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© 2009, Genentech / Proprietary information – Please do not copy, distribute or use without prior written consent.

Benefits of a Risk-Based Cleaning Validation Approach during New Product Introduction

Jenna Carlson,Sr. Technical Manager

New Product Introduction (NPI)

Establishment of risk-based controls and requirements for introduction of:

• commercial product at a facility licensed only for single-product operations

• clinical product at a facility licensed for production of commercial products.

• product derived from a host cell not currently licensed for production at the facility.

Risk based cleaning validation strategy:• Risk management to evaluate cross-contamination or

operational risks• Laboratory studies• Establish cleaning validation acceptance limits• Pre-introduction cleaning studies• Determine commercial scale cleaning validation strategy

Risk Management Process

•FMEA used to evaluate cross‐contamination risks associated with multiuse operations•FMEA considers the following risk categories

•Retention/Residue•Mechanical Transfer•Product Mix‐ups•Airborne Transfer

Assessment assumes that in order for cross contamination to occur there must be a touch point which allows the possibility of transporting components from one product stream into another product stream

Touch Point Analysis


Example of Risk Analysis Multiple Commercial Products

Failure EffectMultiple commercial

productsClinical and Commercial

Products

Clinical and Commercial

products; Multiple hosts

Cross-contamination with adventitious agents

8 8 10

Cross-contamination of one product with another

8 10 10

Cross-contamination of cells between products

8 10 10

Non-routine event during processing 8 8 8

Cross-contamination of one denatured product with another

6 6 6

Cross-contamination of raw materials from one product to another (animal derived)

6 6 6

Cross-contamination of raw materials from one product to another (non-animal derived)

4 4 4

Laboratory studies

• Rinse Recovery Studies • Swab Recovery Studies • Visual Limit of Detection Studies • Product Grouping Studies

Recovery Studies• Can the process residues be effectively detected on the equipment material of

construction (MOC) by rinse or swab sampling?

• Multiple Process Residues of the process stream are challenged

– e.g. Cell Culture Fluid, Harvested Cell Culture Fluids, and Formulated Bulk

• Performed on major process-contacting materials of construction in the manufacturing facilities

– e.g. Stainless Steel, Glass, & EPDM.


Stainless Steel Swab & Rinse Data

Cell Culture Fluid (CCF)

Harvested Cell Culture Fluid (HCCF)

Formulated Bulk (FB)

Swab Rinse Swab Rinse Swab Rinse

N 36 36 36 36 34 34

MIN 61% 81% 83% 83% 69% 70%

MAX 114% 115% 115% 115% 109% 117%

AVG 97% 101% 95% 102% 93% 101%

σ 7 7 6 7 9 8

Conclusion: No comparable difference between swab and rinse.


Elastomer Swab & Rinse Data

Cell Culture Fluid (CCF)

Harvested Cell Culture Fluid (HCCF)

Formulated Bulk (FB)

Swab Rinse Swab Rinse Swab Rinse

N 35 35 35 35 33 33

MIN 81% 81% 83% 84% 69% 70%

MAX 114% 115% 115% 115% 106% 117%

AVG 99% 102% 96% 102% 94% 101%

σ 7 8 7 7 8 8

Conclusion: No comparable difference between swab and rinse.


Stainless Steel Swab, Rinse, & Visual Comparison

Cell Culture Fluid (CCF) Harvested Cell Culture Fluid (HCCF) Formulated Bulk (FB)

Swab Rinse Visual Swab Rinse Visual Swab Rinse Visual

N 36 36 30 36 36 30 34 34 30

MIN 61% 81% <0.25ppm 83% 83% <0.25ppm 69% 70% <0.25ppm

MAX 114% 115% 0.43 ppm 115% 115% 0.39 ppm 109% 117% 0.93 ppm

AVG 97% 101% 0.26 ppm 95% 102% 0.26 ppm 93% 101% 0.32 ppm

σ 7 7 0.04 6 7 0.03 9 8 0.13


© 2009, Genentech / Proprietary information – Please do not copy,

distribute or use without prior written consent.

Bench scale model for cleaning comparability

(adapted from Biotech. Prog., 2008)

• Soil coupon with known amount of product. Let to dry undisturbed for 24 to 72 h under the hood at room temperature.

• Submerge coupon into cleaning solution. Minimal agitation to mimic worst case

• Output: Cleaning time

• Cleaning time recorded as time to visually clean and time to reach maximum absorbance at 280nm

© 2009, Genentech / Proprietary information – Please do not copy,

distribute or use without prior written consent.

Cleaning in pictures

(1) Dried(2) Startcleaning…

(3) Cleaning…

(4) StillCleaning…

(5) Clean!

Formulated Bulk on Stainless Steel

n=3n=3

Process/Protein Residue Acceptance Limit

Acceptance criteria must meet the most stringent of the following criteria:– Not more than the maximum allowable carryover (MAC) according to

the acceptable daily exposure (ADE)– Not more than 10 ppm of any product to appear in another product.

ADE = No Observed Adverse Effect Level * Body WeightCumulative Adjustment Factor

MAC = (Acceptable Daily Exposure * Smallest Batch Size)Maximum Daily Dose

Swab Limit = MAC * Test Area * Recovery FactorShared Surface Area

Rinse Limit = MAC * Test Area * Recovery FactorSurface Area * Volume of Rinse

ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Product. Volume 7. ISPE September 2010.


Pre-Introduction Cleaning Study

Performed to challenge the ability of the standard cleaning procedures to remove the new process residues from representative equipment surfaces.

• Conducted using:– Representative equipment

• Equipment selection based on level of control in the plant– In-process soils

• Typical soils used are Cell Culture Fluid and Formulated Bulk– Worst-case cleaning methods.

• All methods used in the plant (e.g. CIP, COP, Glassware washers, Manual)

• Product residue acceptance criteria are the same as used during cleaning validation

• Requires 3 successful consecutive cleaning runs• Maximum dirty equipment hold time is challenged for all 3 runs• Sampling for residues include: rinse, swab, & visual


Representative Testing Equipment

Material Type Representative Equipment Cleaning Method

Stainless Steel 10” Filter Housing Manual

Stainless Steel Miscellaneous Small Parts

COP Washer

Stainless Steel Transfer Lines CIP

Stainless Steel 120L cryovessel CIP

Plastics Hoses Manual

Plastics Hoses CIP

Plastics Associated spinner parts Manual

Elastomers EPDM gaskets Manual

Elastomers EPDM gaskets CIP

Glass Spinner flasks Manual

Glass Spinner flasks Glassware Washer


Before Introduction to Facility

• Risk Management Report approved• Laboratory studies completed

– Analytical methods effectively detect process residues.– Product grouping assessment (new worst case?)

• Scientifically justified acceptance limits for cleaning validation• Acceptable results in the pre-introduction evaluation study allow a new

product to be introduction in a facility. – Determines amount of effort and sampling techniques required during

concurrent validation.

Cleaning validation of the major multi-use, product contacting equipment must be executed concurrent with manufacturing.

Acknowledgements

John McShane

Lara Collier

Marisa Goo

Sue Zanne Tan

Prateek Gupta

Stephen Gomez

Julia Edwards

Emma Ramnarine

Krista Terry

Questions?

Thank You

Appendix

Multi-product Risk Assessment Example

Visual Limit of Detection Studies

1. Spike 3 replicate sets of coupons (stainless steel, or other surface material of interest) at varying residue levels:

• Negative control spiked with DI or better water2. Dried for 24 hours3. All Coupons visually inspected by 3 technicians

individually:

4. After coupons are inspected, they are swabbed.

30uL

5uL 1uL

15uL 10uL

Neg

30uL

5uL 1uL

15uL 10uL

Neg

30uL

5uL 1uL

15uL 10uL

Neg

30uL

5uL 1uL

15uL 10uL

Neg

30uL

5uL 1uL

15uL 10uL

Neg

30uL

5uL 1uL

15uL 10uL

Neg

‐ Use standard manufacturing lighting conditions‐ Coupons not handled during inspection‐ Determine minimum residue level that all technicians visually detect residue‐Must detect residual soils below 1.0 ppm (5 μg/cm2) to be considered acceptable


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