Pharmaceutical Facility Design

Pharmaceutical Facility Design

Session 1-5

Basic Biopharmaceutical Unit Operations

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 Pharmaceutical Facility Design

Table of Contents
1 Basic Biopharmaceutical Unit Operations .............................................................. 3
1.1 Upstream Processing and Fermentation ........................................................ 3
1.2 Harvesting / Recovery ..................................................................................... 4
1.3 Separation ....................................................................................................... 4
1.4 Purification ..................................................................................................... 4
1.5 Filling ............................................................................................................... 5
1.6 Bioanalysis ....................................................................................................... 5

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 Pharmaceutical Facility Design

1 Basic Biopharmaceutical Unit Operations

Based on ISPE Knowledge Brief KB-0002-Jun08, Jeffery Odum, (2008))

The basic unit operations below represent the ‘standard’ operations that most
companies implement in their manufacturing operations.

Basic biotech process elements are:

1. Upstream Processing
2. Fermentation
3. Harvesting / Recovery
4. Downstream Processing
a. Separation
b. Purification
5. Filling

1.1 Upstream Processing and Fermentation

Fermentation refers to the large-scale cultivation of microorganisms. Cell
culture is a specific type of fermentation that involves the process of taking
cells from living organisms and growing them under controlled conditions. Cell
culture is part of the upstream processing operations; literally engineering and
growing the cell line to be used to manufacture the drug product. Once
fermentation is complete, the desired product must be harvested, recovered,
separated out, and purified.

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 Pharmaceutical Facility Design

1.2 Harvesting / Recovery

Harvesting and recovery is the separation of crude product from microbial
mass and other solids and liquid medium, to prepare it for purification. In
many instances product recovery usually requires some type of cell disruption.
There are a number of different methods for breaking down cellular material,
and the most common is centrifugation:

• Non-mechanical
o Freezing
o Detergents
o Enzymes
• High pressure
o Centrifugation
o Homogenization
• Mechanical Grinding

1.3 Separation
The downstream operations begin by separating the ‘good’ from the ‘waste’ in
the product materials via a filtration operation (cross-flow-filtration (CCF) /
tangential-flow-filtration (TFF)).

The separation steps are:

• Extraction and Precipitation
• Filtration
o Microfiltration
o Ultrafiltration

1.4 Purification
The purification steps are high risk chromatography operations and are very
costly to perform:
• Gel / Size-Exclusion filtration (SEC)
• Ion exchange (IEX)
• Hydrophobic interaction (HIC)
• Affinity

The required protein must be modified to a stable, sterile form that can be
taken by the patient. Traditionally biotech products are sterile injectibles, but
there is also progress in inhalation and transdermal delivery options.

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 Pharmaceutical Facility Design

1.5 Filling
Filling is the process of putting the drug product into a container. Two general
categories of filling are:
• Bulk
• Final

Bulk filling is defined as the placement of larger quantities (5L-100L) of

product into containers for shipment/storage.

Final filling is defined as the placement of drug product into its final container/
closure system. The majority of production facilities produce product in bulk.
Many companies ship their bulk to contract filling firms.

Some examples of containers are:

Vials
Ampoules
Syringes

1.6 Bioanalysis
The analysis phase of manufacturing is critical as proof of the drug's safety,
purity, and efficacy. Analytical methods are required for the following:
• Back up regulatory submissions.
• Support pre-clinical and clinical studies.
• Monitor environmental conditions during manufacturing.
• Monitor quality of the manufacturing process.

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 BSc (ord.) in ‘Manufacture of Pharmaceutical Products’

M M

Media Buffer
Prep CIP
Prep

M
3000 L
Seed
Buffer
Mezzanine Hold

M Nutrient feed

CIP CIP

15,000 L
Bioreactor
Bioreactor Viral M
& Purification Nano-
Harvest Capture filtration

Centrifuge 15,000 L UF/DF

Harvest
Break
Tank
Formulation To Fill /
Finish

CIP CIP CIP CIP

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