parenteral api cleanroom design for microbial control and

Parenteral API Cleanroom Design for Microbial Control and Potent Compound Containment, A Case Study

PDA Midwest Meeting 2021 – Microbial Contamination & Control

James Ratway

September 22, 2021

James Ratway is an employee of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the presentation.

Agenda

PDA Midwest Meeting 2021 – Microbial Contamination & Control 2

AbbVie API Pilot Plant Overview

ADC Bulk Drug Substance – A Potent Parenteral API

AbbVie Facility Design Standards

R12 ADC Facility Design

Facility Microbial Control Performance

1. Agenda

2. AbbVie API Pilot Plant

Overview

3. ADC Bulk Drug Substance –

A Potent Parenteral API

4. AbbVie Facility Design

Standards

5. R12 ADC Facility Design

6. Facility Microbial Control

Performance

AbbVie API Pilot Plant Overview


1. Agenda


Overview




Standards



Performance

Role of the API Pilot Plant


• Produce API to support key development activities– Pre-clinical toxicology studies

– Clinical studies

– Formulation development

– Primary API stability batches/Registration Runs

• Develop and demonstrate robust commercial synthetic routes

• Introduce new technology for commercial manufacturing

• Protect IP by in-sourcing critical final steps

• Ensure resource availability to meet mission critical development timelines

API Pilot Plant Facilities OverviewNorth Chicago, IL


Buildings: C19, R8, R9, R12, S20, S20A, S20B, S42

R12 Kilo Lab Facility


Strategic Function:

• Preparation of API for pre-clinical and FIH enabling studies

• Drug Product solvent-based formulations for GLP toxicology studies (also GMP capable)

• Scale: Up to 100L Reactions

• Potent Drug Capable

Building R12North Chicago Campus

R12 Facility Layout


Project Area

ADC Bulk Drug Substance – A Potent Parenteral API


1. Agenda


Overview

3. ADC Bulk Drug Substance

– A Potent Parenteral API


Standards



Performance

Antibody Drug Conjugates (ADCs) Overview

• ADCs take a highly potent cytotoxic drug (also

known as a payload or warhead) and couple it

to a monoclonal antibody (mAb) using novel

linker chemistry.

• ADCs act as a targeted drug delivery platform -

mAbs are engineered to bind to antigens

expressed by cancer cells and deliver the

cytotoxic drug directly to cancer cells –

reducing off-target toxicity.

• This approach widens the therapeutic window

enabling a higher dose of a more potent

cytotoxic drug than is typically provided by

traditional chemotherapy.

• Cytotoxic drugs used in ADCs are often highly

potent, with exposure levels typically less than

1 µg/m3, some are less than 100 ng/m3.


ADC Manufacturing


• The cytotoxic drug and linker are often synthesized together and isolated as a single compound, typically referred to as a “drug linker” .

• The drug linker and antibody are conjugated and purified to form a parenteral bulk drug substance (BDS). The BDS is not considered sterile and has an allowable microbial and endotoxin specification.

• As part of the drug product manufacturing step, the BDS is formulated, sterile filtered and lyophilized in a vial. The lyophilized drug product is typically reconstituted with WFI and administered by injection in the clinic.

Small Molecule Drug-Linker Synthesis(Warhead & Linker)

mAb Manufacturing

Bulk Drug Substance (Non-sterile)mAb/Drug Linker Conjugation &

Purification

Drug Product (Sterile)Formulation, Sterile Filtration, Vial Fill

& Lyophilization

Typical ADC Manufacturing Scheme

Performed in R12

PBLEC Banding System


Criteria PBLEC 1 PBLEC 2 PBLEC 3 PBLEC 4

Potency (mg/day) >100 >10 to 100 0.1 to 10 <0.1

Exposure Control Limit (µg/m3)

>100 >10 to 100 1 to 10 <1

• AbbVie uses a Performance Based Level of Exposure Control (PBLEC) banding system to define employee exposure in the absence of enough information to create a formal Employee Exposure Limit (EEL).

• Prior to ADCs, AbbVie had traditionally used a 4-band strategy

Criteria PBLEC 1 PBLEC 2 PBLEC 3 PBLEC 4 PBLEC 5

Potency (mg/day) >100 >10 to 100 >0.1 to 10 >0.01 to 0.1 <0.01

Exposure Control Limit (µg/m3)

>100 >10 to 100 >1 to 10 >0.1 to 1 <0.1

• With the introduction of highly potent drug linkers, a 5-band strategy was established.• Most drug linkers fall into PBLEC categories 4 or 5

AbbVie Facility Design Standards


1. Agenda


Overview




Standards



Performance


Particulate-Controlled Facility Classification Matrix

• AbbVie has established four room/workspace classifications (A-D) which meet ISO 14644-1 criteria where process quality requirements include airborne particulate control limits.

• The values in the table below are for use during the design process to determine the necessary air changes based on the room classification.

Environmental Summary for Airborne Nonviable Particulate

AbbVie Grade

FDAIn Operation & Rest

Particle Limits

ISO Class

Fed Std 209E(Superseded)

(0.5 µm particles/ft3)

At Rest Limit (particles/m3)

In Operation Limit (particles/m3)

≥ 0.5 µm ≥ 5.0 µm ≥ 0.5 µm ≥ 5.0 µm

A ISO 5 100 3,520 20 3,520 20

B ISO 7 10,000 3,520 29 352,000 2,900

C ISO 8 100,000 352,000 2,900 3,520,000 29,000

D N/A N/A 3,520,000 29,000 N/A N/A


Controlled Non-Classified (CNC) Areas

• For manufacturing or supporting operations, which do not require a cleanroom environment covered in ISO 14644-1 classification system, AbbVie has established a category of Controlled Non-Classified (CNC) areas.

• A CNC room is a controlled room or area that has varying levels of control; (e.g. microbial, temperature, humidity, room pressurization, etc.), based on requirements but is not classified to an ISO particulate class.

• AbbVie uses the following two levels of CNC rooms:

Category

CNC+ Open or Exposed Product applications – product protection and cross contamination considerations in which bioburden control monitoring may or may not be required, with temperature and humidity control based on process requirements.

CNC Closed Product applications, secondary packaging and general non-processing but GMP-relevant space such as airlocks supporting a CNC+ area, warehouse areas and staging areas with temperature and humidity control based on product requirements and operations.


ADC Bulk Drug SubstanceFacility Room Classifications by Process Function

Process Function AbbVie Class

A B C D

Weigh-Dispense X

Buffer Prep X

Buffer Hold X

Conjugation X

Purification X

Bulk Fill Room X

Bulk Fill Workstation (BSC) X

Using a quality risk-based approach, AbbVie has established the following room classifications for the various ADC BDS manufacturing process functions.


Facility Containment Standard

• AbbVie has established a risk-based standard for secondary (facility) containment design for facilities handling highly hazardous compounds.

• The key parameters of the risk assessment include:

o Quantity of API handled

o Primary Containment Robustness (compliance to Primary Containment Standard)

o System Energy (i.e. milling vs. scooping)

o Hazard Severity (PBLEC category)

SecondaryContainment

Strategy

PBLECCategory

HazardRiskSystem Energy

Primary Containment Robustness

Quantity of API

DispersionPotential


Facility Containment Strategy

PBLEC DP-1 DP-2 DP-3 DP-4

1 FS-1 FS-1 FS-1 FS-1

2 FS-1 FS-2 FS-2 FS-3

3 FS-2 FS-2 FS-3 FS-3

4 FS-2 FS-3 FS-3 FS-4

5 FS-3 FS-3 FS-4 FS-4

• Strategy 1 – Typical facility design with appropriate cross contamination controls.

• Strategy 2 – Facility with secondary containment elements and/or enhanced administrative controls.

• Strategy 3 – Contained potent handling room.

• Strategy 4 – Fully contained potent handling room.

• AbbVie has established progressive levels of facility containment strategies that are based on the PBLEC category of the material being handled and the potential for the material to be released/dispersed from the primary containment equipment.

• The new R12 Highly Potent API (HPAPI) Suite is designed to handle up to 500g of a PBLEC 5 material.

• Handling 500g of product in a containment isolator is considered to have a dispersion potential of DP-2.

• A facility strategy of FS-3 was selected for the R12 HPAPI suite.

R12 ADC Facility Design


1. Agenda


Overview




Standards



Performance

R12 ADC Facility Design Requirements


• Ability to synthesize and isolate up to 500g of highly potent small molecule APIs (HPAPIs) and perform ADC conjugations.

• Grade C (ISO 8) cleanrooms for ADC bulk drug substance

manufacturing (conjugation, purification, final fill) and buffer prep.

• Contained facility following containment strategy FS-3

o Air locks

o Misting shower

o Contained drain system

o Terminal supply and exhaust HEPA filters

o Negative room pressure, relative to adjacent corridors

o Differential pressure monitoring

• Floor Mounted & Bench hoods for liquid handling operations

• Containment Isolators for solid potent handling, designed to 1

nm/m3

• Contained API drying equipment – bulk lyophilizer, tray dryer

• ISO 7, Class II, Type B2 Bio Safety Cabinet for ADC bulk fill

Containment

(Negative Pressure)

Biologic

(Positive Pressure)

Requirement for containment needs to be balanced with requirement for cleanroom environment for biologics


Design/Construction Features for AbbVie Grade C Area

Design/Construction Feature

AbbVie Engineering Standard Requirement R12 Facility Design

Barriers Airlocks should be provided to separate zones from adjacent spaces of less stringent classification.

Personnel In/Material AirlockMisting ShowerPersonnel Out Airlock

Airlock Interlocks

Airlocks must be interlocked to prevent simultaneous opening of two or more doors when required by product.

Interlocked using central door interlock controller

Ceilings • Portland cement plaster w/epoxy coating• Cementitious backer board w/epoxy coating• Fiberglass Reinforced Plastic (FRP) panels suspended and

sealed in stainless steel or anodized aluminum T-bar grid

FRP panels sealed in stainless steel T-bar grid

Flooring Suitable for cleaning and sanitization, pitched to drains Corrosion Engineering Tufchem™Tiling System, Novolac grout w/carbon, Electrostatic Dissipative (ESD)

Walls Suitable for cleaning and sanitization High Impact, mold-resistant drywall with integral fiberglass mat, high-performance Tnemec multi-layer epoxy coating

Doors & Frames

Suitable for cleaning and sanitization Stainless Steel

Windows Vision panels must be flush with wall surface, fixed glazing, or must have sloped sills and all joints sealed, and no ledges.

Per standard


HVAC Design for AbbVie Grade C Area

HVAC Design

AbbVie Engineering Standard Requirement R12 Facility Design

Air Balance & Classification

• When airflow is designed to cascade from an airlock into a production room the airlock must be designed to be, as a minimum the same AbbVie Room Category it serves.

• When the direction of airflow is designed to cascade from a production room into an exit airlock, the airlock must be designed to be, as a minimum the same AbbVie facility category in the at-rest state as the production room it serves or one category lower (less stringent particulate air requirement).

Per standard

Temperature 60°F to 77°F Summer: 68°F ±5°FWinter: 67°F ± 5°F

Relative Humidity

30% - 60% Summer: 55% ± 5%Winter: 43% ± 5%

Room Pressurization

Design room pressure differential of at least 12.5 pascals (0.05”, w.g.) between the processing room and adjacent connected room separated by an airlock/gowning room.

Per standard

Facility Layout w/Room Class & Pressurization Scheme


Main Gowning Airlock

Personnel In/ Material Airlock

HPAPI Process Room

Emergency Exit

Misting Shower

Personnel Out Airlock

31 30 35 45 76 30

Air Changes/Hr – HPAPI Suite

R12-160 Highly Potent API Suite


Equipment from right to left includes Walk-In Fume Hood, Process Isolator and Benchtop Fume Hood

Equipment from right to left includes Process Isolator, Benchtop Fume Hood, Preparation Isolator, and Walk-In Fume Hood



Walk-in fume hood enables liquid reactions up to 100L Benchtop fume hood enables liquid reactions up to 5L. Fume hood integrated into isolators to enable transfer of solids for handling within containment.



Tray dryer integrated into isolator8-shelf bulk tray lyophilizer integrated into isolator.



Corrosion Engineering Tufchem™ ESD flooring system. Floor electrical ground connection shown on right.

Safe change HEPA exhaust filter integrated into ceiling.



Misting ShowerDe-gowning airlock with integrated waste chute.

R12-170 Buffer Preparation Suite


Equipment from right to left includes Biosafety Cabinet and Buffer Preparation Fume Hood

Class II, Type B2 Biosafety Cabinet for final packaging of ADCs

Facility Microbial Control Performance


1. Agenda


Overview




Standards



Performance


HPAPI Suite Performance Qualification (PQ)Testing Plan and Acceptance Criteria

• Facility PQ testing was performed in accordance with AbbVie’s facility qualification standards and

Environmental Monitoring Program.

• Testing was performed over a period of eight days and three shifts, of which three days were under At

Rest conditions and five days under In Operation conditions.

• Under In Operation conditions, the people load per room for the HPAPI suite was as follows:

o Main Processing Suite – 6

o Personnel In/Material Airlock – 4

o Personnel Out Airlock/Mist Shower – 2

o Emergency Exit Airlock - 2

Testing Condition

AbbVie Grade C CNC+

Sampling Days

Non-Viable Particulate (particles/m3) Room Air

Viable (cfu/m3)

Surface AMC

(cfu/25cm2)

Sampling Days

Room Air Viable

(cfu/m3)

Surface AMC

(cfu/25cm2)>0.5µm >5.0 µm

At Rest Day 1-3 ≤352,000 ≤2,900 ≤100 ≤25 N/A N/A N/A

In Operation Day 4-8 ≤ 3,520,000 ≤ 29,000 ≤100 ≤25 Day 4-6 ≤200 ≤300

PQ Testing Protocol Summary


Facility PQ Sampling Locations

• The minimum number of sample locations is based on ISO 14644-1:2015E, Table A.1 Sampling locations related to cleanroom.


PQ Test Results – HPAPI Process Room (Grade C)Non-Viable Particulate Air Sampling

Acceptance Criteria: ≤352,000 Acceptance Criteria: ≤3,520,000

Acceptance Criteria: ≤2,900 Acceptance Criteria: ≤29,000


PQ Test Results – HPAPI Process Room (Grade C)Room Air Viable & Surface AMC

Acceptance Criteria: ≤100

Acceptance Criteria: ≤25


Summary

• PQ test results for the HPAPI process room far exceed Grade C acceptance criteria and

approach Grade B performance.

• All other support rooms (airlocks, misting showers, etc.) exceeded acceptance criteria.

parenteral api cleanroom design for microbial control and

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