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© Biophorum Operations Group Ltd
This paper will be published in a ‘Special Section’ of the PDA Journal of
Pharmaceutical Science and Technology, in May/June 2015.
Microbial Monitoring For Biological Drug Substance Manufacturing: An Industry Perspective.
Authors
Diane Hardy, Chief Microbiologist, Regeneron
Brian L. Bell, Senior Scientist, Bristol-Myers Squibb
Ren-Yo Forng, Site Microbiologist, Astra Zeneca
Michael Knight, Senior Manager QC Microbiology, Genentech
Anita Bawa, Director QC, Bayer
Stephanie Ramsey, Manager Quality Systems, Baxter
Christine Arbesser-Rastburg, Director Quality Operations / Microbiology, Baxter
Mousumi Paul, Associate Director Engineering, Merck
Christopher Ton, Associate Director, Merck
Fran Leira, Global MSAT / QC Head, Lonza
Claudia Roman, Site Head QC Microbiology, GlaxoSmithKline
Kim McFarland, Director QC Microbiology, Alexion
David Phillips, Senior Director QC, Shire
Jean Stuckey, Manager QC Microbiology / Lab Services, Patheon
Christian Bauer, Head of Biotech Compliance and Projects, Sanofi
Andreas J. Calvo, Senior Scientist, AbbVie
Corresponding author: David Bain, Facilitator, BPOG Corresponding author contact information: BPOG, 5 Westbrook Court, Sharrow Vale Road, Sheffield, S11 8YZ, United Kingdom, david@biophorum.com
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Introduction
The purpose of this paper is to provide guidance and drive consistency in regards to
microbial control for manufacturers of low bioburden bulk biologics. This paper provides
recommendations based on biologics produced using cell cultures such as monoclonal
antibody (mAb) based products, and recombinant protein manufacturing process. These
recommendations, from the members of the BPOG Bioburden Working Group, are intended
to assist biopharmaceutical manufacturers develop microbial monitoring strategies and
product safety assessments. Each manufacturer is unique, therefore, alternative strategies
may be justified and/or qualified.
Scope
This paper focuses on the following topics:
Microbial in-process monitoring during inoculum expansion
Culture expansion, and protein purification process of bulk drug substances
Setting alert/action levels limits
Objectionable organisms in bulk biologics, responding to bioburden excursions
Assessing impact to product quality
Background
The biopharmaceutical industry produces non-sterile bulk biologics (i.e. Drug Substances)
using bioburden controlled processes in accordance to Q7A and Annex 2. Sterile final
dosage forms are produced in accordance to Annex 1. A mammalian cell mAb process
consists of upstream and downstream processes. Upstream operations include the protein
production phase of manufacturing where the host cells are grown to generate the product
molecule. Primary recovery (centrifugation and depth filtration) is the first step in removing
the unwanted production components while retaining the product molecule. Capture of the
target molecule is often achieved with affinity chromatography. Some firms chose to perform
capture as a part of downstream manufacturing. Downstream operations, which typically
include chromatography, viral clearance, concentration and diafiltration, progressively refine
the product to its final bulk form suitable for manufacturing into the final drug product.
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The following diagram illustrates a generic mammalian cell mAb process.
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In-Process Product Stream Monitoring and Testing
A comprehensive in-process sampling and testing plan is necessary to monitor and
control the biological manufacturing processes. The following sampling approach is
typically incorporated as part of the general sampling plan. Additional sampling
locations may be necessary in some cases due to specific process considerations.
In general, samples for bioburden and/or endotoxin should be taken at critical
process steps, e.g. pre-filtration samples, or after hold times, where bioburden could
get introduced into the process or proliferation could occur. Such sampling points
for bioburden and/or endotoxin should be determined and documented by
performing a risk analysis of the manufacturing process (prior to establishing the
sampling and testing program).
Sample Collection
Bioburden/endotoxin sample containers and procedures are key elements of
the overall monitoring program given the potential risk of false positive and
negative results. Materials must be well mixed just prior to sampling.
Containers used for bioburden sampling must be sterile. The recommended
containers include disposable systems that are closed to the environment and/or
sampling assemblies with equipment interfaces that can be cleaned or steamed with
the manufacturing equipment.
Containers used for endotoxin sampling must be sterile, pyrogen-free and made of a
material that does not interfere with the recovery of endotoxin (e.g. glass,
polystyrene).
Containers used for both bioburden and endotoxin sampling should be dedicated to
minimize the number of times the sample is manipulated prior to testing. Where
relevant, sampling flow paths may need to be flushed to ensure the process and
fluids from previous sampling operations are expelled so process/sample integrity
are not compromised. Technicians that perform sampling operations must be
trained in proper sampling techniques. The manipulation of bioburden samples on
the manufacturing floor should be minimized as much as possible prior to delivery to
Quality Control (QC), which should occur as soon as possible. Bioburden samples
are recommended to be stored at 2-8ºC and tested within 24 hours of collection.
Process Media Preparation
To evaluate bioburden levels associated with media preparation, it is
recommended that an appropriate number of batches at scale, based on
statistical analysis and/or risk assessment, are sampled/tested for
bioburden/endotoxin just prior to filtration or sterilization of the media.
Preferably, batches should be sampled/tested prior to Process Validation
batches, for bioreactor media (for all bioreactors in the process). This data
may be used to support the maximum hold time of media prior to sterilization.
Media preparation for bioreactor steps is typically the longest preparation for
upstream solutions. Where processes include complex feeds with several
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preparation steps (e.g. protein hydrolysates), the feeds should also be
considered for sampling and testing.
Routine monitoring of bioburden/endotoxin at this step may not be needed
when maximum media preparation and filtration times are established.
However, periodic monitoring is recommended annually or after prolonged
shutdowns.
Buffer Preparation
For filtered buffers, it is recommended that bioburden and endotoxin testing be
performed on an appropriate number of batches at scale, based on statistical
analysis and/or risk assessment. For final diafiltration/formulation buffers,
endotoxin testing is recommended to be performed prior to use to assess the
buffer’s microbial quality for all batches.
All buffers which are not filtered (e.g. non-filterable buffers) should be freshly
prepared and used as soon as possible. Bioburden and endotoxin
sampling/testing for non-filtered buffers is recommended to be performed for all
batches prior to use (buffers used for cleaning/sanitization steps may be
excluded), unless a risk based assessment justifies another approach (e.g.
buffers prepared immediately prior to use, or buffers that are not growth
promoting). For buffers that are stored for longer than 24 hours, a hold time
validation (including bioburden and endotoxin data) are expected.
Inoculum Expansion Operations
Prior to transferring from passive control (i.e. passive control of pH and dissolved
oxygen) inoculum expansion to the first active control expansion step, at full
scale, a bioburden sample may be taken. This sample is in addition to routine
visual examination for viability and absence of microorganisms or purity check
(for microbial processes). Given potential contamination risks and sample
volume concerns associated with sampling at earlier inoculum expansion stages
(Erlenmeyer flasks, roller bottles, etc.) sampling for bioburden is not
recommended. Endotoxin testing is not routinely performed at inoculum
expansion stages.
Testing for bioburden of the final culture from passive control inoculum
expansion to the first active control expansion is recommended on an
appropriate number of batches at scale based on statistical analysis and/or risk
assessment.
NOTE: To support potential contamination investigations, some companies
collect and retain samples at the end of each expansion operation until batch
release.
Bioreactor (Inoculum and Production) Operations
Prior to transfer into the next bioreactor, a bioburden sample may be tested or
kept as a back-up sample (perform a purity check in the case of microbial
processes). For inoculum bioreactors, consider testing the pre-transfer culture
for bioburden on an appropriate number of batches at scale based on statistical
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analysis and/or risk assessment. In the case of production bioreactors, all
batches should be tested for bioburden at the end of production (unprocessed
bulk sample). Endotoxin testing is not routinely performed at inoculum
expansion stages since these stages are expected to be essentially sterile.
For continuous cell lines, bioburden samples should be taken in order to
reflect the individual manufactured batches
Harvest Operations
Clarified harvest pool (filtered or unfiltered) at the end of harvest operations
should be tested for bioburden/endotoxin for all batches just prior to the start of
the following process step. Only in the case when clarified harvest is filtered
into a pooling tank, is it recommended to test the clarified harvest prior to
filtration for bioburden for an appropriate number of batches at scale based on
statistical analysis and/or risk assessment. This provides adequate evaluation
of bioburden control for the harvest operation (sampling pre-filtration should be
performed as close as possible to the end of the harvest operation).
Chromatography and Ultrafiltration/Diafiltration (UF/DF) Operations
To evaluate column and UF/DF performance during operations it is
recommended that bioburden and endotoxin testing be performed on an
appropriate number of batches at scale, based on statistical analysis and/or risk
assessment at the following steps:
○ WFI rinse (at retentate or drain line) following removal of storage solution (if
system is stored wet). This is a valuable sample points for evaluating column
and resin storage effectiveness.
○ WFI rinse following pre-use sanitization step (prior to the start of equilibration
phase). This is a valuable sample points for evaluating column and resin
cleaning effectiveness.
○ Equilibration buffer at the end of membranes equilibration step (prior to the
start of product concentration phase)
Note: Some events have shown that microorganisms can be bound to the
resin during equilibration phase and elute with wash/elution buffers).
○ WFI rinse following post-use cleaning/sanitization step (prior to start of
storage phase)
Each protein pool (filtered or unfiltered) at the end of chromatography and UF/DF
operations should be tested for bioburden and endotoxin. When the protein pool
is filtered into a pooling tank, the protein elution is recommended to be tested for
bioburden prior to filtration. This ensures adequate evaluation of microbial
control of the chromatography and UF/DF operations (sampling pre-filtration
should be performed as close as possible to the end of the final elution step).
Microbial control of reusable filters, resin storage conditions of new and unused
resins, and resin stored in columns, should be demonstrated and validated.
Resin storage conditions should be tested for bioburden to demonstrate
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bacteriostatic conditions. Acceptance criteria for these samples should be set
using the vendor’s specifications for new and unused resins (typically ≤100
CFU/mL).
Bulk Dispensing Operations
Bioburden and endotoxin samples should be taken from the final bulk drug
substance (post filtration). There are many different configurations for bulk
filling operations. The bioburden/endotoxin samples collected should be
representative of the operation, taking into consideration the risk associated
with sampling, and the nature of the filling operation (e.g. closed vs open filling;
single container vs multiple containers).
Microbial Test Methods
Endotoxin testing can be performed using any of the approved compendial
methods, although the kinetic chromogenic/turbidimetric techniques are
recommended as these methods are more precise and data interpretation is
automated.
Bioburden testing can be performed using any of the approved compendial
methods or validated rapid microbial methods using at least 10mL samples and
should be conducted in a suitably controlled environment to minimize the
potential for laboratory introduced contamination. Given the matrix
characteristics of bioreactor samples, it may be necessary to use more than
one filter to process a 10mL sample (e.g. 5 filters with 2 mL sample on each
filter). Use of validated rapid microbial methods is recommended to reduce
time to results which enables quicker responses to microbial excursions.
NOTE: Suitability testing should be performed using cultures from a recognized
culture collection (e.g. ATTC) and environmental microorganisms for each
sample matrix or family of sample matrixes to ensure the ability to recover low
levels (<100 CFU) of microorganisms.
Additionally, laboratory managers need to ensure that bench microbiologists
are adequately trained to differentiate between bacteria, yeast and molds, as
well as the presences of spreaders/confluent growth of microbes.
Microbiologists should also be able to distinguish macroscopic colonial types
by morphology (with or without magnification). If there is a frequent recovery of
spreaders/confluent colonies, the laboratory may need to read the samples on
a daily basis to determine an accurate estimation of the bioburden level.
Plate count recoveries exceeding 250 CFU on the most dilute sample are
reported as Too Numerous to Count (TNTC). A TNTC result for any in-process
bioburden sample should automatically result in an Action Level or Out Of
Specification (OOS), which requires an investigation. A TNTC recovery on an
in-process bioburden sample should be a rare occurrence due to measures
taken to prevent/minimize bioburden contaminations from occurring in
biologically manufactured products. A valid TNTC result indicates that there
has been a potential breach to the manufacturing controls put in place to
prevent contamination from occurring. Investigations initiated in response to
TNTC results need to be robust and thorough to ensure patient safety.
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In the case of microbial processes, the testing used at the end of the
production bioreactor is typically a Purity test to confirm absence of non-host
microorganisms by plating on selective and non-selective media and visual
examination. The microbial purity method should also be validated using spike
recovery studies. The spike recovery studies should be performed using
samples containing host cells at a viable titer that is representative of the
process.
Setting Bioburden Control Levels (Alert/Action)
Unlike non-sterile dosage forms, there are no recommended bioburden levels
provided in regulatory guidelines or compendia for the protein purification processes
of biologic or other biopharmaceutical products, therefore, manufacturers are
responsible for setting bioburden control levels for biologic production processes.
The BPOG Bioburden Working Group conducted a member survey of bioburden
action levels and found that the majority of biologic processes action levels were set
between 1-10 CFU/mL. When control levels (i.e. action and/or alert levels) are set
appropriately, drifts or deviations from normal operating conditions can be promptly
detected, investigated and remediated. When control levels are not set appropriately
(e.g. too loose or too tight), a loss of microbial control may go undetected, or
unnecessary investigations may be performed. Therefore, setting appropriate control
levels is a key component of a successful microbial control strategy.
Since control levels are set prior to product licensure, they are often set with limited
data; or are based on comparable processes until enough data can be attained
reflecting process capabilities. After commercialization, additional data will be
available and periodic review is required to ensure control levels reflect process
performance over time. Consideration should be given to correlate results of
bioburden testing to results of routine environmental monitoring of the manufacturing
facility and equipment. Review of control levels should be proceduralized to ensure
consistency across the manufacturer’s product portfolio.
Objectionable Organisms
The concept of objectionable organisms is applicable to non-sterile drug products
because viable microorganisms may be delivered to the patient. However, this
concept is not applicable to biologics manufacturing of sterile drugs because no
microorganisms are allowed in the final dosage form. Furthermore, creating a list of
objectionable organisms for biologic in-process samples may actually limit the scope
of investigation and keep objectionable manufacturing conditions from being
assessed and addressed.
Unlike non-sterile drug manufacturing where the processing environments are often
hostile to microbial growth or include the addition of preservatives, manufacturing of
biologics require growth mediums (upstream cell culture steps) that enhance
bacterial growth or process buffers (downstream protein purifications steps) that are
often bacteriostatic. Due to these manufacturing environments bioburden levels in
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biologics must be controlled to and reach near sterile conditions in upstream process
steps and ≤ 10 CFU/mL during downstream processing.
Responding to Bioburden Excursions
When bioburden control levels are exceeded, an investigation with the rigor
commensurate with the risk (e.g. action level vs alert level excursion) should be
conducted. To ensure adequate and consistent responses to bioburden control level
excursions and adverse trends (variation from the historical mean over time),
manufacturers should establish written procedures for the investigation of these
events. The following are recommended actions to take in response to control level
excursions:
Adverse Trends:
When adverse trends are noted they should be investigated, using at minimum, a
comparable approach as action level excursions (see below).
Alert Level Excursions:
Alert levels are set to monitor process performance and provide early warning of
an adverse trend or action level excursion. As such, the following actions are
recommended:
Initiate an investigation record in the quality system
Review historical data for adverse trend
Identify microorganisms to species level, if possible, for microorganism
trending purposes
Notify affected departments and Quality Assurance and/or as defined by local
procedures
Action Level Excursions:
Action levels are set to ensure the process is operating as designed, and require
investigation and remediation if not met. In addition to the actions required for alert
level excursions the following actions are recommended to determine the cause of
the excursion, evaluate the significance of the excursion in the contexts of other data,
and to initiate action to restore intended operating conditions.
Initiate an investigation record in the quality system
Obtain feedback from a cross-functional investigational team (e.g.
Manufacturing, Quality Control, Quality Assurance, Facilities, Engineering,
etc.)
Perform concurrent laboratory and manufacturing investigations
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Determine root cause (e.g. review utilities; compressed gases and WFI
systems;, equipment maintenance, engineering changes, environmental
monitoring, training, etc.)
Assess potential product quality impact
Implement corrective and preventive actions (CAPA)
Perform CAPA effectiveness check; where appropriate
NOTE: Bioburden excursions that meet or exceed the action level do not necessarily
indicate that product quality has been compromised but do indicate the need to
investigate. Consider conducting a risk assessment to evaluate if the process should
be halted pending resolution of the issue and completion of a “return to service” plan.
When bioburden action level excursions or adverse trends are noted, product safety
and product stability need to be assessed. The following information can be used for
this assessment, in addition to other factors:
What organism(s) was recovered? When possible, identify the species level.
Is the disinfectant procedure effective at removing the recovered organism, if
applicable?
What toxins and/or microbial byproducts does the organism(s) produce or
release?
What stage in the process did the excursion occur?
What downstream purification steps were performed after the organism(s) was
recovered? Are the purification steps validated to remove bioburden? Is there
data that supports clearance of the possible microbial byproducts?
Are there any connections or links to other bioburden excursions in either
upstream or downstream processes?
Have the same organism(s) been observed during the production of the previous
lot?
How long was product held at the step (residence time of organism) where the
excursion was detected and at what temperature and at which pH?
Were changes made to the manufacturing process (e.g. equipment
modifications) prior to the excursion(s)?
What potential impact could the recovered organism(s) have on the
manufactured protein?
What is the impact of the microbial byproduct production (toxins) on the patient
or product safety? Is there stability data that would provide assurance that the
drug substance or drug product has not been impacted?
Are all In-Process Control (IPC) results within historical trends and does the drug
substance meet all release specifications?
What information was gathered from literature searches and/or during studies
conducted during the investigation?
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Assessing Impact to Product Quality
Assessing residual microbial byproducts related to patient and product safety
EXAMPLE 1
For Adverse Trends or Action Level excursions, the following areas should be
assessed and may be included in an investigation:
Perform laboratory investigation, which should include but is not limited to, the
review of analyst’s training, calculations, negative controls, sampling handing,
and test materials.
Review HVAC performance in the respective manufacturing area i.e. last filter
certification reports, differential pressures for date under investigation, and
trend history.
Review environmental monitoring and critical utility data for the respective
manufacturing area.
Review work order system to examine operation of equipment for anomalies
(e.g. belt grinding and producing elevated total particulates).
Review cleaning and sanitization of the impacted area, including agents used,
their preparation, and their effectiveness against the recovered organism (s).
Review any changes to the facility, utilities (e.g. compressed gases and WFI
systems), equipment (e.g. chromatography skids, column packing operations,
etc.) or process (e.g. logbooks and work orders).
Review batch record for any interventions that may have contributed to the
excursion(s).
Conduct interviews of the personnel involved i.e. manufacturing associates
and laboratory analysts.
Confirm microbial identification to the species level. If the organism is the
same as previously recovered in the process, perform strain typing to
determine if it is from the same source.
Conduct a literature search on the recovered microbe to determine the worst-
case toxin that might impact patient safety and publish in peer reviewed
journals.
Determine if the organism strain recovered has the gene encoding the worst-
case toxin.
Determine if the worst-case toxin is expressed in the specific condition in
which the recovered microbe was isolated.
ADDITIONAL SUGGESTIONS:
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o Determine if the level of the worst-case toxin in subsequent
processing unit operation(s) can be reduced using a scale-down
model.
o When there is not an identifiable worst-case toxin, use a surrogate
toxin (protein) for data gathering and risk assessment.
For bulk drug bioburden excursions perform filtration risk assessment of the
product specific validated retention capacity to calculate safety factor.
EXAMPLE 2 (Model developed by Roche)
Though bioburden is easily removed by filtration steps during the purification
processes, Residual Microbial Byproducts may possibly be co-purified with the
product and have detrimental effects on patient and product quality. Quality impact
assessments should include the following:
Criticality of the process step
o Excursions during cell culture are not acceptable, and if contamination is
confirmed, the batch should be rejected.
Review of trend data
o Ensure data provides assurance that there is no systemic failure or
evidence of biofilm.
Assessments of Microbial Byproducts that can have adverse effects on patient
safety. These are primarily:
o Exotoxins:
Protein Exotoxins (e.g. Botulinum Toxin A
Non-Protein Exotoxins (e.g. Aflatoxin)
o Endotoxin
o Flagellin
o Microbial DNA
o Cell wall polysaccharides
With the exception of endotoxin, there are no available GMP assays to detect
these Microbial Byproducts. However, worst-case calculations of the levels of
these components can be performed and compared to a specific safety level
using the following:
o Identity of the contaminant(s). Identification by genotypic methods is
highly recommended.
o Literature search on the contaminants for cell size and known exotoxins.
o The level of the contamination (CFU/mL).
o Concentration of the Drug Substance.
o Maximum dosage.
An example of such a calculation is as follows:
Scenario: A downstream purification pool is contaminated with 100 CFU/mL of
Bacillus cereus.
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Assumptions:
Protein Concentration of the Drug Substance: 22.5 mg/mL.
Dosing: Product has a maximum dose of 750 mg
Calculated value Result Detailed calculation
Volume of single cell
(Bacillus cereus) 37.7 µm3
(max cell radius)2 × π × (max cell
length) = 1 µm2 × π × 12 µm
Moist mass of single cell 37.7 pg Density of bacterial cell = 1
g/mL
Total moist mass in
contaminated downstream
processing sample
3770 pg/mL 37.7 pg ×100 cells/mL
(= 100 CFU/mL)
Total dry mass (B. cereus) 1131 pg/mL 30% of 3770 pg/mL
Total protein content (B.
cereus) 622.05 pg/mL
Proteins present 55% of total dry
mass
Fraction of protein
exotoxins
0.311025
pg/mL
Protein exotoxins present 0.05%
of total bacterial protein content
Number of doses per mL 0.03 22.5 mg/mL drug substance ÷
750 mg
Potential protein exotoxin
contamination per dose 10.3675 pg 0.311025 pg/mL ÷ 0.03/mL
Potential protein exotoxin
contamination per kg body
weight per day
0.20735 pg 10.3675 pg ÷ 50 kg body
weight
Factor of potential protein
exotoxin contamination
below TDLo* of Botulinum
Toxin Type A
5.8 1.2 pg/kg ÷ 0.20735 pg/kg
*TDLo = Toxic dose low. The lowest dose of a substance which, whatever the
dosage form and over an indeterminate time period, causes a documented toxic
effect in humans (RTECS Guideline, US Dept. of Health and Human Services).
Conclusion: A contamination event of a downstream purification pool with 100
CFU/mL of Bacillus cereus resulted in a potential toxin contamination that is below
the TDLo of Botulinum Toxin Type A by a factor of 5.8 and therefore does not have
an impact on patient safety.
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Conclusion:
This paper provides recommendations from a biopharmaceutical industry perspective
on microbiological monitoring of in-process intermediate products, including drug
substances. Additionally, recommendations on subjects commonly encountered in
the establishment of a monitoring program, such as setting alert/action levels,
objectionable organisms in bulk biologics, responding to bioburden excursions and
assessing impact to product quality, are included.
These recommendations assist biologic manufacturers in refining their current
microbial control strategy, as well as developing control strategies for new processes
and products. Establishing appropriate microbial control levels provides indications
of the effectiveness of the manufacturing process.
Responding to bioburden excursions can be difficult and are often inconsistent within
the same company. This paper provides information that can be used to develop an
investigational checklist that will help drive consistent and thorough investigations,
and provides examples for assessing impact to product quality when bioburden
excursions occur. To ensure consistent impact assessments and successful
regulatory review of microbial excursions, formal impact assessment models are
recommended. .
An important aspect of all impact assessment models is the treatment of
objectionable organisms. The BPOG members that contributed to this paper believe
the concept of objectionable organisms is not applicable to biologics; since all
organisms recovered in in-process and drug substance samples should be identified
to species level, and trended and investigated thoroughly when recovered above the
action level. Furthermore, final drug product formulations are sterile which greatly
reduces the risk of delivering microbes to the patient.
In the future, the BPOG Bioburden Working Group will use this paper to present an
Industry perspective on microbial monitoring and control of biologic manufacturing
processes to regulatory agencies to gain their acceptance and to influence future
regulations of non-sterile bulk biologic manufacturing.
References
1. Quality Guideline Q6B: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products; International Conference on Harmonisation:
1999. www.ich.org (accessed June 24, 2014).
2. Quality Guideline Q7A: Good Manufacturing Practice for Active Pharmaceutical
Ingredients; International Conference on Harmonisation: 2005. www.ich.org
(accessed June 24, 2014).
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3. Technical Report No. 33: Evaluation, Validation, and Implementation of Alternative
and Rapid Microbiological Methods; Parenteral Drug Association: 2013.
www.pda.org (accessed June 24, 2014).
4. General Chapter <1111>Microbial Examination of Nonsterile Products: Acceptance
Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use.
USP 37/NF32; U.S. Pharmacopeia 2014. www.usp.org.
5. Annex 1, Manufacture of Sterile Medicinal Products; EudraLex, The Rules
Governing Medicinal Products in the European Union, Volume 4 EU Guidelines to
Good Manufacturing Practice Medicinal Products for Human and Veterinary Use.
Brussels, 25 November 2008. www.ec.europa.eu
6. Annex 2, Manufacture of Biological active substances and Medicinal Products for
Human Use; EudraLex, The Rules Governing Medicinal Products in the European
Union, Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal
Products for Human and Veterinary Use. Brussels, 25 November 2008.
www.ec.europa.eu
7. von Wintzingerode, Friedrich "Biologics Drug Substance Production: Safety
aspects of bioburden contaminations of non-sterile process intermediates" ECA,
European Microbiology Conference, Copenhagen, April 24-25, 2013
Acknowledgements
We thank the following for their help and support: Marc Kinnelly of Astra Zeneca,
Bastian Omokoko and Eileen Economy of Bayer, Barbara Daddis of Bristol-Myers
Squibb, Jeri Bonilla of Genentech, Jay Stout and Beth Junker of Merck, Cheryl Mowen
of Novavax, Randall Thompson and Cathleen O’Connor of Shire, Friedrich von
Witzingerode of Roche, Jose A. Marrero of AbbVie and David Bain of the BioPhorum
Operations Group (BPOG).
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