Environmental monitoring, how to avoid recalls
Agenda
What objectionable organisms are
The harm they can cause
How they get into products
How to monitor them in the product
What assistance is available
Factors which make an organism objectionable
Cause illness, injury or harm with use of the product
Affect product stability
Affect container/closure system
Affect analytical testing
Affect active ingredient
Produce odors, flavors or undesirable metabolites
Potential to grow and exceed the TAC specifications
High virulence/low infection dose
Resist to antimicrobial therapy
Which text to follow?
European Pharmacopeia: 5.1.4. Microbiological quality of non-sterile
pharmaceutical preparations and substances for pharmaceutical use
USP <1111>: Microbiological examination of nonsterile products: acceptance
criteria for pharmaceutical preparations and substances for pharmaceutical use
Which text to follow?
The risk vary with several factors
The isolate may be pathogen
Route of administration
Affects a product
Environmental contaminants
American Pharmaceutical Review, Volume 15, Issue 1.
The risk vary with several factors
Finding objectionable organisms depends on:
– Good isolation techniques
– Good identification capabilities
– Trending and tracking capabilities
– Reviewing of available data
If I find one objectionable, what should I do?
– Isolate it
– Grow a pure culture of it
– Characterize it
– Determine risk to consumer and product
Recalls from 2004 to 2011
642 microbiological recalls recorded by the FDA
2004-2011 recalls by sterility 2004-2011 recalls by type
Cosmetics Dietary
Non-sterile supp/probiotics
22% 7%
OTC
11%
Medical
device
65%
Pharmaceuticals
15%
Sterile
78%
American Pharmaceutical Review, Volume 15, Issue 1.
Recalls from 2004 to 2011
Sterile product are more affected by quality assurance
Non-sterile products are more affected by microbiology
Sterile recalls by reason Non-sterile recalls by reason
Failed GMP
Diagnostic kit error Failed disinfectancy
test 1%
6% 5%
Microbial
contamination Diagnostic kit error
11% 7%
Microbial
contamination Objectionable
15% organism
Lack of
sterility 72%
assurance
American Pharmaceutical Review, Volume 15, Issue 1.
“Each lot of a component, drug product container, or closure with potential for
contamination that is objectionable in view of its intended use shall be subjected
to microbiological tests before use.”
FDA U.S. Code of Federal Regulations (CFR) Title 21, Sec. 211.84
“Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be established
and followed.”
FDA CFR Title 21, Sec. 211.113
“There shall be appropriate laboratory testing, as necessary, of each batch of
drug product required to be free of objectionable organisms.”
FDA CFR Title 21, Sec. 211.165
Environmental Monitoring Doesn’t Stop
at Detection
Microbiologics and Scott SUTTON
Technical Report No. 67 Exclusion of Objectionable Microorganisms from Nonsterile
Pharmaceuticals, Medical Devices, and Cosmetics
Figure 9.3-1 Objectionable Microorganism Risk Decision Tree
Technical Report No. 67 Exclusion of Objectionable
Microorganisms from Nonsterile Pharmaceuticals,
Medical Devices, and Cosmetics
Table 7.5-1 Decision Matrix for Screening for
Objectionable Microorganisms
How are products kept safe from objectionable organisms?
Good manufacturing practices Test product
People: training Microbial Enumeration Test
Plant: water system… Tests for Specified Microorganisms
Procedures: use of disinfectants…
Processes: pest control…
Practices: EM program
How are products monitored for objectionable organisms?
Test environment Test product
Monitor environment Test products for objectionable
Identify suspicious organisms on agar organisms
plates Identify organisms on aerobic count
Test products for environmental plates
organisms
Environmental isolates are used as controls in many tests
Disinfectant Qualification: USP <1116>
Growth Promotion Testing: USP <61>, <62>, <71>
Validation of Neutralization Methods: USP <1227>
Suitability Testing: USP <61>, <62>, <71>
Antimicrobial Effectiveness Testing: USP <51>
Water for Pharmaceutical Purposes: USP <1231>
Aseptic Processing Environments: USP <1116>
“...Your firm does not perform challenge testing to the sterility media with
environmental isolates from the environmental monitoring program.”
FDA Warning Letter October 29, 2010
“... Your firm failed to establish an adequate system for monitoring environmental
conditions in aseptic processing areas. (…) Your firm did not investigate this failure
of media to support growth”
FDA Warning Letter October 13, 2016
Once an environmental isolate is cultured it loses its “wild-type” trait
Maintaining the organism to be within 5 passages
Preparation of suspension if specific concentration needed
May miss target concentration – won’t know until test complete
May need to refrigerate suspension for several days
How many strains should we consider?
From our experience, between 2 and 5 is the most frequent
– Water organisms: Methylobacterium, Ralstonia…
– Human flora: Micrococcus, Staphylococcus…
– Filamentous fungi: Zygosaccharomyces, Cladosporium…
– Critical strains: Burkholderia cepacia, Bacillus cereus…
How long to keep them?
– No detection after 1 year doesn’t guarantee it will not occur again
o This is why we store them 4 years!
What kind of strains to consider?
It depends on:
– The activity of the pharma company
– The type of product manufactured
From where? Selection depend on criticality
– Water supplies
– Operators
– Raw materials
– Finish products
– Air
– Containers
– Pests…
What about trending and tracking?
Data analysis turns costs in added value by providing data
Identification is made to detect drifts before the product harms the patient
Trending and tracking helps to identify the root cause of a contamination
– Water
– Cleaning procedures
– Raw material
– Air/surfaces
– Operators
– Equipment…
Example of objectionable organisms?
Burkholderia cepacia Nasal spray Bacillus cereus Alcohol wipes and swabs
Creams, lotions, oils Tablets
Waters Antibiotics
Surfaces Parenteral nutrition
Wipes Surfaces
Yeasts and molds Air and surfaces Pseudomonas sp. Hand Sanitizer
Oral suspensions Water
Swabs Capsules
Tablets Toothpaste
Wipes Eye drops
Antibiotics and disinfectants Enterobacteriaceae Mouthwash
Lotions and serums
Soaps and shampoos
Surfaces
Example of frequent objectionable organisms
Elizabethkingia meningoseptica: iodine pad, blood collection kit
Enterobacter gergoviae: baby wipe, body wash
Methylobacterium extorquens: water pipe
Micrococcus luteus: human contamination
Pseudomonas putida: mud mask, hand sanitizer
Staphylococcus aureus: antiacid
Staphylococcus warneri: iodine pad, moisturizing body wash
Serratia marcescens: shampoo
Stenotrophomonas maltophilia: iodine pads, skin moisturizer
American Pharmaceutical Review, Volume 15, Issue 1.
Takeaway
The “specified organisms” in Ph. Eur. are not the only “bad” organisms
Consider risks when deciding if organism is objectionable
Environmental isolates can be objectionable
Preserve objectionable environmental organisms for future testing
Why test with environmental controls?
Microbial contaminations
Objectionable microorganisms
Failed testing –e.g. AET
1. Product recall
Diagnostic kit errors
How to justify to the auditor the
strain was lost?
4. Back-up 2. Regulations
storage and audits
Regulatory agencies will review QC
processes & testing for objectionable
Avoid possible disaster [Link] environmental organisms
(Triad Group) safety
How Can
Microbiologics Help?
Four Options for Isolates in QC Testing
Reference
1
cultures
In-house
2
maintenance
Prepared
3
cultures
4 Do nothing
Advanced ID processes helps minimize isolate
misidentification
In our experience, labs misidentify 1/3 of environmental isolates they find
Advanced ID helps bring greater accuracy to isolate ID
Procedure
Identify suspected isolate
Contact Miclev:
– Type of organism
– Type of media and growth requirements
– Frequency of use
– Type of product requirement
– If quantitative numbers required
Microbiologics will provide quotation for:
– Setup
– Kit price
Customer notifies Miclev upon acceptance of quotation
Microbiologics applies for importation licence
Customer send organisms
Custom Quotation - what is included?
Set up cost
Full genotypic and phenotypic identification
Strain banking for a minimum of 4 years, free of charge
24 months warranty
Full documentation
An isolate you can trust
Peace of mind
Custom Solutions
Environmental monitoring is a critical concern in pharmaceutical laboratories
Microbiologics is the ONLY provider of Custom Solutions with affordable
pricing, the most convenient formats and superior technical support!
Any question about our manufacturing process?
You are welcome to audit us!
Thank you for your attention