Presented at the 2018 PMF Fall Forum, "Current Trends in Pharmaceutical Microbiology".

1. Burkholderia cepacia
complex
Current Regulatory Trends
Bob Westney, M.S., RAC, CMQ/OE
Director of Quality and Operations
Cryologics, Inc.

2. Agenda
 History / Clinical Significance
 The “Complex”
 FDA’s First “Salvo”
 Recalls / Warning Letters
 FDA’s Second “Salvo”
 Pitfalls of Recovering and Identifying Bcc Organisms
 Current United States Pharmacopeia
 Conclusion
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3. History / Clinical Significance
 When was Burkholderia cepacia first discovered?
 B. cepacia was discovered by Walter Burkholder in 1947 as the cause of onion skin rot
(“sour skin rot”) (Lynn Torbeck, Diane Raccasi, Dennis E. Guilfoyle, et al. “Burkholderia cepacia: This Decision Is
Overdue”. PDA J Pharm Sci and Tech 2011, 65 535-543)
 When did B. cepacia become clinically significant?
 First described as a human pathogen in the 1950s (Burkholder WH (1950). "Sour skin, a bacterial rot
onion bulbs“. 01355). Phytopathology. 40 (1): 115–7.)
 First isolated in patients with cystic fibrosis (CF) in 1977 (Pseudomonas cepacia) (A clinical
survey of bacteria isolated from urine specimens of patients with various urological disease. Yamasaki Y, Tajima K,
Arima K, Ogawa H, Hayashi N, Yamamoto I, Matsumoto J, Tochigi H, Tada S. Hinyokika Kiyo. 1984 Dec;30(12):1899-
909.)
 The clinical significance of B. cepacia in CF patients was first described in 1984 in a
seminal report by Isles et al. (Isles A, Maclusky I, Corey M et al. Pseudomonas cepacia infection in cystic
fibrosis: an emerging problem. J Pediatr 1984; 104: 206-210.)
 Outbreaks of B. cepacia in individuals with CF have been associated with a 35% death
rate (Ledson MJ, Gallagher MJ, Jackson M, et al Outcome of Burkholderia cepacia colonisation in an adult cystic
fibrosis centre Thorax 2002;57:142-145.)
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4. History / Clinical Significance
 How did we get from “onion skin rot” to “human pathogen”?
Onion Skin Rot
Cystic Fibrosis
Trench Foot
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5. History / Clinical Significance
 "Burkholderia cepacia ... was known as Pseudomonas cepacia prior to 1992. Walter H.
Burkholder, while teaching at Cornell University in 1947, identified the microbe as the
source of onionskin rot (cepacia is Latin for “like onion”). Since then, it has been
associated with numerous health issues including endocarditis, wound infections,
catheter-related urinary infections, intravenous bacteremias, and foot infections or
'foot rot’.” (Lynn Torbeck, Diane Raccasi, Dennis E. Guilfoyle, et al. “Burkholderia cepacia: This Decision Is
Overdue”. PDA J Pharm Sci and Tech 2011, 65 535-543)
 “While infection in patients with cystic fibrosis is most common and extremely
detrimental, Burkholderia cepacia can also infect non-cystic fibrosis patients, even
immunocompromised patients. B. cepacia has been associated with cutaneous foot
lesions in military personnel, a malady known as ’swamp foot.’ B. cepacia isolates have
been obtained from catheters, wounds, sputum, urine, etc. It can even infect hospital
soaps, dextrose solutions, and much more.” (Jones AM1, Dodd ME, Webb AK. "Burkholderia
cepacia: current clinical issues, environmental controversies, and ethical dilemmas“. Eur Respir J. 2001
Feb;17(2):295-301.)
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6. History / Clinical Significance
 Biofilm
 Significant research into this area
 “There is convincing evidence that B. cepacia complex bacteria can form biofilms,
not only on abiotic surfaces (e.g., glass and plastics), but also on biotic surfaces
such as epithelial cells, leading to the suggestion that biofilm formation plays a
role in persistent infection of cystic fibrosis lungs.” (Coenye T. “Social interactions in the
Burkholderia cepacia complex: biofilms and quorum sensing”. Future Microbiol. 2010 Jul;5(7):1087-99. doi:
10.2217/fmb.10.68.)
 “Bcc organisms are difficult to eradicate because of their innate resistance to a
range of antibiotics and their capacity to form biofilms.” (Acker, Heleen Van, et al. "Biofilm-
Grown Burkholderia cepacia Complex Cells Survive Antibiotic Treatment by Avoiding Production of Reactive Oxygen
March 13, 2013. https://doi.org/10.1371/journal.pone.0058943)
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7. History / Clinical Significance
 Ubiquitous
 "The organism is ubiquitous and versatile; it seems to thrive under adverse
conditions and can even use penicillin for its food supply. The organism is
and resistant to many disinfectants, antiseptics, and preservatives.“ (Bacterial Pneumonia,
Lung Abscess, and Empyema. Susan E. Crawford, Robert S. Daum, in Pediatric Respiratory Medicine (Second Edition),
 Antibiotic Resistance
 “One difficulty associated with the treatment of infections with this organism with
antibiotics has been, and remains, the acquisition of antimicrobial resistance.
Previously, many centres have reported high levels of resistance against several
classes of antibiotics.” (Moore, J., et al. “Antibiotic resistance in Burkholderia cepacia at two regional cystic fibrosis
centres in Northern Ireland: is there a need for synergy testing?”. Journal of Antimicrobial Chemotherapy, Volume 48, Issue
1 August 2001, Pages 319–321)
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8. The “Complex”
 How many different species comprise the Bcc?
 “The Burkholderia cepacia complex (Bcc) is a collection of genetically distinct but
phenotypically similar bacteria that are divided into at least nine species.”
(Mahenthiralingam E, Urban TA, Goldberg JB. “The multifarious, multireplicon Burkholderia cepacia complex”. Nat Rev
Microbiol. 2005 Feb;3(2):144-56.)
 “The genus Burkholderia currently comprises more than 60 species. Bcc consists
17 closely related species of the β-proteobacteria subdivision.” (Lynn Torbeck, Diane Raccasi,
Dennis E. Guilfoyle, et al. “Burkholderia cepacia: This Decision Is Overdue”. PDA J Pharm Sci and Tech 2011, 65 535-543)
 "The Burkholderia cepacia complex (BCC) consists of at least 18 closely related,
distinct, species of bacteria.“ (THE CANADIAN BURKHOLDERIA CEPACIA COMPLEX RESEARCH AND
REPOSITORY (CBCCRRR). https://www.cysticfibrosis.ca/our-programs/research/core-facilities/cbccrrr. 2013)
 “The Burkholderia cepacia complex (Bcc) is a group of ten closely related species
associated with poor clinical prognosis in cystic fibrosis (CF).” (Molecular Medical
(Second Edition), 2015)
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9. The “Complex” (?)
 B. cepacia
 B. multivorans
 B. cenocepacia
 B. vietnamiensis
 B. stabilis
 B. ambifaria
 B. dolosa
 B. anthina
 B. pyrrocinia
 B. ubonensis
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10 Species

10. The “Complex” (?)
 17 species
 “Recovery of Stressed
(Acclimated) Burkholderia
cepacia Complex Organisms”
(Julie Barlasov, Scott Sutton, Richard Jakober.
American Pharmaceutical Review. April 29,
2014.)
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11. FDA’s First “Salvo”
 "Burkholderia cepacia: This Decision Is Overdue"
 FDA: Lynn Torbeck, Diane Raccasi, Dennis E. Guilfoyle, Rick L. Friedman, and
Hussong
 May 2011… DRAFT
 Submitted to peer reviewers
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12. Burkholderia cepacia complex: Current Regulatory Trends12
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13. FDA’s First “Salvo”
 “Burkholderia cepacia: This Decision Is Overdue”
 Published September-October 2011 (PDA J Pharm Sci and Tech 2011, 65 535-543)
 Sections
 Introduction
 FDA Guidance
 Pathogenicity and Risk of Disease Complications
 Manufacturing Control Measures
 Lessons Learned from Product Recalls
 Conclusion
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14. Burkholderia cepacia complex: Current Regulatory Trends
FDA’s First “Salvo”
 “Burkholderia cepacia: This Decision Is Overdue”
 Conclusion
 “Bcc organisms pose a clear and present danger to patient health and safety.”
 “The challenge is undeniable; now is the time to remove Bcc from our pharmaceutical
manufacturing areas and products.”
 Was this enough to “wake people up”? Maybe not…
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15. RECALLS
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16.  2008
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17.  2011
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18.  2012
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19.  2014
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Nutek Disposables, Inc. initiated a nationwide voluntary product recall at the retail
level of all lots of baby wipes that it manufactured under the brand names Cuties,
Diapers.com, Femtex, Fred's, Kidgets, Member's Mark, Simply Right, Sunny Smiles,
Tender Touch, and Well Beginnings, because some packages may contain bacteria.
These wipes were distributed by Nutek prior to October 21, 2014 to the following retail
stores: Walgreens, Sam's Club, Family Dollar, Fred's, and Diapers.com.
After receiving a small number of complaints of odor and discoloration, Nutek
conducted microbial testing that showed the presence of the bacteria Burkholderia
cepacia (B. cepacia), in some of these products.

20. PMF Fall Forum 2018
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Nutek Disposables of Pennsylvania has issued a voluntary recall for its
baby wipes because some packages may contain a bacteria that's often
resistant to common antibiotics… Nutek hasn't yet pinpointed how the
bacteria got into the supply. It has stopped shipping baby wipes made
in that facility.

21.  2016
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PharmaTech LLC of Davie, FL, the manufacturer of the Rugby® -
branded product, is voluntarily recalling all lots within the expiry of
Diocto Liquid, a docusate sodium solution due to a risk of product
contamination with Burkholderia cepacia.

22.  2016
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Sage Products announced today it is voluntarily initiating a nationwide recall
of one lot of Comfort Shield Barrier Cream Cloths to the distributor and
health care facility/user level. The recall is being initiated due to product
contamination with the bacteria, Burkholderia cepacia.

23.  2016
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Sage Products announced today it is expanding its voluntary
nationwide recall to include an additional lot of Comfort Shield
Barrier Cream Cloths at the distributor and healthcare facility/user
level. The recall is being initiated due to product contamination
with the bacteria, Burkholderia cepacia.

24.  2016
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Sage Products announced today it is expanding its voluntary worldwide recall to include
specific lots of impregnated cloth topical skin products at the distributor, healthcare
facility, retail and consumer/user levels. The recall is being initiated due to potential
product contamination with the bacteria, Burkholderia cepacia.
Burkholderia cepacia complex: Current Regulatory Trends

25.  2016
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26.  2016
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Nurse Assist, Inc. announced today that it is voluntarily recalling all
unexpired lots of I.V. Flush Syringes due to a potential link to
Burkholderia cepacia bloodstream infections with the product.

27.  2017
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28.  2018
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Multistate Outbreak of B. cepacia complex linked to Medline
Remedy Essentials No-Rinse Cleansing Foam

29.  2018
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30.  2018
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HelloLife, Inc. in Grand Rapids, MI is initiating a voluntary recall of four different
products, Neuroveen, Respitrol, Thyroveev and Compulsin, within expiry, to the retail
and consumer level due to possible microbial contamination. Neuroveen has been
tested and found to be contaminated with Staphylococcus saprophyticus and
Burkholderia cepacia. Compulsin has been identified as containing Burkholderia
cepacia.

31. PMF Fall Forum 2018
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0
1
2
3
2006 2008 2011 2012 2014 2016 2017 2018
Number of Recall Announcements

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Nasal decongestent, 2
Wipes/cloths, 3
Liquid products (OTC,
dietary supplements), 2
Mouthwash, 2
I.V. Flush Syringes, 1
Cough syrup, 2
Homeopathic drug/pet
products, 1
Cleansing foam, 1
RECALLS BY PRODUCT TYPE

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WARNING LETTERS

34.  2016
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You used water produced from this system to manufacture (b)(4) API. Of
note, you identified Burkholderia cepacia, a waterborne organism known
to contribute to biofilm formation in water systems, in several
of your alert-level and action-level investigations.
Burkholderia cepacia complex: Current Regulatory Trends

35.  2018
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Your firm used non-pharmaceutical grade drinking water, obtained
from a bottled water dispenser located in the break room of your
facility, in the production of nonsterile
stock solutions and non-sterile drug products. Our investigators
determined that the water was used in the production of dozens of
drug products. During the inspection, our investigators collected a
sample of the water obtained from the dispenser. FDA analysis of the
(b)(4) identified the presence of Burkholderia cepacia, which is
considered an objectionable microorganism.

36.  2018
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Benzalkonium chloride antiseptic drugs that are similar to your firm’s
handwipes product have been historically found to harbor
objectionable water-borne microorganisms such as B. cepacia when
good manufacturing practices were not strictly followed.

37.  2017 – Establishment Inspection Report
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38. FDA’s Second “Salvo”
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39. PMF Fall Forum 2018
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0
1
2
3
2006 2008 2011 2012 2014 2016 2017 2018
Number of Recall Announcements

40. Pitfalls of Recovering and Identifying Bcc Organisms
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Pitfalls of Recovering and Identifying Bcc Organisms
“There are several reports that describe the failure of most commercial test
systems to identify B. cepacia complex isolates with sufficient sensitivity and
specificity, with isolates commonly misidentified as B. gladioli, S. maltophilia, or
Ralstonia spp.”

42. Current United States Pharmacopeia
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43. Conclusion
 History / Clinical Significance
 Biofilm
 Ubiquitous
 Antibiotic Resistance
 The “Complex”
 How many different species comprise the Bcc?
 FDA's "Salvos"
 "Burkholderia cepacia: This Decision Is Overdue" (2011)
 "FDA advises drug manufacturers that Burkholderia cepacia complex poses a
contamination risk in non-sterile, waterbased drug products" (2017"
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44. PMF Fall Forum 2018
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Conclusion
 Recalls
 Topicals / Wipes
 Oral Solutions
 Warning Letters
 Pitfalls of Recovering and Identifying Bcc Organisms
 Stressed organisms - challenges for recovering
 Identification
 Current United States Pharmacopeia
 44(5) In-Process Revision: <60> Microbiological Examination of Nonsterile Products -
Tests for Burkholderia Cepacia Complex

45. Contact Information
Bob Westney
Director of Quality and Operations
Cryologics, Inc.
E-mail: rwestney@Cryologics.com
Phone: (610) 847-8781
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46.  August 2018, United Kingdom
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47. QUESTIONS?
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