tools and techniques for assessment of containment...

Tools and Techniques for Assessment of Containment

And Exposure in The Pharmaceutical Industry

Matthew J. Meiners, CIH

Division Manager

Bureau Veritas North America

2

Containment – Functional Definition

There are three basic elements to pharmaceutical

manufacturing…

► Product

► People

► Facilities and surrounding

environment

For our purposes, containment

is the isolation* of the first of these

(product) from the other two.

3

Why Contain Pharmaceutical Processes?

► Protect workers, facilities and environment from product. Though considered a chemical hazard, pharmaceuticals are unique - they are intended to have biological effects at even very low levels.

► Protect product from the environment

► Prevent production losses of product

4

Containment… To What Level?

Containment (isolation*) is not an absolute, and must be further defined.

► “Zero” can never be assumed, and is impossible to measure.

► Thresholds limiting product migration to the other two elements (people and environment) must be defined.

► Limits, sometimes called “Containment Performance Targets” (CPT), are rationalized and set.

5

Containment Strategies

Containment strategies (equipment and procedures) are selected based upon the “CPT”, with consideration to the underlying process.

Strategy 1: Controlled general ventilation

Strategy 2: Localized capture of airborne particles

Strategy 3: Barrier isolation

Strategy 4: Barrier isolation with closed transfer

Strategy 5: Complete isolation with remote process control.

6

The Containment Challenge….

A paraphrased quote – source unknown…

“A required containment level of 5 nanograms/m3 is the equivalent of one grain of pollen in an average sized living room.”

Containment to and testing against such criteria present significant challenge.

Techniques for Assessing Containment Performance

8


► Parametric testing

► Visualization

► Tracer gases

► Functional testing with surrogates

► Live process testing (direct analysis for fugitive APIs)

9


Parametric Testing

► Examples – face velocity (open system) and pressure drop.

► Useful for indicating air handling equipment is operating within specification

► Weakness - Does not necessarily relate to effectiveness of the system

10


Visualization

► Examples – smoke tubes and candles

► Useful for seeing flow patterns, air movement/direction and can be used to visualize barrier isolation

► Weakness - qualitative

11


Tracer Gases

► Detectable vapor metered into the system and collected at critical points where containment may be lost

► Examples – ASHREA 110 (SF6), Freon, Cinnamon.

► Can be performed quantitatively, with high sensitivity

► Weakness – Vapors behave differently than aerosols: they disperse evenly and are drawn away from surfaces. Particles settle and create a source of recontamination.

12


Direct Testing During Manufacturing

► The most accurate measure of containment performance.

► Requires that a sampling and analytical method of adequate sensitivity for the API has been developed, validated and is available.

► Weakness – If relied upon as the initial measure of containment, and performance does not meet specification (CPT), it can result in unacceptable and preventable employee API exposures and facility contamination.

13


Functional Testing with Surrogates

Substitution of process API with another solid material of similar characteristics, low toxicity, with a sensitive assay.

► Useful in that it allows for equipment/procedural testing of

aerosol containment performance prior to introduction of

API material.

► Can be performed quantitatively, with high sensitivity, and

short of actual sampling of API during manufacturing, is the

best indicator of containment performance

► Sensitive methods are defined and available.

► Can provide “challenge” testing for multi-use equipment

► Provides “standardized testing” for comparison of relative

performance

Surrogate Testing: When and How?

15

Factory Acceptance Testing (FAT)

Standardized performance testing of equipment prior to installation at the site.

16

Site Acceptance Testing (SAT)

The evaluation of newly installed containment equipment and procedures at the site, prior to

introduction of actual process API.

17

Operational Qualification (OQ)

Performance testing of in-use equipment and procedures

18

Elements of a Successful Surrogate Evaluation

#1 - Establish Containment Target (CPT)

► Driven by IH, toxicology, QA or engineering specification

► Often based upon OEL or other health limits

► Consideration of PPE is incorporated if specified

► Incorporation of safety factors is common

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#2 - Determine the Means to Simulate the Operation

► Testing facility configuration – goal is to simulate “in-use process train”, incorporating all critical steps in the process

► Multiple operators, assuming sub-optimal conditions

► Don’t rely on a single test – several runs or operations should be tested.

20


#3 - Selection of Surrogate Material

► No perfect surrogate material, but there are standardized materials – the best choice will depend upon the particular manufacturing process and the situational priority of a variety of variables.

21


#4 - Develop a Sampling Plan

► Area sample at critical containment points

► Operator exposure sampling

► Task sampling – make sure task duration provides adequate sensitivity for meaningful results!

More sensitive methods (example: LC/MS/MS application vs.. HPLC)

Higher flow rates

Longer sample times (multiple iterations for tasks)

► Consider surface sampling if it adds value

22


#5 - Perform Simulation and Sampling

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#6 - Interpretation of Results

► Report should describe the testing method in detail, with objective interpretation of result. Pictures are helpful.

► Report should demonstrate if the CPT specification is being met

Factors in Which Drive Surrogate Selection

25

Surrogate Selection

Meets Requirements for the Manufacturing Process

► Flowability (bulk powder movement)

► Compactability and adhesion (tableting)

► Solubility (emulsion vs. solution)

26

Surrogate Selection

Relative Hazard or Toxicity of Test (surrogate) Material

► OEL or other health limit

► Process safety concerns

27

Surrogate Selection

Sensitivity of the Sampling and Analytical Method

► Internal or Commercial Lab

► Analytical sensitivity

► Air sampling flow rate

► Duration of task or test

28

Surrogate Selection

Selectivity of the Analytical Method

► Possible interferences in the test environment

► Possible environmental background of surrogate material

29

Surrogate Selection

Quality Concerns

► API vs. non-API

► Cleanability

► Established cleaning procedures

30

Surrogate Selection

Test Material Availability and Cost

► How much test material is needed?

► Cost of bulk material

► “Off the shelf” vs. Custom manufacture (micronization)

31

Surrogate Selection

Appropriate “Containment Challenge”

► “Dustiness” - defined as the propensity of a material to emit dust during manufacturing: may be considered analogous to vapor pressure on a molecular scale.

► Flour vs. Sugar

► Though studied in a variety of ways (gravity dispersion, mechanical dispersion and gas dispersion), a standardized measure of “dustiness” has not been established.

► A variety of individual particle characteristics effect relative dustiness.

32

Surrogate Selection

Factors Effecting the Dustiness of Bulk Powders

► Powder Mass/Bulk Density

► Moisture Content

► Particle size and size distribution

► Particle density

► Flowability and Cohesion

► Particle Shape

33

Material Characteristics Relative to Dustiness

Powder Mass and Bulk Density

► The effect of sample mass on dust generation demonstrates an initial increase in dustiness with increase in mass, followed by a decrease after a critical point is reached.

► The observed decrease in dustiness index with sample weight is a function of both the dust generator itself and a decrease in the volume of entrained air.

► Conclusion: the measuring instrument, process being evaluated and containment system itself can affect “dustiness” index of a bulk powder.

34


Moisture Content and Humidity

► Generally, an increase in moisture content for bulk powders results in decreased dustiness.

► Mechanism – Moisture content increased the cohesion of powders as well as particle weight.

► Generally, dustiness indices are highest for dried powders, tested at low humidity.

► Spray dried lactose is an important exception – it absorbs less than 2% moisture up to 75% relative humidity with little change in measured dustiness compared to its respective dried powder.

35


Particle Size and Size Distribution

► Characteristic with the greatest

impact on powder dustiness

► Generally, decrease in particle size

results in increase in dustiness

► Powders blended to contain only a

portion of small particles were found to

be nearly as dusty as powders

comprised entirely of small particles

► For most materials, as the proportion of

small particles in a blend diminishes, the

faction of small particles in the generated dust increases.

36


True Density

► Particle size, not density, governs the motion of aerosol powders

► Studies have found no clear relationship between density and dustiness

37


Flowability and Cohesion

► Measured by Angle-of-Repose

► Subjective

► Found to correlate poorly with dustiness measurements

► No satisfactory relationship has been found between powder cohesion and powder aerosolization.

38


Particle Shape

► Important in it’s relation to particle size measurements

► Shape factors (aspect ratio, circularitry, elongation ratio, …) do not directly correlate with dustiness indices of powders

► Materials with significant elongation ratios such as acetaminophen cause correlation problems.

► Pujara (Abbott) has found a good relationship between “empirical shape coefficient” and dustiness by incorporating an elongation ratio into the equation.

39

Material Characteristics – Conclusion

Dustiness of Surrogate Material to API

► A variety of factors affect the “dustiness” of bulk powders

► The best way to determine the relative “dustiness” of surrogate to API would be by direct measurement of the bulk powders by the same technique.

► In the absence of dustiness measurements, the best means of selecting a representative surrogate is by mean particle size, with similar distribution.

Common Process Surrogates

41

Common Process Surrogates

The most commonly used process surrogates in the Pharmaceutical and Containment Industry

► Lactose

► Naproxen Sodium

► Mannitol

► Acetaminophen

► Riboflavin

► Sucrose

► Arizona Road Dust

► Insulin

42

Surrogate Selection Criteria – Relative toxicity

Surrogate

► Lactose

► Naproxen Sodium

► Mannitol

► Acetaminophen

► Riboflavin

► Sucrose


► Insulin

Typical OEL

► 10 mg/m3

► 2.5 mg/m3

► 10 mg/m3

► 3 mg/m3

► 5 mg/m3

► 10 mg/m3

► 3-10 mg/m3

► .003-0.3 mg/m3

43

Surrogate Selection Criteria – Analytical Method

Surrogate

► Lactose

► Naproxen Sodium

► Mannitol

► Acetaminophen

► Riboflavin

► Sucrose


► Insulin

BVNA LOQ Mass/Sample

► 2.5 ng*

► 0.2 ng

► 1.0 ng

► 0.5 ng*

► 5 ng

► 5 ng

► 10,000 ng

► NA

Method Selectivity

► Good

► Very Good

► Good

► Exceptional

► Good

► Good

► Poor

► Exceptional

44

Surrogate Selection Criteria – Quality Concerns

Surrogate

► Lactose

► Naproxen Sodium

► Mannitol

► Acetaminophen

► Riboflavin

► Sucrose


► Insulin

Type

► Excipient

► API

► Excipient

► API

► API

► Excipient

► Dirt

► API

Cleanability

► Highly Soluble

► Highly Soluble

► Highly Soluble

► Modestly Soluble

► Sparingly Soluble

► Highly Soluble

► Insoluble

► Poorly Soluble

45

Surrogate Selection Criteria – Availability and Cost

Surrogate

► Lactose

► Naproxen Sodium

► Mannitol

► Acetaminophen

► Riboflavin

► Sucrose


► Insulin

Relative Cost

► 1

► 100-1000

► 5

► 5-10

► 15

► 5

► 10-20

► Very high

Multiple Specification

► Yes – wide variety

► Custom

► Yes – variety

► Custom

► Custom

► Yes – variety

► Yes – variety

► NA

46

Surrogate Selection Criteria – Summing it up…

Selection of the best surrogate material for your application depends upon…

► which criteria are your drivers

► particular surrogate characteristics that may also drive the selection process…

47

Lactose

Selection Drivers ► Least expensive in bulk, wide

variety of specifications

(particle size distribution)

available “off the shelf”

► Low hazard

► Minimal quality concerns,

easily cleanable

► Sensitive and specific

method available (2.5

ng/sample)

► Specified surrogate in ISPE

guidance document

► Dustiness independent of

humidity and moisture

content

Potential Concerns ► Common excipient – may be

used in the test formulation

or facility may have

background levels.

► International shipments can

be complicated by bovine

product import concerns

► May lose specification upon

storage of micronized

material

► Complicated analytical

method limits options for

analysis

http://www.foremostfarms.com/index.php

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Naproxen Sodium

Selection Drivers

► Highest sensitivity (0.2

ng/sample)

► Easily cleanable

► Uncomplicated analysis

increases availability of

method

► Widely accepted

surrogate, first alternative

in ISPE Guidance

Document

► Good containment

challenge (high dustiness

index)

Potential Concerns

► High relative material cost

if handling in bulk

► API introduction may

cause quality concerns

► Custom sieving or

micronization needed for

specific size distribution

49

Mannitol and Sucrose

Selection Drivers

► Low cost in bulk, variety of

specifications (particle size

distribution) available

► Low hazard

► Minimal quality concerns,

easily cleanable

► Sensitive and specific

method available (Mannitol

is 1.0 ng/sample)

► Good alternative if Lactose

is present in formulation or

facility

Potential Concerns

► Common excipients – may

be used in the test

formulation or facility may

have background levels.

► Complicated analytical

method limits options for

analysis

50

Acetaminophen (Paracetamol)

Selection Drivers

► Relatively low cost API in

bulk

► Highly sensitive and

specific method available

(0.5 ng/sample)

► Good surrogate for

tableting or tablet handling

activities.

► Was one of the first

commonly used surrogate

materials (EU)

Potential Concerns



► More difficult to clean




► Unusual elongation ratio

for crystals

► High cost and limited

options for analysis

(LC/MS/MS)

51

Riboflavin (Sodium Acetate)

Selection Drivers

► Common use for CIP

coverage testing may

eliminate quality concerns

► Surface contamination can

be visualized by black light

Potential Concerns



► More difficult to clean




► Low level environmental

background common

52

Standardizing Surrogate Testing

ISPE Guidance Document

► “SMEPAC” product

► Adopted and published by ISPE in 2005

► “Good Practice Guide”

► FAT and SAT – intended to provide standard testing and comparison of relative performance and against common criteria

► Updated (Second Edition) in 2012

53

The Next Step – Ongoing Containment Verification

► FAT and SAT testing is performed in order to predict with some degree of certainty, that CPTs and worker exposures are not exceeding limits.

► FAT and SAT testing is performed on newly installed equipment, in optimal working conditions.

► Performance of containment equipment can degrade or fail over time.

► Ongoing evaluations of containment and employee exposures during routine operations is the only means to be confident that containment is maintained, and potent materials are handled safely!

Process Sampling and Analytical Methods

For Ongoing Containment Verification

55

Introduction

A control specification has been established (CPT).

Are process controls meeting the specification?

→Over full process duration

→Tasks and short duration activities

→Consideration of PPE

The above question should be answered definitively, and control within the specification should be demonstrated on an

ongoing basis.

This requires a sampling and analytical method with adequate sensitivity, accuracy, precision and specificity.

56

Sampling & Analytical Methods - Validation

Methods need to be verified prior to use -“Validation”

Validation Elements:

► Analytical method (ICH Guidelines)

► Collection media selection

► Collection efficiency

► Recovery from collection media

► Stability of collected samples

► Robustness and Ruggedness

57

Validation Spike Prep - Standard Model

► Results of experiments are variable based upon mass level

► Validation must therefore be performed at critical mass levels

► Highly Potent API methods must be validated at very low mass loadings

► Only practical means of low mass spike generation is by direct application of dilute API in solvent

58

Solution Deposition – the standard model

Airborne Particles are partially protected

Surface area increased, material exposed.

59

N

O

F

CH3

NCH3

Case Study - Escitalopram

OEL = 30 mg/m3

0.1x OEL 15 minutes = 90 ng

0.1x OEL 30 minutes = 180 ng

Unacceptable Collection Efficiency using standard Model

60

Initial Escitalopram Experiments with Liquid Spiking

Experiment:

Capped in dark 1 day: 96.3%

Capped in light 1 day: 99.6%

Uncapped 1 day: 58.7%

4 hour air draw: 47.6%

4 hour air draw uncapped 1 day: 23.3%

4 hour air draw uncapped 2 days: 10.8%

4 hour air draw uncapped 7 days: 1.2%

4 hour air draw capped 7 days: 48.4%

Conclusions:

Not light sensitive

Air related

Low concentration contaminant

Contaminant depleted quickly

61

Test Atmosphere

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

N2 O2 Ar CO2 Ne He CH4 Kr H2 N2O CO Xe O3

pp

m

62

Possible Culprits

- Nitrogen

- Oxygen

- Argon

- Carbon Dioxide

- Neon

- Helium

- Methane

- Krypton

- Hydrogen

- Nitrous Oxide

- Carbon Monoxide

- Xenon

- Ozone

Concentration

Inert

Most Suspicious

63

The prime suspect: Ozone

- Extremely powerful oxidizing agent

- Half-life of about half an hour at normal atmospheric conditions

- Branches of exploration – solid deposition, susceptible classes,

and prevention.

64

Some Methods Fail to Validate…

“Essentially, all models are wrong… but some are useful”

George E.P Box, Statistician

65

Aerosol Deposition – Actual Sample Collection

Deposition of particles - ng/sample - practicality

66

A New Model - Low Mass Aerosol Spikes

67

Collection onto the Filter

68

Total Dust Sampling vs Cyclones for Deposition?

► 37mm total dust cassette

- Rapid deposition

- Minimal size discrimination

► Cyclone

- Improved precision of mass deposition

- Smaller particles allows for lower mass

- Longer entrainment

- Worst case for degradation and a variable tool for degradation studies

69

Extraction of Small Particles using Cylone

Cyclone

http://upload.wikimedia.org/wikipedia/commons/8/80/Baffle_chambers.svg

70

Degradation Inversely Related to Particle Size

Grit Pot Filter

71

Comparison of Liquid vs Aerosol Models:

Escitalopram Spikes After Air Challenge

ug recovered ug recovered

R1 0.128 L1 0.126

R2 0.126 L2 0.103

R3 0.108 L3 0.129

R4 0.087 L4 0.114

DE avg. 0.120 Air avg. 0.107

0.0110 0.0192

%RSD 9.21 %RSD 17.9

89.3% Recovery for Aerosol Deposition

15% Recovery for Liquid Deposition

72

Escitalopram Results: Nominal 120 ng/sample

120 ng STD

Immediate Extraction.

Extract after 8 hours

Aerosol spike after 8 hours of air sampling

Liquid spike after 8 hours air sampling

73

A second example…

Antifungal Echinocandin

mg recovered mg recovered

R1 0.1068 L1 0.0826

R2 0.0846 L2 0.0892

R3 0.0874 L3 0.0806

R4 0.0804 L4 0.0934

DE avg. 0.09052 Air avg. 0.0841

0.0103 0.0045

%RSD 11.33 %RSD 5.35

Aerosol Deposition: 92.9% retained following 8 hours air sampling

Liquid Deposition: 20.9% remains following 8 hours air sampling

74

Degradation –Cannon Ball vs Grape Shot Analogy

75

SEM Images – Aerosol vs Liquid Deposition

76

Surface Area and Degradation

Penetration to a depth of 10 nm (0.01 mm)

A 1 mm particle would have 5.9% degradation A 100 mm particle would have 0.06% degradation

0

100,000

200,000

300,000

400,000

500,000

600,000

0 20 40 60 80 100

Mass

Particle Diameter (micrometers)

Inner Volume

Surface Volume

77

Functionality Attributed to Observed Degradation

CH3

CH3

NH

N

F

CH3

CH3

N

ON

78

If Validation by Aerosol Deposition Fails…

Ionic Gel Coated Sampling Filters

► Designed to both chemically and physically protect collected aerosols from oxidation during air sampling

► Aerosol particulates impact on gel during sampling, absorbed into the gel.

► Employed for a growing number of BVNA API applications

► Limitations:

Can’t be used for hydrolysis susceptible APIs

New, proprietary technology – limited availability

79

Questions??

Matthew J. Meiners, CIH

[email protected]

(847) 726.3720

If you would like more information, or

have any questions, contact me.

THANK YOU!

mailto:[email protected]

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