API Cross Contamination in Multi Product...

1 Biogen | Confidential and Proprietary

API Cross Contamination in Multi

Product Facilities

Barry Ballinger, CIH

Sr. Manager, EHS

[email protected]

HPAPI Conference, Boston MA

July 15, 2015


Guidelines/Regulations

Risk Assessment

ADE determinations

Routes of Cross Contamination

Evaluation of Engineering Controls

Agenda


“The trouble with quotes on the Internet is

that you can never know if they are genuine.”

- Abraham Lincoln

Disclaimer


• The EU published GMP updates for managing the risk of cross contamination

in August 2014 and which became effective March 1, 2015. The new GMPs

call for risk assessments to determine if products can be produced in shared

facilities. Also states that dedicated facilities are required if:

–the risk cannot be adequately controlled by op or tech measures,

–scientific data from the toxicological evaluation does not support a

controllable risk (e.g. allergenic potential from highly sensitizing materials

such as beta lactams) or

–relevant residue limits, derived from the toxicological evaluation, cannot be

satisfactorily determined by a validated analytical method

EU GMPs


Risk-Based Manufacture of Pharmaceutical Products (Risk-

MaPP), September 2010

• This document outlines a process for assessing the risk of cross

contamination and introduced the acceptable daily exposure

(ADE) as a measure of harm from the hazard (the compound) and

the four possible modes of cross contamination in a multiproduct

facility.

ISPE (Risk-MaPP)


• Evaluation of systems to see if cross contamination is controlled

–Sufficient cleaning validation program

–Contained & Controlled processes

• Does another product present a risk of contamination

–High Risk compounds

• Assess risks of your product contaminating others

• Plans/Schedule for ADE/PDE development

Risk Assessment


• ADE = (NOAEL) / (UFC x α x MF)

Calculating an ADE

Modifying Factor: to

compensate for most

sensitive sub populations

α ∶ 𝑝ℎ𝑎𝑟𝑚𝑎𝑐𝑜𝑘𝑖𝑛𝑒𝑡𝑖𝑐 𝑓𝑎𝑐𝑡𝑜𝑟

Similarly, UFHD may be

calculated as follows:

[PD parameter] + 2SD

[PD parameter]

When the lowest clinical dose is

selected as the POD, it’s regarded

as a LOAEL using this approach.

http://powerpictures.crystalgraphics.com/photos/view/cg7p1942875c/weight_sign_icon


•Assuming you can just do it yourself

•Assuming an ADE is same as an OEL

•Assuming an ADE is a measure of the Risk of Cross Contamination

•Not establishing a cleaning limit

•Having an ADE that is below your cleaning validation detection limit.

•Waiting too long, Dec 1, 2015 is coming

Ways to get it wrong


• Mechanical Transfer: The transfer of material from contaminated

non-product contact surfaces into the product. Particulate

transfer on clothing/feet from operators and equipment alternating

between 2 or more processing areas

Mitigations: Procedures (e.g., gowning control, dedicated shoes,

established traffic flow patterns, equipment wipe down) closed

process and facility controls

Routes of Contamination


• Airborne Sedimentation: Processes that are inherently dusty can

have the potential to spread contamination. Airborne transfer can

only occur if sedimentation takes place onto open product contact

surfaces.

Mitigations: Containment, closed process, segregated areas, and

facility control (e.g., HVAC filtration, pressure differential and

airlocks) Demonstrate effectiveness with IH sampling



• Mix up: inadvertent mistake, human error, leading to a cross

contamination event. Most commonly occurs through labelling,

receipting, line clearance type problems

• Mitigations:

– Labelling

– Batch records

– GMPs, SOPs, quarantine, QC release

– Use of electronic tracking



• Retention: Visual limits have been around for years, even before validated

cleaning limits existed. Many cleaning processes are manual and also use

a visually clean premise in addition to analytical testing to ensure no carry

over contamination.

– Average limit of visual acuity 2 ug/cm2

Mitigations:

–Use of Robust & validated cleaning methods

–Establish a visual residue limit (VRL) within your protocols

–Visual acuity testing for staff

–Dedicated facilities, Disposable technologies



Hierarchy of Controls

Elimination

Avoid the hazard

Engineering

Move the hazard away

Substitution

Reduce the hazard

Administrative

“Procedural-ize” and train to mitigate the

hazard

Protective Equipment

Add a physical barrier to protect against

that hazard

First

Choice

Last Line

of Defense


Performance of Engineering Controls

Control Technology Performance (µg/m3)

General Ventilation 100- 10,000

Local Exhaust (snorkel) 100 – 5000+

Down Flow Booth 25-1000

Dust Caps 100-500

Fume Hood 10-200

Vented Enclosure 1-100

Continuous Liner 1-50

Flexible Isolator 1-10

Rigid Isolator 0.1 -10

Split Butterfly Valve 1-10

High Containment Valves <0.1

Rapid Transfer Port <0.1


15

May Not Always Work


• Chemical Name: Dimethyl Fumarate

• Trade Name: Tecfidera, 120 mg and 240mg oral capsules

• Indication: Relapsing forms of multiple sclerosis

• Pharmacological/Chemical Class: Anti-inflammatory/Nrf2

activators

16

API - Dimethyl fumarate


• Active ingredient in Fumaderm™ (Germany) 1994

• Used historically as anti-fungal and mold inhibitor

• Recognized as an allergenic sensitizer

17

Dimethyl Fumarate - Background

• Numerous cases in Europe/Finland of skin reactions

• 1998 EU ban on use of DMF in furniture

• Other API facts:

Sublimes at room temp

High Kst

Low MIE

Skin sensitizer


Dispense, Blending, Milling & Compression

Isolator w/ N2 inertion

High containment split butterfly valves

Milling w/ N2 inertion

Pressure cascade process rooms

Misting shower

Ex rated dust collection system

Airlock Breathing air supply


Engineering Controls


Ventilated Enclosures

• Ideal for Lab Scale operations

• Designed to contain powders/dusts

• Can be Exhausted or Recirculated

• HEPA & Carbon filtration options

• Containment in the 1-10ug/m3 range


21

Fume Hood Dispensing

• Operator can lean into the

fume hood

• Technique dependant

• Changes to process aren't

easy to accomodate

• May reach <10ug/m3 with

good technique


• Inexpensive: $500 to 6K

• Custom LEV at point of source can reduce dust levels

• Very technique dependent

• Not effective for high risk compounds

• Always-on; energy wasters

Local Exhaust Ventilation


• Operator in the path of contamination

• Containment screen option improves containment

• 25 to 1000µg/m3 containment

• Variable widths, depths and heights

• Recirculatory or Single Pass

• Higher energy cost to run

• 100K and up

Downflow Booth


• Retrofitted to existing equipment

• Cheap

20k+ for passive

50K+ for active

1K for flexi canopy

• 1-10µg/m3

• Quick

• Robustness?

• Short to Mid term fix

• Ergonomics issues

Flexible Isolators


• Not dependant on technique

• Point of transfer, weak point

• Long lead time

• Excellent containment

• Long term fix

• Ergonomics issues?

• Costly, 200k+

Rigid Isolators


26

Continuous Liner

& Crimp

• Used for pack-off, waste, dust collectors

• Anti static bags

• 1 - 50µg/m3

• Variety of thickness bags

• Cassette & Hardware 5k+

• Roll of liners $200 - 500


27

Split Butterfly

Valves

• Closed transfer

• Safety sensors

• Pin guided

• Grounded

• Auto or Ergo Handles

• <1ug/m3

• Costly (10-30K) / valve


• Alpha/Beta configuration

• Variable sizes

• Containment to <0.1µg/m3

• Limited to small size transfers

• ~10k +

Rapid Transfer Ports


Wash in Place/ Clean in Place

• CIP: Cleaning of interior surfaces without need for equipment disassembly.

Is usually automated with a validated system that has a computer user

interface with programmable recipes for cleaning.

• WIP: A combination of manual and automated washing of equipment which

may require some level of disassembly for complete washing.

Spray balls

http://bykowskiequipment.com/media/djcatalog2/images/sprayball3s.1_f.jpg


Fogging/Misting Shower

• Fogging and or Mist shower

• Programmable timing

• PPE waste disposal

• Ventilated chamber

• Lighting/Benches

• ~40k+


• Know your process risks from start to finish

• Utilize your network and professional services

• Contain at the source for operations and for cleaning operations

• Containment is just one piece of the puzzle

• Avoid technique dependant systems

• Don’t forget material transfers

• Aspire to be PPE free

Take Away Messages

http://www.bing.com/images/search?q=image+of+silver+bullet&id=EA818B13089973A0E27780E87561ACFA1D857BC1&FORM=IQFRBA

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