IND Review Chart (for submission of IND to CDER)

NDA Review Chart (for submission to CDER)

A Warning Letter

Picture of a Clean Room

Diagram of the Flow Pattern of HEPA-Filtered Air Through a Typical Clean Room

Incoming air supply

HEPA filter

Items of clean room equipment

Exhaust unit

Ceiling

Clean Room ClassificationHow clean rooms are classified:Two standards are used to classify clean rooms. The first, Federal Standard 209E, is used domestically and the newer standard is TC 209 from the International Standards Organization (ISO). Both standards classify a clean room by the number of particles found in the laboratory’s air. If a laboratory is a class 10 clean room by the Federal Standards, there are less than 10 particles per cubic foot. The following chart relates FS to ISO classifications and recommended action levels of microbiological quality, i.e. the maximum levels in the clean room air that microorganisms should be allowed to reach:

Federal Standard

(particles/ft3)a

ISO Particles/m3

Microbiological Action Levels

(cfu/m3)b

1 <1 >0

2 4 >0

1 3 35 >0

10 4 352 >0

100 5 3,520 1c

1,000 6 35,200 7

10,000 7 352,000 10

100,000 8 3,520,000 100

aParticles are of size 0.5 μm; the standard varies for particles of different sizes.bcfu means colony forming units.c Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

Generalized Clean Room Design

Clean room

Transfer lockTransfer lockdoor

Entry ofraw material

Entry ofpersonnel(changingroom)

BenchTransfer lock

Exit of product

Exit ofpersonnel(changingroom)

Photo showing some clean room attire

A Tri-Clamp Connection

Diaphragm Valves

Piping in Biomanufacturing

A Peristaltic PumpPrinciple of operation

Rotor

Flexible Tubing

Fluid

Side Cross-Section of Centrifugal Pump

General Components of Centrifugal Pump

Rotary Vane Positive Displacement Pump

On/Off valve

Steam(in)

Water(in)

Steam (out)

Water (out)

Diagram of a typical jacketed processing vessel• Such vessels are usually made from high grade stainless steel• By opening or closing the appropriate valves, steam or cold water can be circulated through the jacket• In this way the vessels contents can be heated or cooled, as appropriate• In addition, passage of steam through the jacket of the empty vessel will effectively sanitize its internal surfaces

The range of CIP agents most often used to clean/sanitize chromatographic columns

0.5-2.0 M NaClNon-ionic detergents (0.1-1.0%)NaOH (0.1-1.0 M)Acetic acid (20-50%)Ethanol (~20%)EDTA (~1.0 mM)Protease solutionDilute buffer

Most CIP protocols would make use of two or more of these agents, allowing them to percolate sequentially through the column at a slow flow rate. Contact time can range from several minutes to overnight.Sodium hydroxide (NaOH) is particularly effective at removing most contaminant types.

Sterilization-in-Place Module

Bulk Freeze-Thawing of Purified Protein

Formulation Process(Addition of Necessary Buffers,

Purified (Thawed) Protein,and other Ingredients)

Preparation & Posidyne-Filtration of Required Buffers

Filtration of FormulatedMaterial through a0.22 micron Filter

Filling of VialsSchematic of Formulation-Fill Unit Operation Sequence(The unit operation train will be different for a sustained-delivery formulation or a formulation that requires the use of a delivery device)