Creating GMP in an Academic 

Research Setting and Clinical 

Hospital Environment – Challenges 

and Lessons Learned at the NIH

Anna F. Lau, Ph.D., D(ABMM)

Chief, Sterility Testing Service

Department of Laboratory Medicine

Clinical Center

National Institutes of Health

1
Disclosures

• None

• This work was supported by the Intramural Research Program of the 

National Institutes of Health. The content is solely my responsibility 

and does not represent the official views of the National Institutes of 

Health. 

2
• World’s largest biomedical research institute

• 27 institutes/centers (ICs)

NIH Clinical Center (CC)

3
NIH Clinical Center

• Research hospital dedicated 

solely to bench to bedside clinical 

research. First in human trials.

• Every patient is enrolled in a 

clinical trial

• Novel therapeutics developed 

since 1980s

• Investigational New Drugs (INDs)

4
Variety of Products Manufactured at the NIH

5
1980s 1990s

First in human 

trials

Sterility testing in 

clinical micro

USP<71>

Tedious, labor 

intensive, slow

Expansion of INDs

2000s

New clin micro director switches to sterility 

testing using automated blood culture bottles

Long History of Sterility Testing at the NIH

Clinical microbiology lab in DLM

6

2004 2006
CO2 Respiration = Blood Culture Systems

• In every clinical microbiology laboratory

• Designed for automated detection of bloodstream infections

BacT/ALERT, BioMerieux BACTEC, Becton Dickinson VersaTREK, ThermoFisher

Clinical branch

Industry branch

- Different media bottles marketed

- Dual-T instrument; 30-35°C and 20-25°C

Clinical branch only

35-37°C

Clinical branch only

35-37°C

7
2004

• Mononuclear cells in 6 different matrices

• Plasma, infusion medium, freeze mix, RPMI, XVIVO-20, RPMI+ABX

• 10 European Pharmacopeia organisms

• 10 CFU and 50 CFU

• 3 methods = USP<71>, BacT/ALERT, BACTEC

8
0

10

20

30

40

50

60

70

80

90

100

USP<71> BacT/ALERT BACTEC

Sensitivity by matrix Overall sensitivity

• Overall, significant faster time to positivity of respiration methods compared 

with USP<71>

Khuu et al (2004), Cytotherapy 9
2006

• 36-month real time parallel evaluation of USP<71> vs automated respiration 

method (BacT/ALERT or BACTEC)

• 1,617 samples (in-process and final)

• Rate of true positivity equivalent between USP<71> and automated respiration 

method

• USP<71> high false positive (7.3% vs 0.2%)

• Automated systems faster time to detection

10
11

2004

2006

Long accepted by FDA for all NIH INDs

(DMF regardless of product type)
1980s 1990s

First in human 

trials

Sterility testing in 

clinical micro

Gold standard method

Tedious, labor 

intensive, slow

Expansion of INDs

2000s

New clin micro director switches to sterility 

testing using automated blood culture bottles

Long History of Sterility Testing at the NIH

Clinical microbiology lab in DLM

2015

12

2004 2006
• April 2015

– Two albumin vials found grossly 

contaminated with Cladosporium spp. and 

Aspergillus nidulans

– FDA for-cause inspection.

– Form 483, observations.

– Hospital pharmacy was shut down.

First Contamination Event (2015)

13

Published: 05 June 2015
• Mold observed in NK cell 

product on final release 

testing Gram stain

• BACTEC failed to detect gross 

growth of mold in the bottles

• Multiple bottles collected during 

“in-process” testing were positive

• Aspergillus terreus

Second Contamination Event (2015)

14
Red Team Report (2015 – 2016)

15
2016 Nov 3;375(18):1705

-1707 16
1980s 1990s

First in human 

trials Expansion of INDs

2000s

Creation of the Sterility Testing Service

Clinical microbiology lab in DLM

2015 2018

• Creating brand-new GMP testing lab (core microbiology 

lab to support for IRP), systems, operations, facilities, 

personnel from scratch.

• Challenge – to maintain operations during build out.

STS in DLM
Matthew England, Ph.D., D(ABMM) Frida Stock

• Larger and diverse organism challenge 

set (n=118)

• 7 system comparison

• Current technology and media 

formulations

2019
Equivalent Performance when Testing the

6 USP<71> Organisms % detected

Matthew England, Ph.D.

0

20

40

60

80

100

USP<71> BacT/ALERT BACTEC

England et al, J. Clin. Microbiol. (2019)

Gold standard, manual Respiration methods
98.7

90.2

95.8 94.8

70.7

86.4

79.2

46.3

67.8

0

20

40

60

80

100

Bacteria (n=77) Fungi (n=41) Total (n=118)

USP<71> BTA 32.5C Bactec

Expand organism test set (n=118) and extended incubation to 14 days % detected

England et al, J. Clin. Microbiol. (2019)

****

*

****  

Matthew England, Ph.D.
21

System did NOT 

detect gross 

contamination
Culture on SDA Improves Fungal Detection (n=41)

87.7

63.4

43.9

100

0

20

40

60

80

100

USP<71> BacT/ALERT Bactec 35C SDA 20-25C

% detected

** 

****

p=0.0549

 

** **

Matthew England, Ph.D.

England et al, J. Clin. Microbiol. (2019)
Revamp Sterility Testing Program at NIH

23

0

20

40

60

80

100

Bacteria (n=77) Fungi (n=41) Total (n=118)

Matthew England, Ph.D.

USP<71>

BTA+SDA

(NIH Alternative method, 

starting 2019)

BacT/ALERT iFA+ and iFN+ 

bottles (32.5°C) with SDA 

culture (22.5°C)

England et al, J. Clin. Microbiol. (2019)
24

Putnam & Lau, J. Clin. Microbiol. (2021)

2021

Nicole Putnam, Ph.D., D(ABMM)

iLYM: Lactic Acid, 

Yeast, Mold
25

This is becoming an increasingly 

common request in clinical 

laboratories

American Society for Microbiology 

listservs
Why are Clinical Micro Lab asked to do Product 

Sterility Testing?

26

Proximity of 

microbiology lab 

to manufacturing 

suites

On-site 

microbiological 

expertise

In-house testing 

more convenient 

(cost, result TAT)
27

2020

2021

2022

2021
Sliding Scale of GMP

28 PDA Technical Report 56
Workshop Questions/Comments

• “Risk assessment” - Risk is subjective

• Depends on expertise. Who is included in RA? You don’t know what you don’t know.

• Organisms recovered from facility  included in PQ and validation  depends on quality of the 

EM program (facility design, cleaning program, gowning program, materials management etc)

• Clinical industry has 510K cleared in vitro diagnostic tests (IVDs)

• IVD risk is just as high

• Can there be an equivalent for GMP? Vendor DMF with beta testing for XX product categories.

• Clinical LDT (validation), Clinical IVD (verification) = requirements clearly defined by accrediting agencies.

• Better define the level of validation needed for phase I, II, III, commercial (not all can be 

USP<1223>)?

• Is test PQ and product method suitability testing alone sufficient for early phase products?

29
30

NIH Sterility Testing Service