PME 535

Good Manufacturing Practice

in Pharmaceutical Facilities
Design

Lecture 2. Process Engineering

© 2015 Stevens Institute of Technology 1

Process design considerations

 Basic unit operations

 Process configuration
 Equipment requirements
 Process utility requirements
 Waste treatment
 Process control
 Facility requirements
 Facility layout and process flows
 Cleaning of equipment and piping

© 2015 Stevens Institute of Technology 2

Process Design Tools

 Process description
 Block Flow Diagrams (BFD)
 Process Flow Diagrams (PFDs)
 Material and energy balances
 Piping and Instrumentation Diagrams (P&IDs)
 Process and utility equipment list
 Utility requirements table
 Instrument list
 Valve and specialty items lists
 Equipment specifications and/or Data Sheets
 Instrumentations specs and/or Data Sheets
 Piping specs
© 2015 Stevens Institute of Technology 3
Block Flow Diagram (BFD) – Tablets
Manufacturing

Raw Granulation/
Ingredient
Drying/ Blending Compression
Materials Dispensing
Milling

Granulation Coating
Solution Solution Coating
Prep Prep

Packaging

© 2015 Stevens Institute of Technology 4

 Block Flow Diagram – Tablets Manufacturing

Active Ingredient 1 6 Raw Material

Raw Material 2 7 Raw Material

Raw Material 3 Weigh 8 Raw Material

Excipient 4 9 Lubricant

1 2 3 4 5 6 7 8 9 10
Raw Material 5 10 Raw Material

Purified Water/Solvent 11
Mill/Sift

2 3 4

Gran Solution Prep Granulation

Dry

5 6 7 8 9 10

Mill
This BFD represents
the same process as Blend

on the previous slide

but has more details. Blend

11 Purified Water/Solvent

Compress

Coat Coating Solution Prep

© 2015 Stevens Institute of Technology 5

Information on the BFD
 The process shown on the BFD in the previous slide can be
described as follows:
 Material constituents are weighed and dispensed in required quantities
 API and other raw materials are sifted or milled
 The active and raw materials are granulated - blended together and
wetted down with a binding solution to form wet granules.
 The wet granules are milled.
 The wet granules are dried.
 The dried granules are milled to achieve the desired particle size.
 The dried granulation is then blended with the remaining excipients
(“final blending”)
 Final blend is compressed into tablets.
 Compressed tablets are coated (using coating solution prepared in a
separate step).

© 2015 Stevens Institute of Technology 6

Block Flow Diagram and its Uses

 BFD identifies major process operations and their

relationships to each other
 BFD can be useful for:
 Determining the needs for process rooms/areas
 Visualizing relationships between different rooms
 Creating a conceptual building layout or “bubble diagram”
 Identifying major process equipment needed
 BFD is used at very early project stages
 BFD can be considered as a precursor to a PFD – Process
Flow Diagram

© 2015 Stevens Institute of Technology 7

Process Flow Diagrams (PFD’s)

 PFD’s are graphical representations of the manufacturing process

based on manufacturing instructions
 PFD’s are reference tools that support manufacturing and assist
engineers and constructors with developing facilities and equipment
design requirements.
 There are no universal standards for PFD’s. Each company uses its
own methodology and symbology.
 All PFD’s contain at a minimum the following basic information
 Material balance and material streams based on formulation and batch
size
 Graphical representation of the major steps in the manufacturing
process
 Identification of the equipment used in the manufacturing process
 You will need to utilize PFD’s as we move forward in this course.

© 2015 Stevens Institute of Technology 8

Process Flow Diagram

© 2015 Stevens Institute of Technology 9

Info on the Sample PFD

1. Icons depicting pieces of process equipment, with tag number,

name and brief description.
2. Lines indicating flows of raw materials, intermediates and
products to and from each process operation. These lines are
numbered, and streams entering and leaving the page are
labeled for easier identification.
3. Stream table (material balance) indicating amount of each
material in each process stream.
4. This sample PFD also has such elements as Equipment List ,
Production Capacity Summary and Cycle Time info. These are
not common for PFDs – typically separate documents.
5. Often several PFD pages are needed to adequately describe
the entire manufacturing process.
© 2015 Stevens Institute of Technology 10
Material Balances and Material Streams on PFD
 The material balance and waste stream identifies and quantifies the
composition of the materials being processed during each step of
the manufacturing process
 There is a direct correlation between the material mass and the
equipment size and selection during process development
 The material balance also defines the requirements for material
containerization and handling
 How the material streams are defined:
 At the start of the process each material is considered its own material
stream
 When materials are combined the combined mass becomes a new
unique material stream with the composition of the individual
components
 Any time a new material is added to the stream, it is considered a new
unique material stream. (Refer to the material balance and stream table
on the PFD shown on the previous page)
© 2015 Stevens Institute of Technology 11
Process Flow Diagrams

 PFDs may be used to describe only the main manufacturing

steps or (better) include the support operations, such as liquid
as solid waste treatment, exhaust gas treatment, generation
and distribution of purified water and other utilities
 PFD is a document generated early in a project – usually
during “conceptual design” stage, and may be updated to
reflect changes incorporated at later stages
 PFDs may be used for developing preliminary equipment list
and sizing of the major equipment
 PFDs help architects to allocate appropriate spaces for all
process operations and develop logical plant layout
 PFDs are also used as a basis for more detailed process
drawings called P&IDs – Piping and Instrumentation
Diagrams © 2015 Stevens Institute of Technology 12
Piping and Instrumentation Diagrams

P&ID is a pictorial representation of

 Process equipment, including all piping connections
 Piping (including information on sizes, materials, insulation
etc.)
 Instrument details
 Control schemes
 Safety and regulatory requirements
 Basic operational information

One aspect of particular importance for GMP operations is

cleaning of process equipment and piping – special
requirements for that may also be depicted on P&IDs
© 2015 Stevens Institute of Technology 13
Sample P&ID (see full-size attached)

© 2015 Stevens Institute of Technology 14

Sample P&ID - simplified

© 2015 Stevens Institute of Technology 15

A P&ID should include:

 Mechanical equipment with names and numbers

 Instrumentation and their designations
 All valves and their identifications
 Process piping, sizes and identification
 Miscellaneous - vents, drains, special fittings, sampling lines,
reducers, etc.
 Control inputs and outputs, interlocks
 Computer control system input
 Vendor and contractor interfaces
 Identification of components and subsystems delivered by
others

© 2015 Stevens Institute of Technology 16

Info on P&IDs

 P&IDs provide a lot of detailed information about how the

system shall be designed and how it should function.
 P&IDs are used to convey process information to
multiple people including:
 Process and mechanical engineers
 Instrument and control engineers
 Piping designers
 Construction personnel
 Operators
 Validation and QA personnel

© 2015 Stevens Institute of Technology 17

Other Process Design documents

 Equipment list
 Equipment data sheets and/or specs (needed for purchasing
of that equipment)
 Instrument data sheets/specs (including gauges, transmitters,
automatic valves etc.)
 Line List that identifies all piping lines needed, with info on line
size, material, pressure and temperature rating, insulation etc.
 Valve List for manual valves
 Control algorithms
 Equipment and Piping layout drawings
 Electrical drawings

© 2015 Stevens Institute of Technology 18

Equipment List Sample

© 2015 Stevens Institute of Technology 19

Equipment Data Sheet Sample

© 2015 Stevens Institute of Technology 20

Vessel Data Sheet Sample

© 2015 Stevens Institute of Technology 21

Piping Spec Sample

© 2015 Stevens Institute of Technology 22

Guidelines for Process
Equipment and Piping

Sanitary design practices

© 2015 Stevens Institute of Technology 23

US Regulations/ Standards / Codes

 Federal : FDA, USDA, EPA, DEA, OSHA

 Professional: ISPE, ASME, ASHRAE, ASTM, IEEE,

NFPA, etc…

 Others: BOCA, etc…

© 2015 Stevens Institute of Technology 24

ISPE Publications

 Baseline Pharmaceutical Engineering Guides

 Bulk / API Manufacturing
 Oral / Solid Manufacturing
 Sterile Manufacturing
 Water Systems
 Commissioning / Qualification
 Biopharmaceutical Manufacturing Facilities
 Packaging, Labeling, and Warehousing
 Risk-Based Manufacturing of Pharma Products
 Good Automated Manufacturing Practice
Guide (GAMP5)
 Good Practice Guides

© 2015 Stevens Institute of Technology 25

Bioprocessing Equipment - ASME BPE
Standard-2014
 Recognized standard intended for design, materials,
construction, inspection, and testing of vessels, piping, and
related accessories such as pumps, valves, and fittings for
use in the biopharmaceutical industry
 Needs for equipment designs that are both cleanable and
sterilizable
 Need for special emphasis on the quality of weld surfaces
once the required strength is present
 Need for standardized definitions that can be used by
material suppliers, designers, fabricators and users
 Need to integrate existing standards covering vessels,
piping, appurtenances and other equipment necessary for
the biopharm industry without infringing on the scopes of
those standards

© 2015 Stevens Institute of Technology 26

General Guidelines

 All surfaces shall be cleanable

 Eliminate surface imperfections where feasible
 Equipment shall be fully drainable (if not, it may
require disassembly and manual cleaning)
 Avoid areas of low flow where soil can collect
 All product contact surfaces shall be accessible
to cleaning solutions
 Avoid threaded connections exposed to product

© 2015 Stevens Institute of Technology

27
General Guidelines (cont’d)

 Avoid sharp internal corners. Where possible,

make corners with radius 1/8” or more for easy
cleaning
 All equipment parts, including elastomers shall
be capable of withstanding sterilization
conditions (130°C in case of steam sterilization)
for a minimum of 100 hrs.
 All product contact surfaces shall reach the
required temperatures during steam sterilization

© 2015 Stevens Institute of Technology

28
General Guidelines (cont’d)
 Materials of construction shall be corrosion resistant to
process and cleaning solutions and shall not
compromise the product purity
 Most common metallic material used is 316 or 316L
stainless steel; higher grade alloys (i.e. AL6XN) are
occasionally used in special applications
 Plastics and elastomers shall be tested for conformance,
particularly in regards to leaching out plasticizers or
other ingredients (USP Class VI)

© 2015 Stevens Institute of Technology

29
General Guidelines (cont’d)

 Surfaces exposed to process fluids (including

coated and electroplated surfaces) shall be:
 Homogeneous
 Impervious
 Inert
 Nonabsorbent
 Nontoxic
 Insolubleby process or cleaning fluids
 Resistant to corrosion, scratching and distortion

© 2015 Stevens Institute of Technology

30
General Guidelines (cont’d)
 Stainless steel surfaces shall be protected from contamination
during equipment fabrication (i.e. welding and assembly)
 Protect surfaces during shipment, preferably without
preservative fluids
 Is preservatives are used for shipping, they shall be fully
removed before equipment or piping is placed in service

© 2015 Stevens Institute of Technology

31
Vessels
 Free draining
 Vessels subject to steaming or to hot water shall be
designed for full vacuum service.
 Nozzles and openings shall be designed for easy
cleaning
 Number and locations of spray devices shall be selected
to provide full coverage, eliminating shadows from mixer
shaft, dip tubes, baffles etc.
 Avoid using nozzles of 1” or smaller diameter (hard to
clean)
 Manway cover shall be of dished shape (not flat)

© 2015 Stevens Institute of Technology

32
Vessel Design

 The design on lower

right is preferred
because the nozzles are
easier to clean by a
spray ball located on the
vessel’s center line
 The downside of such
design is that it requires
custom made piping
connections to those
sloped nozzles (unless
flexible hoses are used)

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology

33
Nozzle Details

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology
34
Sight Glasses

The detail in the

photo is the most
sanitary. Pad is
welded into the
vessel, sight glass is
attached to it.

Source – ASME BPE Standard Source - www.ljstar.com

© 2015 Stevens Institute of Technology
35
Side Instrument Ports

 In addition to sloping
side ports as shown
here, it is important to
avoid a circular gap
between its ID and
the inserted
instrument. This is
achieved by having
O-ring gasket sealing
that gap as close as
possible to the
vessel’s wall
Source – ASME BPE Standard

© 2015 Stevens Institute of Technology

36
Dip Tubes

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology
37
Side and Bottom Connections

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology
38
Tank Outlet Valve

 This is a weir style

diaphragm valve
designed for the tank
outlet. The valve’s body is
welded into the vessel.

Source - www.engvalves.com
© 2015 Stevens Institute of Technology
39
Equipment Exterior

 Easily cleanable, corrosion resistant

 Be able to withstand the wash-down if used for the area
cleaning
 Burrs and weld marks shall be removed
 Avoid sharp edges on equipment surfaces, skid frames,
control cabinets etc.
 Minimize horizontal surfaces. For example, electrical
cabinets for clean rooms are usually made with slopped
top for easier cleaning
 If painted equipment is used, paint shall be non-flaking,
resistant to cleaning materials, compatible with cGMP
requirements
 Provide at least 6” clearance under equipment for routine
cleaning
© 2015 Stevens Institute of Technology
40
Sanitary Piping - CIP, SIP, WFI, USP

 Material of Construction
 316 L stainless steel tubing, 180 grit internal polish
 Joints
 Butt-weld, tri-clamps used only where necessary
 Welding
 Automatic orbital welding with inert gas protection
 Piping Design
 Slope horizontal lines to low point , no dead legs, no hard piped
cross connections without use of safeguards, use “steam locks”
at locations where sterility has to be maintained
 Passivation of Stainless Steel
 Nitric or Organic acids are used

© 2015 Stevens Institute of Technology 41

Sanitary Tubing

 Mechanically polished
and often electropolished
(EP) for highest quality
finish
 Finish requirements may
vary from 10-20 to 40-50
microinch RA (roughness
average) depending on
the application

Source - www.trenttube.com

© 2015 Stevens Institute of Technology

42
Connections and Fittings
 Minimize number of piping connections; use welded
joints where practical
 Use connections and fittings of hygienic design (see
examples on the following slides)
 O-ring (gasket of circular cross-section) is the preferred
type of sealing element for most sanitary connections
 Standard piping flanges with flat gaskets shall be
avoided whenever possible
 All connections in product contact lines shall be capable
of being cleaned in place and (where needed) steamed
in place. That implies the need to be self-draining

© 2015 Stevens Institute of Technology

43
Hygienic Fittings

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology
44
Design of Sanitary Systems

 Avoid dead legs longer

than 2 pipe diameters
(measured from the ID
wall of the main line).
Note that if a flow is
maintained in the branch
line during cleaning and
sterilization, it is not a
dead leg.
 In this sketch dimension
B shall be less than 2*ID.

© 2015 Stevens Institute of Technology 45

Design of Sanitary Systems (cont’d)
 Do not rely on a single valve to prevent cross contamination
of critical product streams. Methods of separation commonly
used are:
 Transfer panel with U-bend pieces
 Removable spool piece
 Double block and bleed valve arrangement
 Mix-proof valves

© 2015 Stevens Institute of Technology 46

Double Block and Bleed Assembly

 Such valve assembly

(without dashed valve) is
used in critical applications
to reliably isolate any two
systems. When both block
valves are closed, bleed
valve is open
 Adding the fourth (dashed)
valve makes this into a
“steam block” assembly –
area between the two block
valves can be sterilized by
introducing steam through
the upper valve and
removing condensate
through the lower valve

© 2015 Stevens Institute of Technology 47

Elbows

 Long radius elbows are

preferred
 Elbows designed for automatic
orbital welding have straight
extensions beyond tangent line
as shown here

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology
48
Welds and Weld Defects

© 2015 Stevens Institute of Technology 49

Hoses
 Here are a few
examples of hoses
used in biopharm
industry
 Upper photo shows
teflon hose with
stainless outer braid;
lower photo –
reinforced silicon
hoses

© 2015 Stevens Institute of Technology 50

Hoses
 Most common types of process
hoses used in biopharm
industry are Teflon and silicon
hoses
 Very often a hose consists of
an inner layer and one or more
outer layers provided to
increase its mechanical
strength and durability
 Pay attention to sagging of
horizontal hoses. Where
practical, slope the line at 30 to
45° to prevent non-drainable
section due to hose sagging

Source – ASME BPE Standard

© 2015 Stevens Institute of Technology 51

Diaphragm Valves (weir style)

Source - www.engvalves.com
© 2015 Stevens Institute of Technology 52
 Point of Use Valves

Such valves are commonly used in USP Water and WFI distribution systems.
© 2015 Stevens Institute of Technology 53
Specialty Fabrications

 Here are a few

examples of specialty
assemblies with
diaphragm valves
designed to minimize
the dead legs

Source - www.engvalves.com

© 2015 Stevens Institute of Technology 54

 Take-off Valves (Radial Style)

Source - www.asepco.com

NovAseptic Valve (by EMD Millipore)

© 2015 Stevens Institute of Technology 55

Process Module with Piping

© 2015 Stevens Institute of Technology 56