamination control
strategy
• Prevention
• A contamination control strategy should have in place a good system for
addressing CAPAs. To arrive at an effective CAPA, there needs to be a system
in place for trending, conducting investigations, arriving at root causes, and
then for suggesting and implementing appropriate CAPAs.
• Continuous improvement
• No contamination control strategy should stand still and it should be regularly
reviewed and updated.
Objectionable
microorganisms and
BCC
Thinking about objectionable
microorganisms
• Need to move thinking beyond the organisms listed in USP and Ph.
Eur. Under ‘Microbial Limits Test’
• Undertake risk assessments to assess whether an organism is
objectionable
• Need to assess materials for:
• Need for testing
• Frequency of testing
• Appropriate limit
• Design test method
How to assess if an organism is
objectionable?
• The foremost factor is whether the organism is a pathogen for if the organism is known
to be a pathogen, and the route of infection is the same as the route of administration
for the product, the organism is most likely objectionable. This approach:
• Ranks administration routes in order of microbiological risk to patient,
• Discusses water activity & self-preservation/micro growth,
• Discusses preservative system for multi-use products.
• The ways by which objectionable microorganisms trigger a risk to the product or have
potential to cause patient harm include:
• Affecting product stability.
• Affecting the security of the container/ closure system
• Affecting the active ingredient.
• Producing off odors, flavors or undesirable metabolites.
• Having the potential to grow and exceed the total aerobic count specification.
• Possessing high virulence and a low infective dose.
• Resistance to antimicrobial therapy.
Burkholderia cepacia complex
• Burkholderia cepacia complex refers
to a group of Gram-negative, non-
spore forming rod-shaped.
• B. cepacia emerged as a human
respiratory opportunistic pathogen in
individuals with weakened immune
systems or chronic lung disease,
especially cystic fibrosis patients.
• BCC bacteria exist throughout the
environment, especially in soil and
water environments.
• In 2017, FDA sent out an alert
notification.
Burkholderia cepacia complex
• Burkholderia cepacia and related species
are human opportunistic pathogens
• They can cause pneumonia in
immunocompromised individuals.
• Other risks to susceptible patients
include:
• Endocarditis,
• Wound infections,
• Intravenous bacteremia,
• Foot infection,
• Respiratory infections.
• Some patient groups are at a greater risk
than others: elderly people, young
children, cancer patients, pregnant
women, people with chronic illnesses
Burkholderia cepacia complex
• As it is challenging to detect BCC, the FDA called for manufacturers of
non-sterile, water-based drug products to put in place risk
assessments and special tests for this group of organisms.
• 2019, there will be a new USP chapter.
• Standard bioburden tests are unlikely to be sufficient.
• The test for bile-tolerant Gram-negative bacteria described in USP<62> may
detect some types of BCC. But there are weaknesses.
Burkholderia cepacia complex
• 〈60 Microbiological Examination〉
of Nonsterile Products—Tests
for Burkholderia cepacia Complex
• BCSA contains peptones and sugars
that supply nutrients for the growth
of Burkholderia cepacia, and other
microorganisms.
• Crystal violet is added to inhibit
growth of other organisms.
• Anti-microbials are incorporated to
inhibit other organisms.
• Burkholderia cepacia colonies are
typically translucent and rough.
• On BCSA, the growth of B. cepacia
will cause a color change in the media
from red-orange to yellow.
Burkholderia cepacia complex
• Culture-independent rapid
microbiological methods which are
suitable, such as epiflourescence tests.
• Another possibility for testing is with the
use of polymerase chain reaction (PCR),
which amplifies specific segments of DNA.
• Researchers have developed a Ready-To-Go
PCR beads and specific DNA primers for B.
cepacia, which demonstrated a 100%
correlation between standard methods and
the PCR assay, with results obtained within
27 hours.
• A variant PCR method is with amplification
of the 16S rRNA gene, followed by
restriction enzyme-mediated fragmentation
of the amplicon.
Summary
• The changing environment for pharmaceutical microbiology
• Limitations of methods
• Need for new (rapid) methods
• Separating people form processes
• Single-use technologies
• Environmental monitoring programme
• Best practices
• Rapid methods
• Contamination control strategy
• Objectionable organisms
• Burkholderia cepacia complex
Thank you
Dr. Tim Sandle
Pharmaceutical Microbiologist
http://www.pharmamicroresources.com/

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Pharmaceutical Microbiology: Current and Future Challenges

  • 1. Pharmaceutical Microbiology: Current and Future Challenges Dr. Tim Sandle Pharmaceutical Microbiologist http://www.pharmamicroresources.com/ Delivered to PDA Microbiology Europe, 15th October 2018
  • 2. Introduction • The changing environment for pharmaceutical microbiology • Limitations of methods • Need for new (rapid) methods • Separating people form processes • Single-use technologies • Environmental monitoring programme • Best practices • Rapid methods • Contamination control strategy • Objectionable organisms • Burkholderia cepacia complex
  • 3. The changing environment for pharmaceutical microbiology
  • 4. Origins of pharmaceutical microbiology • 1960s and 1970s – Pharmacy schools, focus on sterilisation and medicinal formulation. • 1990 – The Pharmaceutical Microbiology Forum in the U.S. • 1991 - Pharmaceutical Microbiology Interest Group (Pharmig). • 2000s - Pharmaceutical microbiology courses • 2006 – First Pharmaceutical microbiology Master’s degree
  • 5. Changing environment • Range of activities associated with pharmaceutical microbiology has extended from the laboratory and into the production environment. • Also: • Microbiological audits • Rapid microbiological methods • Conducting risk assessments • Both proactive in terms of minimizing contamination and reactive, in terms of addressing microbial data deviations; • Ensuring that processes meet ‘quality by design’ principles.
  • 6. New understanding • Knowledge • Today’s pharmaceutical microbiologist needs to have an understanding of engineering, regulation, the R&D process, and production workflows. • The microbiologist is expected to understand industrial processes, cleanrooms, and how to effectively evaluate microbial risks to products from people and processes.
  • 7. Limitations of monitoring methods • Recognising the uncertainty with environmental monitoring methods • Sample size • Monitoring times • Accuracy of methods • ABNC phenomenon • Some of these issues are greater in ‘cleaner’ environments e.g. Grade A / ISO class 5
  • 8. Method limitations #1 • The classic techniques: • Active air-sampling: volumetric air-sampler • Passive air-sampling: settle plates • Surface samples: contact (RODAC) plates and swabs • Personnel samples: Finger plates and gown plates • New generation of ‘real time’ viable air samplers.
  • 9. Method limitations #2 • Settle plates • Position in relation to air currents • Desiccation • Meaningfulness of one CFU • Attempt to quantify by Whyte’s deposition rate • Active air samplers • Particle size cut-off (D50 value) • Recovery ~50% • Different instruments
  • 10. Method limitations #3 • Contact plates • Tidswell’s work on organism recovery (~50%) • Disinfectant residues on surfaces and neutraliser selection • Disinfectant rotation and neutralisers • Swabs • Plain swabs ~10-20% recovery • Flocked swabs 40-60% recovery
  • 11. Ways to separate people from product • Quality by design • Control sterilisation • Removing people from Grade A environments • Strengthening barriers between people and product • Such as: RABS, isolators or closed systems for aseptic processing.
  • 12. Single-use technologies #1 • Traditional technologies: • Time-consuming, • Expensive, • Energy hungry, • Require a large footprint, • Prone to occasional control breakdowns, • Sterility assurance concerns. • Single-use technologies: • Reduce concerns around time, • Can reduce costs, • More security in avoiding non- sterility
  • 13. Single-use technologies #2 • Examples: tubing, capsule filters, ion exchange membrane chromatography devices, mixers, bioreactors, product holding sterile bags in place of stainless steel vessels (sterile fluid containment bags), connection devices and sampling receptacles • Need to assess: • Leachables • Extractables • Method of sterilisation • Robustness in relation to contamination e.g. aseptic connector • Inhibition of microbial growth e.g. biocontainer bag
  • 15. Environmental monitoring programme • Forms part of the overall contamination control strategy. • Purpose: • To assess cleanrooms and controlled environments using viable and particulate counting methods. • To verify environmental control (how well is the cleanroom working?) • To assess impact of staff behaviours • To help evaluate risk in relation to excursions (location and event dependent) • To assess event specific incidents e.g. HVAC losing power or maintenance works • Needs to be a written programme, with justifications.
  • 16. Environmental monitoring programme • Where monitoring takes place? • Types of rooms and sample locations • How often monitoring is performed? • Pre-set sampling frequencies • Types of samples required • Methods describing how samples are taken and how they are handled • Who takes the samples? • Data analysis and trending • Level of microbial identification • Investigating out of limits events • CAPA for problems e.g. Cleaning and disinfection • Types of culture media and incubation strategies
  • 17. Importance of trending • A good environmental monitoring programme will seek to show consistent, high quality environmental conditions at any given time. • The programme will seek to detect changes in the contamination recovery rate that may be indicative of changes in the state-of- control within the environment. • This is achieved though a well-designed programme and an emphasis upon trending. • Trends are important: • As counts • As frequency of incidents • As microflora
  • 18. Rapid microbiological methods • Rapid microbiological method technologies aim to provide more sensitive, accurate, precise, and reproducible test results when compared with conventional, growth-based methods. • They normally involve some form of automation. • They normal capture data electronically. • Can support the contamination control strategy
  • 19. Rapid microbiological methods • Time • To prepare the test • Conduct the test • Sample throughout • Time to result • Reduction in the time taken to conduct complimentary tests • Less time for data analysis • Simpler results reporting
  • 20. Rapid microbiological methods • Accuracy • Reduction in human error • Reduction in subjectivity • To detect more accurately in comparison to a conventional method e.g. a cultural method? • To detect what a cultural method cannot?
  • 21. Rapid microbiological methods • Other areas: • Real time data capture • Electronic capture of data • Automation • Connecting apparatus • Example - Real-time continuous monitoring systems, based on optical spectroscopy.
  • 23. Holistic contamination control strategy • Each facility - steriles and non- steriles - should have a detailed, facility-specific contamination control strategy. • To be effective, this needs to be an approach that can assess seemingly isolated contamination events holistically. • The process must be capable of putting appropriate corrective and preventive actions. • The proposed revision to EU GMP Annex 1 provides a working model.
  • 24. Key points for a contamination control strategy • Understanding the design of both the plant and process. • The quality of the design is important for controlling contamination. • Detail of equipment and facilities, • What is the equipment used? • How does it work? • How is it repaired? • When is it calibrated? • Are the best available technologies used?
  • 25. Key points for a contamination control strategy • Training and control of personnel • How well do personnel behave, especially in cleanrooms? • Are staff trained in hygiene, cleanroom practices, contamination control, aseptic techniques, loss of product sterility and in the basic elements of microbiology? • Control of utilities • Utilities need to be controlled and operated within their design parameters. • Compressed gasses, HVAC and water. • Raw Materials Control • Control of raw materials is not only a factor of testing and with controls in place when containers are opened e.g. what safeguards are in place to ensure containers are stored in dry environments?
  • 26. Key points for a contamination control strategy • In-process controls • Appropriate points in the production process need to be selected for monitoring and appropriate limits set. • Product containers and closures • Aseptic processing requires a review of Grade A containment of vials; setting maximum exposure time of sterilised containers and closures prior to closure and ensuring crimping is conducted expediently; and establishing a robust container closure integrity qualification. • Vendor approval • Understanding where materials come from, whether they have been prepared and processed properly, and whether they remain the same as those components used in previous validation.
  • 27. Key points for a contamination control strategy • Outsourced services • Cannot simply outsource services and accept certification when items are delivered, especially with items that have undergone a sterilisation step. Requires audit and expert review of the sterilisation process. • Process risk assessment • A formal risk assessment should be in place for each process step, beginning with the start of the manufacturing process, capturing all processing steps through to final packaging. • Extend to good Distribution Practice.
  • 28. Key points for a contamination control strategy • Process validation • Process validation is an ongoing process and it should be frequently reviewed and adapted as manufacturing feedback is gathered. • An essential part of this is knowledge of microbial contamination rates, particularly in relation to in-process bioburden and to the supporting manufacturing environment. • Preventative maintenance • Control of the regular maintenance of equipment and premises, as either planned and unplanned maintenance, is of importance to ensure product quality and for a consistent process.
  • 29. Key points for a contamination control strategy • Cleaning and disinfection • Cleaning and disinfection are important steps for maintaining control. There should be a rationale in place justifying the use of each disinfectant agent, together with supporting data to show efficacy in terms of microcidal kill on surfaces of a similar type used within the manufacturing area. • Monitoring systems • To assess whether cleanrooms and utilities are functioning as designed, regular checks are required, such as checks of airflows or pressure differentials. To be effective, the monitoring methods need to be continuous so that data can be trended, and equipped with audible alarms.
  • 30. Key points for a contamination control strategy • Prevention • A contamination control strategy should have in place a good system for addressing CAPAs. To arrive at an effective CAPA, there needs to be a system in place for trending, conducting investigations, arriving at root causes, and then for suggesting and implementing appropriate CAPAs. • Continuous improvement • No contamination control strategy should stand still and it should be regularly reviewed and updated.
  • 32. Thinking about objectionable microorganisms • Need to move thinking beyond the organisms listed in USP and Ph. Eur. Under ‘Microbial Limits Test’ • Undertake risk assessments to assess whether an organism is objectionable • Need to assess materials for: • Need for testing • Frequency of testing • Appropriate limit • Design test method
  • 33. How to assess if an organism is objectionable? • The foremost factor is whether the organism is a pathogen for if the organism is known to be a pathogen, and the route of infection is the same as the route of administration for the product, the organism is most likely objectionable. This approach: • Ranks administration routes in order of microbiological risk to patient, • Discusses water activity & self-preservation/micro growth, • Discusses preservative system for multi-use products. • The ways by which objectionable microorganisms trigger a risk to the product or have potential to cause patient harm include: • Affecting product stability. • Affecting the security of the container/ closure system • Affecting the active ingredient. • Producing off odors, flavors or undesirable metabolites. • Having the potential to grow and exceed the total aerobic count specification. • Possessing high virulence and a low infective dose. • Resistance to antimicrobial therapy.
  • 34. Burkholderia cepacia complex • Burkholderia cepacia complex refers to a group of Gram-negative, non- spore forming rod-shaped. • B. cepacia emerged as a human respiratory opportunistic pathogen in individuals with weakened immune systems or chronic lung disease, especially cystic fibrosis patients. • BCC bacteria exist throughout the environment, especially in soil and water environments. • In 2017, FDA sent out an alert notification.
  • 35. Burkholderia cepacia complex • Burkholderia cepacia and related species are human opportunistic pathogens • They can cause pneumonia in immunocompromised individuals. • Other risks to susceptible patients include: • Endocarditis, • Wound infections, • Intravenous bacteremia, • Foot infection, • Respiratory infections. • Some patient groups are at a greater risk than others: elderly people, young children, cancer patients, pregnant women, people with chronic illnesses
  • 36. Burkholderia cepacia complex • As it is challenging to detect BCC, the FDA called for manufacturers of non-sterile, water-based drug products to put in place risk assessments and special tests for this group of organisms. • 2019, there will be a new USP chapter. • Standard bioburden tests are unlikely to be sufficient. • The test for bile-tolerant Gram-negative bacteria described in USP<62> may detect some types of BCC. But there are weaknesses.
  • 37. Burkholderia cepacia complex • 〈60 Microbiological Examination〉 of Nonsterile Products—Tests for Burkholderia cepacia Complex • BCSA contains peptones and sugars that supply nutrients for the growth of Burkholderia cepacia, and other microorganisms. • Crystal violet is added to inhibit growth of other organisms. • Anti-microbials are incorporated to inhibit other organisms. • Burkholderia cepacia colonies are typically translucent and rough. • On BCSA, the growth of B. cepacia will cause a color change in the media from red-orange to yellow.
  • 38. Burkholderia cepacia complex • Culture-independent rapid microbiological methods which are suitable, such as epiflourescence tests. • Another possibility for testing is with the use of polymerase chain reaction (PCR), which amplifies specific segments of DNA. • Researchers have developed a Ready-To-Go PCR beads and specific DNA primers for B. cepacia, which demonstrated a 100% correlation between standard methods and the PCR assay, with results obtained within 27 hours. • A variant PCR method is with amplification of the 16S rRNA gene, followed by restriction enzyme-mediated fragmentation of the amplicon.
  • 39. Summary • The changing environment for pharmaceutical microbiology • Limitations of methods • Need for new (rapid) methods • Separating people form processes • Single-use technologies • Environmental monitoring programme • Best practices • Rapid methods • Contamination control strategy • Objectionable organisms • Burkholderia cepacia complex
  • 40. Thank you Dr. Tim Sandle Pharmaceutical Microbiologist http://www.pharmamicroresources.com/

Editor's Notes

  1. Welcome
  2. Aim is to give a flavour of some of the hot topics, trends and challenges in pharmaceutical microbiology. What is being covered: The changing environment for pharmaceutical microbiology Limitations of methods Need for new (rapid) methods Separating people form processes Single-use technologies Environmental monitoring programme Best practices Rapid methods Contamination control strategy Objectionable organisms Burkholderia cepacia complex
  3. OK, to begin with - how has the environment within which pharmaceutical microbiologists find themselves changed?
  4. Before that – where did pharmaceutical microbiology come from? It is difficult to define when the term ‘pharmaceutical microbiologist’ emerged from the collective shadows of industrial and clinical microbiology. 1960s and 1970s – pharmacy schools, focus on sterilisation and medicinal formulation It not until the 1990s that the term entered common use. This was following the formation of two professional groups: The Pharmaceutical Microbiology Forum in the U.S. (for which the late Scott Sutton was instrumental in its development) The Pharmaceutical Microbiology Interest Group (Pharmig), both of which came into being around 1991. 2000s - Pharmaceutical microbiology courses 2006 – First Pharmaceutical microbiology Master’s degree
  5. Over this time the environment has changed. The range of activities associated with pharmaceutical microbiology has extended from the laboratory and into the production environment. Whilst there is a continuing need for monitoring of the environment and conducting standardized laboratory tests, pharmaceutical microbiology has moved on to embrace: Microbiological audits; rapid microbiological methods; conducting risk assessments, both proactive in terms of minimizing contamination and reactive, in terms of addressing microbial data deviations; and also ensuring that processes meet ‘quality by design’ principles. And getting the microbiologist away from the bench and into the plant.
  6. Knowledge has also shifted. Today’s pharmaceutical microbiologist needs to have an understanding of engineering, regulation, the R&amp;D process, and production workflows. To assess contamination control requires a more holistic approach than simply choosing technologies and disinfectants. Today the microbiologist is expected to understand industrial processes, cleanrooms, and how to effectively evaluate microbial risks to products from people and processes.
  7. We are also more knowledgeable about method limitations, such as recognising the uncertainty with environmental monitoring methods. Such as: Sample size Monitoring times Accuracy of methods ABNC phenomenon Lack of precision of counting methods and limited sample volumes Some of these issues are greater in ‘cleaner’ environments e.g. Grade A / ISO class 5
  8. Take some examples: Settle plates Position of plates in relation to air currents – the location must relate to air distribution, especially in Grade A – otherwise meaningless. Desiccation – can the plate be exposed for 4 hours and not lose excessive weight to cause recovery issues? Active air samplers Particle size cut-off (D50 value) – instruments vary. Recovery ~50% - most calibration standards. Different instruments – do they all work to the same efficiency?
  9. Others: Contact plates Tidswell’s work on organism recovery showed ~50%, although this is surface dependent. Standardization of weight and time is important. Disinfectant residues on surfaces and neutraliser selection Disinfectant rotation and neutralisers – causes a conundrum! Swabs Generally a poor recovery, although this depends on the swab type: Plain swabs ~10-20% recovery Flocked swabs 40-60% recovery
  10. Plus there is the colony forming unit itself: A CFU should not be thought of as a single bacterium or fungus – it is a colony forming unit. The ‘unit’ could be made up from one cell or many. There are several situations where this can arise. Example: Poor mixing of a sample before plating out, where cells stick together or become bound to the sample. Bacillus species, for example, are notorious for clumping; This can also be the result of poor mixing of agar plates; With environmental monitoring, if a skin flake lands on a settle plate, this is often carrying more than one organism.
  11. These issues means we need to focus on risk and other technologies. One is finding ways to separate people from product People are the primary source of contamination. Although good behaviours and gowning can be effective, we need to remove people from Grade A environments and to strengthen barriers between people and product. Best clean room environment design and operating practices cannot prevent the shedding of microorganisms into the environment by human operators Such as: RABS, isolators or closed systems for aseptic processing. Barrier technology reduces the need for interventions into the Grade A environment and hence minimises the risk of contamination.
  12. Another innovation is with single use technology. This involves moving away from equipment that must be sterilised or consumables that are recycled or pose a risk with their transfer into cleanrooms, towards the adoption of disposable and single-use sterile items.  Conventional processing poses a risk in terms of product sterility; cross contamination; failure to achieve sterility such as a wet autoclave load for a stainless steel vessel; or contamination ingress, as with performing a vessel-to-vessel connection. Single-use, sterile disposable technologies, include bag chambers, connectors, tubing, filling needle manifolds and filter capsules. They reduce concerns around time, costs and non-sterility.
  13. However, with single-use systems these need to be qualified. Need to assess: Leachables Extractables Method of sterilisation Robustness in relation to contamination e.g. aseptic connector Inhibition of microbial growth e.g. biocontainer bag
  14. How do out new thought processes affect environmental monitoring?
  15. First, EM needs to form part of the wider contamination control strategy. Is purpose is: To assess how well cleanrooms are performing, using viable and particulate counting methods. To verify environmental control (how well is the cleanroom working?) To assess impact of staff behaviours e.g. gowning. To help evaluate risk in relation to excursions : what is the impact of finding result x in location y? Does the excursion relate to an activity? To assess event specific incidents e.g. HVAC losing power or maintenance works This needs to be part of a written programme, with justifications for each stage.
  16. What should be included? Where monitoring takes place? Types of rooms and sample locations How often monitoring is performed? Pre-set sampling frequencies Types of samples required Methods describing how samples are taken and how they are handled Who takes the samples? Data analysis and trending Level of microbial identification Investigating out of limits events CAPA for problems e.g. Cleaning and disinfection Types of culture media and incubation strategies All of this needs to be captured in a rationale.
  17. We need to see the real value of a microbiological monitoring program in its ability to confirm consistent, high quality environmental conditions at all times. Monitoring programs can detect changes in the contamination recovery rate that may be indicative of changes in the state-of-control within the environment. This places a greater importance on trending. Trends are important: As counts As frequency of incidents As microflora
  18. A way to improve the quality of our data and its integrity have been advanced through rapid microbiological method. Rapid microbiological methods aim to provide more: sensitive, accurate, precise, reproducible test results when compared with conventional, growth-based methods. Often automated and capture data electronically for further analysis. As Dr. Miller has demonstrated, during the past 20 years, the field of alternative and rapid microbiological methods (RMMs) has gained momentum
  19. Such technologies can address the issue of ‘time’: Time to prepare the test Time to conduct the test Less time taken, or eliminating entirely, complimentary tests Less time spent on data analysis and instant reporting. We also need to consider sample throughout. Then there is time to result: knowing faster that something is wrong e.g. Water system failure; or, to please the owners of businesses, time to release being faster.
  20. These technologies can also assist with accuracy A rapid method could help with error reduction such as less human error (counting 100’s of plates) or less subjectivity (squinting at API strips). The second area, is more accurate results based on what a conventional method can detect. This relates to microorganisms that are culturable but where a conventional method isn’t always too good at recovering them e.g. a standard cotton swab It also relates to microorganisms that aren’t culturable. The VNBC question.
  21. Other advantages are with: Real-time measurements Electronic capture of data? Automation? Connecting apparatus? An example in the contamination control space is with alternative real-time continuous monitoring system. These instruments are optical spectroscopy counting devices designed to simultaneously detect the number and size of particles from a volume of air; and to additionally detect whether these particles are microbial and to estimate the numbers of microorganisms.
  22. Now we’ll look at developing a broader contaminations control strategy
  23. Each facility - steriles and non-steriles - should have a detailed, facility-specific contamination control strategy. To be effective, this needs to be an approach that can assess seemingly isolated contamination events holistically. The process must be capable of putting appropriate corrective and preventive actions. The proposed revision to EU GMP Annex 1 provides a working model. The main elements of such a control strategy, together with a short interpretation of what needs to be considered are outlined next.
  24. The first element is with understanding the design of both the plant and process The quality of the design is important for controlling contamination. This includes reducing the number of process steps; using closed systems, where possible, and reducing the numbers of personnel permitted to be a in a cleanroom. Second, the manufacturer should have a thorough understanding of the equipment used and the types of repairs required and justification of the calibration frequency. The best available technologies should also be used such as the use of equipment such as RABS, isolators or closed systems for aseptic processing.
  25. Third is with training and control of personnel How well personnel behave, especially in cleanrooms, is critical towards achieving contamination control. The minimum basis for a training program for a sterile facility would include: hygiene, cleanroom practices, contamination control, aseptic techniques, and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology. Fourth, utilities need to be controlled and operated within their design parameters and supported by appropriate monitoring. The microbiological plan for assessing a water system, for example, needs to justify the sampling frequencies and times. Fifth is with the control of raw materials. This is not only a factor of testing (such as use of the Microbial Limits Test), it also relates to controls in place when containers are opened. Are sterile sampling tools used? Is the environment within which materials are sampled the same as the environment within which materials are dispensed or used in production? What safeguards are in place to ensure containers are stored in dry environments?
  26. Sixth, in-process controls - Bioburden and endotoxin control are an important control mechanism. Appropriate points in the production process need to be selected for monitoring and appropriate limits set. A risk tool like Hazard Analysis Critical Control Points (HACCP) can be effective for achieving this. Seventh, is product containers and closures, especially for sterile products. Sterile is a temporary and transient state. A sterile product can quickly become non-sterile if a nonintegral (that is, uncapped) container is exposed to non-Grade A air or if the sealed container is breached. In addition, assessment of container closure integrity should extend through the shelf-life of the product, being part of formal stability studies. Eighth is vendor approval. This means understanding where materials come from, whether they have been prepared and processed properly, and whether they remain the same as those components used in previous validation.
  27. Ninth concerns outsourced services. It is not simply sufficient for a manufacturer to outsource services and accept certification when items are delivered, especially with items that have undergone a sterilisation step. Sufficient evidence must be provided via audit, and expert review. Tenth, a formal risk assessment should be in place for each process step, beginning with the start of the manufacturing process, capturing sterile processing, through to capping and packaging. Risk assessments should extend to the point where the recipient receives the product. Of particular concern is packaging and container closure integrity.
  28. Eleventh is about process validation, which is about the regular review of the validated status of the process and checking parameters. Often overlooked are microbial contamination rates, yet these are important for process robustness. Twelfth is with control of the regular maintenance of equipment and premises, as either planned and unplanned maintenance. To achieve this means having engineering staff who are knowledgeable about contamination.
  29. Thirteenth, cleaning and disinfection are important steps for maintaining control. Having a sound cleaning (use of a detergent) and disinfection (rotation of two biocides with different modes of activity) regime in place helps to address the risks of microorganisms introduced into cleanrooms, plus supporting data to show efficacy in terms of microcidal kill on surfaces of a similar type used within the manufacturing area. Fourteenth comes monitoring systems, such as to assess whether cleanrooms and utilities are functioning as designed, regular checks are required, such as checks of airflows or pressure differentials. To be effective, the monitoring methods need to be continuous so that data can be trended. Rapid methods can feature here.
  30. Fifteenth is prevention. A contamination control strategy should have in place a good system for addressing CAPAs. To arrive at an effective CAPA, there needs to be a system in place for trending, conducting investigations, arriving at root causes, and then for suggesting and implementing appropriate CAPAs. These activities hinge on effective investigational tools. A sound contamination control strategy will have already identified the main contamination risks and areas where contamination may occur, together with the impact and severity should such an event occur. Sixteenth is continuous improvement. No contamination control strategy should stand still and it should be regularly reviewed and updated. As part of any review, continuous improvement should drive necessary changes, based on information gathered.
  31. Now the final topic – objectionable organisms can Burkholerdia cepacia.
  32. Need to move thinking beyond the organisms listed in USP and Ph. Eur. Under ‘Microbial Limits Test’ Undertake risk assessments to assess whether an organism is objectionable Need to assess materials for: Need for testing Frequency of testing Appropriate limit Design test method
  33. How to assess if an organism is objectionable, the criteria developed by Scott Sutton proves useful. This includes: Assessing whether the organism is a pathogen for if the organism is known to be a pathogen, and the route of infection is the same as the product route of administration, the organism is most likely objectionable. This approach:   Ranks administration routes in order of microbiological risk to patient, Discusses water activity &amp; self-preservation/micro growth, Discusses preservative system for multi-use products.   Also need to weigh up whether the organism: affects product stability, affects the security of the container, affects the active ingredient, produces off odors, has the potential to grow, posses high virulence and a low infective dose, is resistant to antimicrobial therapy.
  34. The big objectionable of recent years and following the 2017 FDA guidance is the Burkholderia cepacia complex. This refers to a group of Gram-negative, non-spore forming rod-shaped bacteria composed of approximately 17 closely-related species which are grouped into nine genomovars. B. cepacia is ahuman respiratory opportunistic pathogen in individuals with weakened immune systems or chronic lung disease, especially cystic fibrosis patients. BCC bacteria exist throughout the environment, especially in soil and water environments.  The number of product recalls involving Burkholderia cepacia complex (BCC) remains relatively high.
  35. Burkholderia cepacia and related species can cause pneumonia in immunocompromised individuals (especially when introduced into the air passages of a susceptible population). Other risks to susceptible patients include endocarditis, wound infections, intravenous bacteremia, foot infection, and respiratory infections. Of interest - the lipopolysaccharide of BCC is 4-5 times more endotoxic than with Pseudomonas aeruginosa. Some patient groups are at a greater risk than others, including elderly people, young children, cancer patients, pregnant women, and people with chronic illnesses
  36. As it is challenging to detect BCC, the FDA is called on manufacturers of non-sterile, water-based drug products to put in place risk assessments and special tests for this group of organisms.  When examining samples for BCC, standard bioburden tests are unlikely to be sufficient. Instead it is necessary to use a pre-enrichment recovery step. The use of rich nutrient recovery agar may prevent some organisms that are stressed or sublethally damaged from being recovered. A further concern is that slower growing Burkholderia cepacia can be missed on conventional media such as blood or MacConkey Agar due to overgrowth caused by other faster growing organisms. This led USP to look at a new test.
  37. A new USP chapter for 2019 - 〈60〉 Microbiological Examination of Nonsterile Products—Tests for Burkholderia cepacia Complex.  Involves: Uses Burkholderia cepacia selective agar Enrichment step in SCDB Surface spread plate method BCSA contains peptones and sugars that supply nutrients for the growth of Burkholderia cepacia, and other microorganisms. Crystal violet is added to inhibit growth of Gram-positive organisms. Anti-microbials are incorporated to inhibit organisms other than Burkholderia cepacia. In interpreting the medium, Burkholderia cepacia colonies are typically translucent and rough. On BCSA, the growth of B. cepacia will cause a color change in the media from red-orange to yellow.
  38. Alternatively, there are culture-independent rapid microbiological methods which are suitable, such as epiflourescence tests. Another possibility for testing is with the use of polymerase chain reaction, which amplifies specific segments of DNA. Some researchers have produced Ready-To-Go PCR beads and specific DNA primers for B. cepacia. A variant PCR method is with amplification of the 16S rRNA gene, followed by restriction enzyme-mediated fragmentation of the amplicon (restriction fragment length polymorphism analysis).
  39. OK, to summarise we’ve looked at: The changing environment for pharmaceutical microbiology Limitations of methods Need for new (rapid) methods Separating people form processes Single-use technologies Environmental monitoring programme Best practices Rapid methods Contamination control strategy Objectionable organisms Burkholderia cepacia complex
  40. End