niimbl-biophorum buffer stock blending system: a …

1

CONNECT COLLABORATE

ACCELERATE TM

NIIMBL-BIOPHORUM BUFFER STOCK BLENDING SYSTEM:

A MORE ADVANCED CONCEPT FOR BUFFER

MANUFACTURING

TM

The National Institute for Innovation in Manufacturing Biopharmaceuticals

NIIMBL-BioPhorum Buffer Stock Blending System 2©BioPhorum Operations Group Ltd | December 2019

Contents ............................................................................................................................................................................................................ 2

1.0 Executive summary .......................................................................................................................................................................... 8

2.0 Keydefinitions .................................................................................................................................................................................. 9

3.0 Vision .................................................................................................................................................................................................10

4.0 Current state ....................................................................................................................................................................................11

4.1 Current state of biomanufacturing and buffer manufacture .......................................................................................... 11

4.2 Market trends and drivers ......................................................................................................................................................... 13

4.3 Buffer volume requirements .................................................................................................................................................... 18

4.4 Stainless steel fed-batch scenario ........................................................................................................................................... 19

4.5 Single-useperfusionvsintensifiedfed-batchscenarios .................................................................................................. 20

4.6 Facility requirements ................................................................................................................................................................. 21

4.7 Buffer stock blending system challenges ............................................................................................................................. 21

5.0 NIIMBL-BioPhorum approach .....................................................................................................................................................22

5.1 NIIMBL-BioPhorum buffer stock blending system ........................................................................................................... 22

5.2 NIIMBL-BioPhorum buffer stock blending system team ................................................................................................ 22

5.3 NIIMBL-BioPhorum buffer stock blending system scope ................................................................................................ 24

6.0 Proposed open-source concept and solution ...........................................................................................................................25

6.1 Design and development of a ‘proof of concept’ ................................................................................................................ 27

6.2 Operator role ................................................................................................................................................................................ 27

6.3 Performance considerations .................................................................................................................................................... 27

6.4 NIIMBL-BioPhorumBufferStockBlendingSystembenefits .......................................................................................... 28

6.5 Cost analysis and business case ............................................................................................................................................... 30

6.6 Buffer management concept for the future ......................................................................................................................... 31

7.0 OpportunitiestomaximizethebenefitsoftheNIIMBL-BioPhorumBufferStockBlendingSkid ..............................32

7.1 Standard stock solutions enable outsourcing of stock solutions ................................................................................... 32

7.2 Component standardization and innovation ....................................................................................................................... 33

7.3 Logistics and supply chain ......................................................................................................................................................... 33

8.0 Systemadaptability ........................................................................................................................................................................35

8.1 Stock Concentrate Handling .................................................................................................................................................... 35

8.2 Future drivers for the biopharma industry and its relevance to buffer management ............................................. 35

Contents


9.0 Path to industry adoption .............................................................................................................................................................36

9.1 Reducing barriers to adoption ................................................................................................................................................. 36

9.2 Scalable design .............................................................................................................................................................................. 36

9.3 Existing Product Adoption in legacy facilities and new facilities .................................................................................. 36

9.4 Perceived risks and mitigation strategies ............................................................................................................................. 36

9.5 Designflexibility .......................................................................................................................................................................... 37

10.0 Systemcommissioningandqualification ..................................................................................................................................38

10.1 Factoryacceptancetestingperformancetospecification .............................................................................................. 38

10.2 Extended factory acceptance testing .................................................................................................................................... 38

10.3 Realization testing ...................................................................................................................................................................... 39

10.4 Packagedinstallation,operation,andperformancequalifications .............................................................................. 39

11.0 Future improvements and applications .....................................................................................................................................40

11.1 Extension of the concept ........................................................................................................................................................... 40

11.2 ntegration in other facility concepts ...................................................................................................................................... 41

11.3 Enabling process analytical technologies and other advanced control strategies ................................................... 42

11.4 Large and small-scale – other roadmaps scenarios ............................................................................................................ 42

11.5 Continuous DSP ............................................................................................................................................................................ 42

11.6 Modular and mobile .................................................................................................................................................................... 42

12.0 Linkagestootherroadmapprojects ...........................................................................................................................................43

12.1 In-line/out-line monitoring and real-time release ............................................................................................................ 43

12.2 Continuous DSP ........................................................................................................................................................................... 43

12.3 Standard facility design .............................................................................................................................................................. 44

12.4 Plug-and-play ................................................................................................................................................................................ 44

12.5 Harvestclarification .................................................................................................................................................................... 44

13.0 Conclusion .........................................................................................................................................................................................45

Appendix .........................................................................................................................................................................................................46

References ......................................................................................................................................................................................................47

Acronyms ........................................................................................................................................................................................................48


Listoftables

Table 1: Key terms and definitions relating to buffer preparation .................................................................................................................................................................................................................. 9

Table 2: Market trends .................................................................................................................................................................................................................................................................................................... 13

Table 3: Calculated buffer volume needs for an estimated worst-case run ............................................................................................................................................................................................. 16

Table 4: Total summed buffer needs for various column sizes ....................................................................................................................................................................................................................... 17

Table 5: Scale and impact comparisons of methodologies ............................................................................................................................................................................................................................... 30

Listoffigures

Figure 1: Downstream buffer demand vs drug product .................................................................................................................................................................................................................................... 14

Figure 2: Drug throughput vs buffer demand for a given column capacity ............................................................................................................................................................................................... 19

Figure 3: Collaborative effort from 20 biomanufacturers, supply partners, engineering partners and funding bodies ........................................................................................................ 23

Figure 4: NIIMBL-BioPhorum Buffer Stock Blending System (3D view) ................................................................................................................................................................................................... 26

Figure 5: NIIMBL-BioPhorum Buffer Stock Blending System (Plan view) ................................................................................................................................................................................................. 26

Figure 6: General buffer stock blending system configuration ...................................................................................................................................................................................................................... 34


With thanks to Natraj Ramasubramanyan

The following participants are acknowledged for their efforts and contributions in the production and review of this paper.

Avantor Carl Schrott Pranav Vengsarkar

Biogen Phil de Vilmorin

CRB Steve Attig

Exyte Carl Carlson

GlaxoSmithKlinePlc. Hiren Ardeshna

Lonza Carrie Mason

Merck Russell Jones Andrew Carass Scott Wilson

Merck&CoInc.Kenilworth,NJ Jeff Johnson Bill McKechnie Kyle Minor

PallLifeSciences Ignatius Gyepi-Garbrah

PM Group Kevin Gibson

RockwellAutomation Ryan Campbell Doan Chau

Thermofisher/Patheon Brad Johnson Becky Moore Shana Usery

Sanofi Nathalie Frau

BioPhorum Danièle Wiseman


About BioPhorumThe BioPhorum Operations Group’s (BioPhorum’s) mission is to create environments where the global biopharmaceutical industry cancollaborateandaccelerateitsrateofprogress,forthebenefitofall. Since its inception in 2004, BioPhorum has become the open and trusted environment where senior leaders of the biopharmaceutical industry come together to openly share and discuss the emerging trends and challenges facing their industry.

Growing from an end-user group in 2008, BioPhorum now comprises 53 manufacturers

and suppliers deploying their top 2,800 leaders and subject matter experts to work in seven

focused Phorums, articulating the industry’s technology roadmap, defining the supply partner

practices of the future, and developing and adopting best practices in drug substance, fill finish,

process development, manufacturing IT, and Cell and Gene Therapy. In each of these Phorums,

BioPhorum facilitators bring leaders together to create future visions, mobilize teams of experts

on the opportunities, create partnerships that enable change and provide the quickest route to

implementation, so that the industry shares, learns and builds the best solutions together.

BioPhorum Technology RoadmappingBioPhorum Technology Roadmapping establishes a dynamic and evolving collaborative technology management process to accelerate innovationbyengagingandaligningindustrystakeholderstodefinefutureneeds,difficultchallengesandpotentialsolutions.ThePhoruminvolves biomanufacturers, supply partners, academia, regional innovation hubs and agencies, serving to communicate the roadmap broadly while monitoring industry progress.

For more information on the Technology Roadmapping mission and membership,

go to https://biophorum.com/phorum/technology-roadmapping/


Abstract

Buffer solutions are critical inputs to the manufacturing processes of therapeutic proteins and other biomolecules. Increasing titers, the addition of capacity to existing facilities and the intensification of bioprocesses have increased volumetric demand for buffers and created operational bottlenecks. While many facilities have improved their capability through the implementation of in-line dilution, demand for buffers continues to grow and buffer supply remains labor-intensive and logistically challenging. In this paper, we describe the NIIMBL-BioPhorum Buffer Stock Blending (BSB) System—a more advanced concept for buffer manufacturing, where buffer solutions are prepared on demand at ‘point-of-use’ directly from single-component stock solutions of buffer components and water for injection (WFI). Buffer stock blending operates as a closed system to enable buffer preparation outside of cleanrooms. This approach will significantly reduce the capital and operating costs of biopharmaceutical facilities in the future.

A cross-functional team, assembled as part of the BioPhorum Technology Roadmapping initiative, has designed and built a full-scale cGMP prototype buffer stock blending system in collaboration with the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL)1 The team adopted an open-source model to promote widespread access, and generous funding from NIIMBL enabled demonstration of this concept. This white paper presents a detailed introduction to the technology design and a compelling business case which will promote awareness and support adoption across the global bioprocessing community.


1.0

Executive summaryThebufferdemandsofbiomanufacturingrepresentasignificanthurdleinsupplyingmedicinestopatientsinanefficientandcosteffectiveway.Supplying buffer for the biomanufacturing industry in a safe, reliable and timely manner is now seen as a key requirement, driven by the changing needs of the industry.

Following the publication of the BioPhorum Biomanufacturing Technology Roadmap, First Edition2,

the Technology Roadmapping Phorum identified buffers and solutions manufactured and used

in biomanufacturing as an important constituent impacting operational schedule, efficiency and

capacity. A diverse team (comprising experts from the biopharma industry, engineering and

design firms, equipment vendors, suppliers, automation and controls providers) has diligently

evaluated many different aspects of buffer solution manufacturing to provide great insights into

key needs and potential solutions.

While many solutions exist today addressing these needs, the team identified an approach that

can deliver an on-demand supply of buffer solutions directly to the biomanufacturing process.

With support from NIIMBL, a prototype, full-scale GMP system is currently being built as a

collaborative effort. The underlying technology and design will be ‘open source’ to drive easier

access and faster adoption.

This white paper describes the intent and opportunities arising from this collaborative effort

and also identifies opportunities to improve the buffer solution manufacturing process

through extensions of the design of the skid. Applications of the technology in other areas of

manufacturing, as well as interfaces with other manufacturing concepts such as continuous

processing3, modular and mobile and process analytical technologies (PAT), are being explored

by industry experts.

This innovative approach to the collaborative development of a solution, and the

democratization of the technology through immediate access to the design, will demonstrate

the value of a simple, yet effective, solution that will significantly reduce costs, increase

flexibility and speed, while ensuring quality whilst the Addendum to this paper due H1 2020 will

provide a full evaluation of the outcome of this proof of concept.


2.0

Key definitions

Term Definition

Traditional buffer preparation Preparation of multi-component buffer solutions at the final required concentration ready for delivery

to the process.

In-line buffer dilution Preparation of multi-component buffer solutions at a higher concentration than that required by the

process, which must be subsequently diluted before use.

Buffer stock blending Preparation of buffers in-line from concentrated single-component stock solutions at the final required

concentration ready for delivery to the process equipment.

Table 1: Key terms and definitions relating to buffer preparation


3.0

Vision Ourindustryisonamissiontobefaster,cheaperandmoreflexiblewithoutcompromisingproductqualityandpatient safety. This collaboration of BioPhorum members envision a biopharmaceutical industry that can rapidly respondtoclinicalpipelineevolutions,processchangesandforecastuncertaintieswithflexibilityandagility,opening new and sustainable opportunities for improved health globally.

Our vision is to enable buffer manufacturing at all scales to achieve the smallest footprint, minimal manual intervention and

simplified equipment, while providing complete flexibility, ease of use and close integration with all unit operations that

require solution preparation. We eventually envision that buffer-preparation systems will expand to fluid-management

systems for the entire plant with the unit processes receiving solutions at point-of-use, and just-in-time (JIT).


4.0

Current stateAs outlined in the BioPhorum Biomanufacturing Technology Roadmap, the cost and complexity of developing and manufacturing biopharmaceuticals remain high. While a tremendous amount of progress has been made in improving the productivity and robustness of biopharmaceutical processes, further improvements are required to address the challenges that the industry will face in the coming years.

The molecule pipeline is showing significant global

growth. It includes new product classes, some of which

are complex, requiring different purification strategies

and scales of manufacture. Coupled with this growth is the

uncertainty related to regulatory changes and acceptance,

as well as continued cost pressures that biomanufacturers

face, due to increased competition and globalization into

emerging markets.

4.1 Current state of biomanufacturing and buffer manufactureBiopharmaceuticals consist of a mix of antibody-based

therapeutics, vaccines and other recombinant proteins

as well as emerging modalities, such as gene therapy.

The current state is described here:

4.1.1 Diversity in products and productivity

There is significant diversity in the portfolio of

biotherapeutics being pursued by biomanufacturers,

varying by indication and modality. This diversity results in

productivity demands on processes that vary significantly.

While platform processes have been developed for

antibody-based products, variability in productivity has

a significant impact on the scale and size of the processes

used to manufacture the same amount of product. Also,

with modalities such as antibody drug conjugates, the

amount of product required is significantly lower, resulting

in a smaller scale of production. Therefore in a single

facility, regardless of whether clinical or commercial, there

is a need to accommodate production processes that have

significantly different productivities. This variability has

the most impact on buffer and solution requirements.

4.1.2 Facility expansion and process improvement

As the size of the market for existing products has

increased, manufacturing processes have been

improved or facilities have been expanded. In the case

of improvements to manufacturing processes, often the

impact on the existing facilities can be accommodated

with increases in the size of columns or skids. However,

these improvements result in increased buffer

requirements that have become hard to accommodate. In

many cases, where it is not possible to improve processes

due to regulatory constraints, bioreactors have been

added to increase the throughput of the facility, with

the aim of utilizing existing downstream operations to

process the additional bioreactor output. This approach

has led to an increased requirement for buffers and

solutions that are beyond the capacity of the existing,

manual buffer preparation operations.

4.1.3 Manual operations in buffer manufacture

Manufacturing organizations have also been scrutinizing

the efficiencies of their operations, partly to address

the needs described above and partly to reduce costs

and complexity. In many facilities, the upstream and

downstream processes run on automated systems with

methods and recipes programmed to execute the entire

process step. However, buffer preparation processes

are largely manual. The process includes weighing and

dispensing individual powders, the manual transfer of

solids into tanks, operator-driven filling and mixing of

tanks, pH and conductivity checks with manual sampling

and, in some cases, stepwise titration of the solutions

to achieve a target pH and/or conductivity. Also, the

prepared buffer needs to be filtered into another hold

tank that, in many cases, has to be manually moved to the

location of use, especially in small and mid-scale facilities.


4.1.4 Complexity in buffer design

Downstream processes have historically been

developed to achieve the best performance at the

step level. Therefore, each step is optimized with

the best possible buffer system, buffer additives

and volumes, determined by the scientist who is

developing the process. This results in a multitude of

buffer systems used in a single process. Given that

each chromatography step requires 3–7 solutions, the

number of solutions and the associated raw material

components increase very quickly. The advent of

antibody therapeutics has led to the development of

platform processes. While this has made the solutions

and raw materials across different products similar, in

many cases, the complexity of the process solutions and

the number of raw materials remains.

4.1.5 Unit operation-based facility and process design

Currently, manufacturing processes and facilities

are designed to be on an unit operation basis. For

example, a capture step is operated with a dedicated

chromatography skid and all the associated equipment

in a specific manufacturing area. While this enables

efficiency in terms of the product moving through the

processing areas, this approach requires that all the

solutions needed for the specific step be connected

to the specific step. Therefore, it is not uncommon

to see 6–10 tanks and/or bags around a capture

chromatography system, containing solutions used for

testing, processing and cleaning of the chromatography

column, as well as solutions for cleaning the

chromatography skid. Given the unit-operations

approach, similar sets of tanks and solutions will be

present around the next chromatography operation.

It is possible to observe in a mid-size manufacturing

facility, 5–8 batches of 0.5 N sodium hydroxide stored

in tanks of various sizes, prepared individually and

placed in different parts of the processing area. While

it is easy to see the redundancy in solutions and tanks,

unit operation-based processing also results in the

need for dedicated pumps for each unit operation with

appropriate scaling, increasing the complexity of the

equipment and the associated costs.

4.1.6Intensifiedandintegratedprocesses

Process intensification and integration are a natural

progression in making facilities and processes

more efficient and productive. Several technology

developments have been instrumental in increasing

the productivity of facilities, on a step, batch, campaign

and yearly production basis. Such developments

include N-1 perfusion, perfusion bioreactors and other

reactor modalities that increase reactor productivity

and single-use bioreactors. Furthermore, the use of

multi-column chromatography, high-capacity resins, and

flow-through chromatography steps utilizing membrane

chromatography have also contributed.

In addition, due to advances in cell line development and

selection technologies, the titers of bioreactors have

increased significantly over recent years. As a result of

these advances, the facility footprints for process areas

have shrunk, the cycle times have been reduced and the

process scale has been decreased. However, all these

advances have resulted in an ever-increasing amount of

buffer and solution required in a facility. It is interesting

to observe that the buffer and solution preparation and

hold areas are significantly larger than the processing

areas themselves.


4.2 Market trends and driversThe biotherapeutics industry is going through significant changes in the delivery of new medicines at production scale and

it is anticipated that several aspects of biomanufacturing, both from a process and technology viewpoint, will need to go

through a transformation to enable this change. As shown in Table 2, the drivers for the future include speed, flexibility and

cost, while maintaining or improving quality.

The market trends outlined in Table 2 are helping to drive the paradigm shift away from traditional bioprocessing, as they

require a significant change in the process technology solutions that will be essential if the industry is to successfully adapt

to the market changes and the opportunities they represent.

Market trend Impact Drivers for change

Global market growth • Regionalized manufacturing and supply

• Cost pressures increasing

• Drive to increase efficiencies

• Increased competition

• A need to increase the speed of new builds

• Improve process flexibility - quicker change-over

• Reduce CAPEX and OPEX

• Maintain high-quality standards

Pipeline development and new

product classes

• Multi-use facilities required

• Flexible processes, with faster product change-over

• Multi-scale manufacturing is a requirement

• Top 100 biomanufacturers all have biosimilar programs

Maturity of single-use • Routine manufacturing-scale decreasing (1,000-5,000L)

• Modular manufacturing becoming an option

• Flexible infrastructure required

• Leads to de-coupling of equipment from facility

• Allows a move toward continuous manufacturing

Table 2: Market trends


There are several key technology developments that have

come together to help the biopharmaceutical industry

realize many of the growth opportunities in the market.

Improvements in the engineering of expression systems,

media development and feed management, and higher

cell densities have resulted in the development of higher

titer processes by increasing the productivity per liter

of bioreactor capacity. In parallel, intensified and high-

yield processes have driven down the scale, facilitating

the uptake, and acceptance, of single-use technologies,

for both upstream (USP) and downstream processing

(DSP)4. Consequently, this has led to the development

and construction of new, cost-effective and flexible

manufacturing facilities, where single-use disposables are

being considered in a number of process steps.

Whereas a typical process would be a traditional-batch

execution, in the near term this will change to intensified

processing, then connected processing, and, in the

longer term, a fully continuous process. While these

improvements will positively impact the industry, they

bring a new set of challenges for buffer preparation.

Buffers are traditionally the largest volume components in

DSP and can quickly become a bottleneck for production

due to volume and complexity, especially as upstream

titers continue to increase.

Different buffer solutions are required for all DSP

steps, including filtration and capture and flow-through

chromatography operations. Aqueous solutions are

also required for cleaning, regeneration and storage of

DSP equipment, such as chromatography matrices and

membrane filtration systems.

The increase of buffer requirements is almost directly

proportional to the mass of protein that needs to

be purified (see Figure 1). Today, buffer production

remains an important part of the facility footprint, labor

requirements and equipment costs, and continues to be a

logistical challenge.

Figure 1: Downstream buffer demand vs drug product

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

0 200 400 1,000 1,200 1,400600 800

Drug product Kg

Annual buffer volume LB

uff

er v

olu

me

L


Typical monoclonal antibody (mAb) facilities utilize

approximately 16–25 buffers in their processes,

which are used throughout the downstream and final

formulation processes. These process buffers can

typically be broken down into 10–15 single-component

stock solutions, which can be made into different

concentrations. The typical single-component stock

solutions will include salts, acids, bases, sugars, complex

organic buffers, detergents and sanitizers. These can be

simplified to essentially six concentrated stock solutions

to be used in our NIIMBL-BioPhorum Buffer Stock

Blending System (See Appendix 15.1 Design specification

for automated buffer stock blending). These solutions

of phosphate salts, acetic acid, sodium hydroxide, Tris,

ammonium sulfate and sodium chloride will be relatively

consistent across most manufacturers of mAb-based

products. While this is an ideal simplified scenario,

previous case studies11 have shown that buffer use in a

manufacturing facility, with 26 buffer components used

in chromatography/ultrafiltration in the manufacturing

of IgG, can be simplified to 11 stock concentrates for

in-line blending.

Table 3 indicates the typical buffer volumes needed for

the various sized columns that are routinely employed.

From this table, we can see that as resin capacity doubles

from 20–40grams product per liter of resin, twice as

much protein can be purified with equal volumes of

buffer. This table represents one unit operation for either

a capture step, wash, flow-through (10 column volumes

each) or a cleaning, sanitizing or elution step (five

column volumes). More or less buffer may be required

based on individual proteins and process development.

In this example, buffer needs will linearly increase or

decrease as flush, load and elute volumes vary but they

are always related to the total volume of resin needed

for a protein load. In a typical operation, two capture

steps and one flow-through is the standard defined in

BioPhorum Technology Roadmap First Edition, but up to

three capture and two flow-through unit operations may

be required. With a worst-case of a 20g/L resin capacity,

the total volume of buffer for the following case can be

approximated by adding up the 10 column volume steps

and five column volume steps (which could be as low as

three column volume steps for cleaning and sanitization)

for a given unit operation. By adding the unit operations

together, one can approximate the buffer volume

required for a given column compliment (and protein

load) for production operations.


Table 3: Calculated buffer volume needs for an estimated worst-case run

Table 3 also indicates the protein quantity purified for one run at a given column size assuming six cycles of the column.

Note that adjustments to protein-load quantities in successive unit operations have not been accounted for, so volumes are

slightly overestimated.

Column

diameter

(cm)

Bed

depth

(cm)

Column

volume

(L)

Column

cycles

Total

resin

volume

(L)

Resin

capacity

(g/L)

Protein

load

(kg)

Number of

column volumes

Column

unit

operation

buffer

volume (L)

Capture

column

(3 units)

buffer

(L)

Flow-

through

column

(2 units)

buffer (L)

Total buffer

volume / run (L)

45 20 31.8 6 190.9 20 3.8 10.0 1,909 17,177 7,634 24,811

60 20 56.5 6 339.3 20 6.8 10.0 3,393 30,536 13,572 44,108

80 20 100.5 6 603.2 20 12.1 10.0 6,032 54,287 24,127 78,414

140 20 307.9 6 1,847.3 20 36.9 10.0 18,473 166,253 73,890 240,143

160 20 402.1 6 2,412.7 20 48.3 10.0 24,127 217,147 96,510 313,656

200 20 628.3 6 3,769.9 20 75.4 10.0 37,699 339,292 150,796 490,088

Column

diameter

(cm)

Bed

depth

(cm)

Column

volume

(L)

Column

cycles

Total

resin

volume

(L)

Resin

capacity

(g/L)

Protein

load

(kg)

Number of

column volumes

Column

unit

operation

buffer

volume (L)

Capture

column

(3 units)

buffer

(L)

Flow-

through

column

(2 units)

buffer (L)

Total buffer

volume / run (L)

45 20 31.8 6 190.9 20 3.8 5.0 954 6,680 4,771 11,451

60 20 56.5 6 339.3 20 6.8 5.0 1,696 11,875 8,482 20,358

80 20 100.5 6 603.2 20 12.1 5.0 3,016 21,111 15,080 36,191

140 20 307.9 6 1,847.3 20 36.9 5.0 9,236 64,654 46,181 110,835

160 20 402.1 6 2,412.7 20 48.3 5.0 12,064 84,446 60,319 144,764

200 20 628.3 6 3,769.9 20 75.4 5.0 18,850 131,947 94,248 226,194

Diafiltration

for column

scale

Protein

load

(kg)

50g/L

concentration.

10 diavolumes (L)

Total

diavolumes

buffer / Run (L)

45 3.8 763 763

60 6.8 1,357 1,357

80 12.1 2,413 2,413

140 36.9 7,389 7,389

160 48.3 9,651 9,651

200 75.4 15,080 15,080

"Worst-case" 3 Capture column units (Equil 10 CV, Load, Wash 10CV, Elute 10CV, Clean/Strip 5CV, Sanitization 5CV, Storage 5CV 1 time)

"Worst-case" 2 Flow-through column units (Equil 10 CV, Load, Wash 10CV, Clean/Strip 5CV, Sanitization 5CV, Storage 5CV 1 time)

CV = Column Volume


Table 4: Total summed buffer needs for various column sizes

Table 3 and Table 4 above show the relationship between drug quantity and corresponding buffer volumes downstream.

Yellow highlight indicates the parameters for a typical unit operation necessary for calculating the required buffer. Green

highlight indicates calculated volumes for the given number of Worst-case operations. Blue highlight indicates the final total

of buffer needed for a given column diameter operational scale.

There are significant opportunities for buffer volume reductions through improved resin capacities (several resin supply

companies have indicated greater than 20 g/L dynamic resin capacities for protein A resin for instance). Also, modest buffer

savings can be accomplished with column overloading scenarios in continuous column chromatography.

Diafiltration buffer needs will correspond to starting and final product concentration volumes and the required diafiltration-

fold. Typical diafiltration processes include a 10x diafiltration at a final product concentration of 50g/L concentrates. Buffer

volume savings can also be achieved with higher final product concentrations at the diafiltration step.

With column-performance improvements, we will see a significant reduction in the operational footprint of a facility and

further technology developments will have to be adapted to a range of facility types, including stainless steel, hybrid,

fully single-use retrofit facilities and new-builds. Also, modular facilities may offer standardization that will facilitate

the optimization of the buffer supply system. The need for holding buffers at use-strength remains the largest footprint

requirement in current production scenarios.

10 CV Buffer Use 5 CV Buffer Use Diafiltration10x

Column

diameter

(cm)

Protein

load

(kg)

Capture column

(3 units) buffer

(L)

Flow-through

column (2 units)

buffer (L)

Total buffer

volume /

run (L)

Capture

column (3

units) buffer (L)

Flow-through

column (2 units)

buffer (L)

Total buffer

volume /

run (L)

Total diavolumes

buffer / run (L)

Buffer

total all

steps (L)

45 3.8 17,177 7,634 24,811 6,680 4,771 11,451 763 37,025

60 6.8 30,536 13,572 44,108 11,875 8,482 20,358 1,357 65,823

80 12.1 54,287 24,127 78,414 21,111 15,080 36,191 2,413 117,018

140 36.9 166,253 73,890 240,143 64,654 46,181 110,835 7,389 358,367

160 48.3 217,147 96,510 313,656 84,446 60,319 144,764 9,651 468,072

200 75.4 339,292 150,796 490,088 131,947 94,248 226,194 15,080 731,362


4.2.1 Managing the buffer demand

Typical operations generate buffers via solids handling,

buffer preparation and hold. While this adds flexibility

in the formulation of the buffers, there is a significant

footprint, scheduling and labor requirement. In a perfusion

operation, the buffers are made and held in a very

intensive scheduling operation. Materials must be staged

and utilized with very little window for failed batches. In

stainless steel facilities, this is compounded by cleaning

and sanitization needs. Hold tanks will have a service life

related to the sanitization and validated hold empty times

so that delays may exceed the validated hold clean limits.

The main operational challenges regarding buffers in DSP

are the preparation and storage of the buffers. These

obstacles create bottlenecks that lengthen processing

times, particularly with high protein titers.

To understand the potential impact of these changes, it is

worth considering how the installed bioreactor capacity

will likely change over the coming years, and what that

means for critical raw materials, such as cell culture media

and downstream buffers.

The projected increase in the installed global bioreactor

capacities will lead to a higher throughput of drug product

and, clearly, an increased demand for cell culture media.

This will challenge the WFI production needs to keep

up with demand. Given that downstream processes are

product mass-driven, an increase in product throughput

upstream will lead to a proportional increase in demand

for DSP buffers and WFI use. Regardless of production

methodology—be it stainless steel, hybrid or single-use—

buffer production will remain a significant portion of the

facility footprint and labor needs and equipment costs. It

will also continue to be a logistical challenge, particularly

if the rate of improvement in production bioreactor titers

surpasses the ability to support the increased production

titer. Considering that current buffer supply is from bulk

powders, ready-to-use as 1x or in concentrate format,

the risk of wasted material, added footprint, resources

and time when preparing buffers from powders should be

considered. In an industry that is driving towards smaller,

more flexible operating footprints, buffer supply can

become a significant constraint to production scheduling.

4.3 Buffer volume requirementsIn terms of raw material format, powder has traditionally

been preferred for larger-scale operations, where the

relative ease and economy of shipping make it the

preferred choice of bulk product. However, hydrating

buffers from bulk powder can lead to some process

contamination risks, as well as employee risks due to

repetitive weighing and potential exposure to hazardous

chemicals. Utilization of ready-to-use sterile liquid buffers,

especially smaller-volume liquid buffer concentrates, could

benefit operator safety when considering the handling

of multiple powders from an exposure and ergonomics

perspective. With the move towards smaller, single-use or

hybrid operating footprints, many of which might be new

builds, it might be reasonable to expect that bulk sterile

liquid, delivered ready-to-use, will be the preferred raw

material format. Even so, the volumes required will remain

high, as outlined in the scenarios identified in Table 3.

As titers increase, many existing facilities find a bottleneck

in buffer preparation. As shown in Table 3, a doubling

in bioreactor titer will double the protein delivered to

downstream. This can only be handled by doubling the

column resin capacity or by doubling the volume of buffer

utilized. In large facilities, doubling the buffer volume can

be problematic as the footprint allocated for buffer hold

is typically already optimized. A 2x concentrate could be

supplied to existing hold tanks if the chromatography skid

can handle the dilution to use-strength. A top-off delivery

to the existing hold tank may be an attractive alternative,

particularly if the buffer can be made faster to relieve the

production schedule. Figure 2 indicates the increase in

buffer demands relative to some typical production scales

and a range of production titers


Figure 2: Drug throughput vs buffer demand for a given column capacity

0

20000

40000

60000

80000

100000

120000

140000

1 5 10 1 5 10 1 5 100

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

Dry

g q

uan

tity

(g)

Titer (g/L)

Bu

ffer volu

me (L)

Drug throughput vs Buffer demand

Drug qty per run (g)

Buffer/run (1.5 x g)

12k Bioreactor 5k Bioreactor 2k Bioreactor

Drug qty from 12k Bioreactor@ 1g/L will be matched withmuch smaller scale Bioreactors

4.4 Stainless steel fed-batch scenarioA worst-case 12kL process at 2g/L titer (24kg) requires

about 230kL of buffers and solutions, assuming a column

resin capacity of 20g/L (117kL assuming an average

resin capacity of 40g/L) and buffer column volumes for

each step as indicated in Table 3 and Table 4. As the titer

increases, for example by five-fold, this could translate to

approximately five-fold higher buffer/solution needs per

run in the facility, therefore a worst-case 12kL process

at 10g/L titer requires about 1,150kL of buffers and

solutions, assuming the same average column capacity

and buffer column volumes for each step as indicated in

Table 3 and Table 4.

This level of increase in upstream productivity results in:

• An increased amount of WFI that needs to be

produced and stored

• A proportional increase in buffer preparation

tanks and footprint

• A proportional increase in buffer hold tanks

and footprint

• A proportional increase in waste treatment

or disposal.

While building a larger WFI-production system and

increasing the footprint of the buffer operations is not

necessarily an unfeasible solution, it has a direct impact

on capital and operating costs. For an existing facility

with higher level of upstream productivity, buffer

production, hold and column unit operations become

significant bottlenecks in addition to WFI demand.

Increased protein loads will require increased space,

capital, and operating costs often limiting downstream

throughput and facility productivity.


4.5 Single-use perfusion vs intensifiedfed-batchscenariosPerfusion operations have an added complication in buffer

management, given that the product is produced over a

longer period, is more dilute, less stable and may require

longer hold times due to column loading (because of lower

capacity columns). This results in multiple column cycles

to handle the longer bioreactor schedules (<90 days) and

can be a strain on traditional buffer production in single-

use facilities. A JIT buffer delivery will be more sensitive

to the continuous processing of a perfusion bioreactor

and will require careful scheduling of buffer supply with a

matching production schedule. Intensified fed-batch uses

higher seeding cell densities through use of a perfusion

mode seed bioreactor to reach peak cell densities quicker

than traditional fed-batch. Intensified fed-batch then uses

the fed-batch mode during regular bioreactor production,

resulting in high titers that will require larger columns and

capacity to accommodate the increased productivity. Both

perfusion and intensified fed-batch approaches increase

the buffer consumption during operations, thus a buffer

stock blending approach would facilitate a more efficient

buffer management solution. Applications of the Buffer

Stock Blending System to accomplish these two scenarios

will be discussed below.

The single-use approach to commercial manufacturing

provides significant advantages, e.g. a CAPEX reduction.

However, it poses challenges from a downstream

perspective, with a direct impact on buffer manufacture,

as follows:

1. The scale, size and limitation of single-use

equipment, especially upstream, results in

multiple batches to be processed, for the same

amount of material to be produced

2. The increased frequency of harvest results in an

increased frequency of the downstream batches

(given the limited hold-time typically allowable

for the harvested material), with a direct impact

on the rate of buffer production

3. While the average buffer requirement is

comparable to an equivalent fed-batch facility,

the need for all of the buffers all of the time poses

additional constraints in terms of being able to

stage the buffer production. For example, in a

fed-batch facility, one may be able to produce

the capture buffers first and then produce the

downstream buffers in a sequential manner

4. Current perfusion titers have been increasing

as technology develops. Significant bottlenecks

could develop as titers increase within the

perfusion platform.

BSB system could help address these issues, by very

rapidly making required buffers in the short production

windows available. The rapid buffer production from a

BSB system, coupled with a buffer top-off strategy, can

address the challenges of perfusion, intensified, and

continuous processes.


4.6 Facility requirements Facility buffer management varies greatly from small- to

large-scale preparations. Once the quantity of buffer salts

raw material passes a handling threshold, the movement of

raw materials and kitting requirements significantly impact

the operational space and personnel required. Also, the

use of fixed hold tanks for buffers becomes problematic

as one passes from 2,000L bioreactor to 5000L and

above. Many single-use facilities at 2,000L scale will meet

portable buffer hold limits as the titer approaches 5–10g/L

titer (depending on column capacities).

Once the manufacturing operation becomes continuous,

the requirements of the facility approach a need for

automation. Continuous operations will not tolerate

hold periods for buffer preparation and the redundancy

required could be prohibitive. The need for decoupling the

buffer preparation and hold from the continuous operation

could become necessary.

Final formulation buffers will most likely be relatively

small volumes and the need for the buffer is separated

by the processing window (5–10 days). The facility will

typically make this buffer in a higher-classified area if

not in the final formulation area. As facilities move to

functionally closed systems and ballroom design, the

manufacture of the formulation buffer would, ideally, be

made in a functionally closed preparation system with on-

line release capabilities.

4.7 Buffer stock blending system challenges Many challenges exist in the development of a buffer

preparation system. It will remove many of the operator

dependencies and solid material handling. It will reduce

labor and buffer costs and reduces the complexity

of buffer salt kitting and staging. However, this adds

storage area footprint and can add to material handling

requirements and safety issues.

In general, implementation of the buffer stock blending

system requires consideration of the following items:

1. Stock solution change-out

2. Stock solution management/storage footprint

3. Versatility of WFI water supply to the system

4. Production upset recovery

5. Instrumentation accuracy and performance

6. Closed system requirements

7. Determination of sterility requirements

8. Maintaining the checks and balances of

the manual preparation operation to the

automated process

9. Continuous DSP buffer supply.

The current state described in Section 4 and many

challenges therein led to the collaboration of subject

matter experts within BioPhorum to develop a User

Requirements Specification for a buffer stock blending

skid. In coming up with this design they quickly identified

the importance of being able to demonstrate the validity

and benefits of their solution and sought out funding to

build and test a prototype.


5.0

NIIMBL-BioPhorum approach

5.1 NIIMBL-BioPhorum buffer stock blending systemThe NIIMBL-BioPhorum team will deliver a system to

support the technology, innovation and expectations of the

buffer preparation needs of the future and make it available

open-source to the industry to encourage adoption. The

barriers to adoption presented by an investment in a

proprietary system in a competitive market are mitigated

by the availability to a collaboratively designed and

performance tested system. Designing a prototype with

no intellectual property constraints and making the design

available as open source will accelerate the pace of change

in the industry by democratizing the technology. Until the

White Paper Addendum and test data is evaluated and

released, only the initial Design Spec. is in the public domain,

the sharing of all design documents and data will follow a

period of Performance Testing by BioPhorum members in

NIIMBL’s labs at the University of Delaware.

Biomanufacturers need a generic, standardized and

intensified platform process to be competitive. There

are many aspects to this, e.g. we may not have a platform

for all products, but developing a defined and consistent

buffer strategy approach that can be leveraged delivers

significant value. Automated buffer preparation

technologies do exist. In-line buffer dilution and in-line

conditioning systems are commercially available. These

technologies are new however and there is room for

improvement, in the system design, facility integration and

system performance. The system will be able to supply, in

an automated manner, at point-of-use and on demand, all

buffers required for a typical mAb purification process, at

a quality that is acceptable and equivalent to traditional

batch buffer preparation.

5.2 NIIMBL-BioPhorum buffer stock blending system team The collaboration with NIIMBL is a first for the BioPhorum

Operations Group, seeking funding for an implementation

project which directly responds to the needs identified in the

BioPhorum Technology Roadmap First Edition2. Funding also

came in a much smaller part from the participating members

who have contributed in kind to the project supplying

components and solutions for the build and test phase.

Figure 3 below presents the team, formed from a strong

collaboration across major biopharmaceutical companies,

engineering firms and suppliers. Each have recognized the

benefits, regardless of whether end-user, engineering or

supplier in developing a prototyped buffer preparation

system of open-source design and committed to an extended

period of collaboration towards the design. Some of these

benefits are:

• Gain early insights into raw material/stock requirements

• Enable incorporation of buffer stock blending into

facility/engineering design

• Design sensors, fittings, valves and other components

that enable better implementation of design

• Introduce new products or add functionality to existing

products using elements of the design

• Ensure seamless integration and connectivity of existing

components and equipment to lower barrier for access

• Determine and enable hardware and software controls

to simplify design or to allow flexibility and integration

with existing products

• Ensure design will meet quality and regulatory

expectations so that the resulting design is ready

to implement

• Influence internal stakeholders at companies to adopt

new technology on the basis of “global consensus”

• Obtain project specific or product specific data to

determine fit and return on investment as well as

technical feasibility

• Identify add-on functionality to be developed –

better components, additional PAT, additional

modules (hardware and software), data connectivity

solutions, etc.

• Early access/awareness of all aspects of the design


Figure 3 below shows the size and complexity of the participation in the initiative to realize the design created by the

BioPhorum team. Working with NIIMBL and the selected Vendor, the teams collaborated to deliver all aspects of the project,

Buffer Chemistry, Engineering, Automation and the authoring of this white paper.

Figure 3: Collaborative effort from 20 biomanufacturers, supply partners, engineering partners and funding bodies

© BioPhorum Operations Group Ltd 1 5

NIIMBLInstitute Director

Kelvin Lee

Project Governance

BioPhorum Sponsor

Steve Jones

University of Delaware Procurement Team

Dale Fleetwood

IPEC

Ryan McGlynn, PMKeith Miller, Tech Specialist

Brittany Noe, MechanicalZachary Kolka, Engineer

Project Engineering Team

Jeff Johnson, Merck MSDDoan Chau, RockwellKevin Gibson, PM GroupPam Docherty, SiemensRyan Campbell, RockwellSteve Attig, CRB

Vendor

BioPhorum/NIIMBL Meetings

NIIMBL (UD)Scientific Project Manager

Melissa Scott

Automation Team

Doan Chau, RockwellPam Docherty, SiemensRyan Campbell, Rockwell

Buffer Chemistry Team

Phil de Vilmorin, BiogenShana Usery, Thermo/PatheonBrad Johnson, Thermo/PatheonNathalie Frau, SanofiScott Wilson, Merck KGAa (LS)Natraj Ram, AlkermesPranav Vengsarkar, AvantorCarrie Mason, Lonza

BSB Skid Modelling(Biosolve/Schedule Pro)

Kevin Gibson, PM GroupCarl Carlson, ExyteNatraj Ram, AlkermesJeff Johnson, Merck MSDSteve Attig, CRBNathalie Frau, SanofiEmily Thompson, CRB

BioPhorumDanièle Wiseman

Facilitator

Buffer Prep White PaperCarl Carlson, ExyteAndrew Carass, Merck KGAa (LS)Carl Schrott, AvantorCarrie Mason, LonzaDoan Chau, Rockwell AutomationJim Grobholz, Merck KGAa (LS)Kevin Gibson, PM GroupNathalie Frau, SanofiNatraj Ram, AlkermesPhil de Vilmorin, BiogenPranav Vengsarkar, AvantorRussell Jones, Merck KGAa (LS)Scott Wilson, Merck KGAa (LS)

BioPhorum Buffer Prep TeamAndrew Carass, Merck KGAa (LSBill McKenchie, Merck MSD)Bojan Isailovic, PallCarl Carlson, ExyteCarl Schrott, AvantorCarrie Mason, LonzaCharles Heffernan, CRBKazuki Otsuka, ChugaiKyle Minor, Merck MSDNathalie Frau, SanofiNatraj Ram, AlkermesMike Seal, PallPhil de Vilmorin, BiogenRussell Jones, Merck KGAa (LS)Scott Wilson, Merck KGAa (LS)Tim Schuster, IPS

Prototyping SME’s

Doan Chau, RockwellBecky Moore, Thermo/PatheonNatraj Ram, AlkermesPam Docherty, SiemensPhil de Vilmorin, BiogenPranav Vengsarkar, AvantorRavi Shankar, E&H/KRyan Campbell, Rockwell

DataPrototype


5.3 NIIMBL-BioPhorum buffer stock blending system scopeThe NIIMBL-BioPhorum Buffer Stock Blending

System has been designed to provide buffer solutions

to the process directly from single-component stock

solutions to prepare various conditioned final process

solutions. Up to 16 buffer stock solutions can be fed

to the skid (four to each metering pump). The process

buffer solutions will be prepared by blending, at most,

four stock solutions through positive displacement

metering pumps. The system will deliver, in a consistent

and automated manner, the final process solutions at

the required specification on a mass flow basis. For

monitoring purposes, the system will be equipped with

pH and conductivity probes. Thus, any produced buffer

that is outside of the specified release criteria will be

diverted to waste. No out-of-specification buffer will

be sent to process stream. The skid will have a capacity

for buffer delivery range of 5–60L/min (equivalent to

60kg/min and a solution density of 1) at an ambient

temperature. Solution recipes is stored and reused.

Data will be collected in a database/SCADA system.

The system is designed to be a GMP-compliant system,

including data integrity, etc.

The skid can be used to feed buffer hold tanks or bags,

or directly connected to process equipment, such as a

chromatography column or a filtration system. The skid

will include cleaning functionality, which will allow the

positioning of the skid in a controlled, non-classified area

(the skid is designed for functionally closed processing).

The flexibility of this prototyped skid will allow its

implementation in a greenfield facility or existing plant

and will address the buffer supply of large-scale stainless

steel production as well as intermediate-scale, single-use

production for biologics DSP.


6.0

Proposed open-source concept and solutionTheprototypebeingdevelopedisafirststepinrealizingthe vision of a buffer stock blending system that will directly utilize raw material of single-component stocksolutionsforblendingintofinalbuffersolutionswith the correct concentrations of salt and buffer components, pH and conductivity. The system will deliver process buffer solutions JIT, on demand and at point-of-use for the process unit operation, or will produce the process buffer solutions in an automated manner for storage in a buffer hold tank for use in a batch process.

Mass flow has been selected as the control basis for our

buffer stock blending. While it is an indirect measurement

of buffer raw material composition, mass-flow control

is considered to be the most accurate and reliable

form of measurement. Given the indirect nature of the

measurement, it is not possible to manipulate the process

using control parameters to overcome variations in the

starting material. This places a heavier burden on the

accuracy of the stock solutions; however, the simplified

single-component nature of these solutions lends itself

towards a standardized and relatively straightforward

preparation. Alternative strategies, such as pH and

conductivity feedback control, offer a direct measurement

of composition and allow the correction of solution flow

to ensure final buffer accuracy. While this correction is

possible, there are drawbacks to pH and conductivity

control as these measurements are less reliable and have a

greater tendency to drift .

The performance testing of the prototype early in 2020

will result in a data set to support the collaborative design

and demonstrate success in meeting the project objectives.

At this point, the design will be made available with the

data set to enable anyone in the industry to adopt and

improve this open-source design.

The key design features of the prototype are listed below

and are detailed in the design specification:

1. Flexible design meeting a wide range of buffer needs.

2. Buffer delivery range of 5–60L/min with the blending of

up to four single-component stock solutions at one time

3. Sixteen stock solutions may be connected at one time.

The system has four stock solution inlets (two high-flow

and two low-flow pumps), with each inlet having four

connection points

4. Corrosion-resistant material of construction facilitates

the connection of highly concentrated single-

component stock solutions

5. System control for buffer preparation is based on

mass-flow control. Mass-flow meters are regarded as

the most accurate and reliable option in-line

6. Instrumentation is provided for the monitoring and

release of produced buffer solutions. Conductivity, pH

and temperature sensors included within the system,

with additional connection points provided for future

analytics (RAMAN, RI, etc.)

7. Independent pH meters are provided for high- and low-

flow salt concentration buffers (to reduce the settling

time associated with the ‘salt memory’ effect)

8. System is designed to facilitate functional closure of

stock solution connections

9. Break tank and WFI flow control are incorporated into

the system for ease of connection to WFI distribution

systems. The system may be connected to either

ambient or hot-WFI distribution system (in the case

of hot WFI distribution, a WFI point-of-use cooler is

outside the scope of the system)

10. Two buffer outlets are provided to facilitate the

connection to multiple destinations at one time.

The flexible system is suitable for connection

to single-use bags, fixed tanks or directly to

chromatography systems


11. It has automated preparation of buffers with minimal

intervention from operating floor. Handshake from

system for GMP operation

12. A fully cleanable system with developed cleaning

cycles for WFI rinse and full CIP

13. Has a programmable logic controller with a standard

interface to distributed-control system

14. Has an IS88 batch philosophy (the scalable phases

in the controller make integration easier)

15. The buffer make-up list is capable of storing 100

recipes. Recipes can include a single buffer or a

series of buffers

16. Communication is through ‘Open Platform

Communications Unified Architecture’ to be used

(all supplier capable assumed).

Figure 4: NIIMBL-BioPhorum Buffer Stock Blending System (3D view)

Future revisions can include more versatile WFI supply (hot, cold and ambient), continuous DSP supply, on-board filtration,

decoupling the 1x cleaning/sanitizing supply, decoupling the distribution to DSP and the addition of more buffer salts.

Figure 5: NIIMBL-BioPhorum Buffer Stock Blending System (Plan view)


6.1 Design and development of a ‘proof of concept’ The prototype for an automated buffer stock blending

system will show that the mass flow approach of buffer

stock blending to a final-use buffer is feasible, and will

document the savings of space, labor, cost and time for

batch productions.

The data and documentation produced will be made

available in H1 2020 following the completion of the

performance testing phase and authoring of a document to

include modelling of economic and facility scenarios.

6.2 Operator roleThe system will minimize operator hands-on operation.

Only recipe assignments, stock solution setup and removal,

compliance requirements, troubleshooting and placing the

system back on-line will require hands on. The system will

document the operation over the buffer preparation time

and will document all cGMP aspects of the production.

It will be capable of on-line release of the buffer produced

over the operational timeframe whether a JIT delivery or a

batch delivery to a hold tank.

6.3 Performance considerations

6.3.1 Error propagation

Our initial testing of the NIIMBL-BioPhorum Buffer

Stock Blending System will study error propagation

and will document the results of operations that may

have pressure, temperature, pH, conductivity and flow

excursions, in order to address the perceived risk of this

new method. The importance of testing the skid will be

to provide evidence that possible excursions from the

operational parameters will not affect the process and

ultimately the buffer production.

6.3.2 Waste mitigation

Having two of the same stocks on-line for buffer stock

change-out could minimize heal loss and reduce waste.

This approach could reduce waste by maximizing the draw

from the first bag before switching to the second bag during

operation as opposed to discarding a bag heal that will be

less than required to produce a buffer.


6.4 NIIMBL-BioPhorum Buffer Stock BlendingSystembenefitsThe expected benefit of utilizing the NIIMBL-BioPhorum

Buffer Stock Blending System would result from

the successful automation of the buffer preparation

operation on an open architecture system. The

collaborative development of the NIIMBL-BioPhorum

Buffer Stock Blending System will produce data and

performance evaluation that will remove obstacles

associated with the implementation of innovation in the

biopharmaceutical industry.

The BioPhorum Buffer Preparation team sought to not

only describe the industry challenges around Buffer

Preparation and offer a solution but to build a prototype

in collaboration with NIIMBL which would enable them to

articulate the value of the Buffer Stock Blending System

beyond the scenario used to inform the prototype design

and describe the benefits across different facilities,

modalities and responding to future industry needs. The

team identified the following benefits in this approach to

developing their System:

• Prototyping to provide data to mitigate risks/

perceived risks and support investment decisions

and progress through wider development.

• Biomanufacturers can refer to White Paper

Addendum (post-test data evaluation) for

Business Case/Value Proposition, modelling data

and alternative use cases to demonstrate the

application of the Buffer Stock Blending System

technology across multiple scenarios.

• Demonstrate the benefit of a collaboration

between end users and supply partners to

develop the buffer stock blending skid.

• Use this expertise to build technology in a way

which addresses the concerns of Tech Ops/makes

end user nervous.

Performance testing by the BioPhorum team at The

University of Delaware in association with NIIMBL will

aim to prove that the system offers a reduced footprint for

buffer preparation operation, reduced operator needs and a

functionally closed system.

The benefits statement which formed part of the funding

application for this project was based on estimates of

the potential value that could be achieved and used as an

example of that potential:

Implementation of buffer stock blending systems

can greatly reduce the capital and operating

costs of biotechnology facilities designed and

built in the future. The technology will enable

SU bags of less than 2000L to be used in place

of large SS tanks (often over 12,000L), at a

savings of perhaps >$20MM per facility built.

Labor requirements will also be greatly reduced,

and buffer preparation can be reduced from a

3 x 7 day operation to a 1 x 5 day operation in

each facility. The technology may also enable

the transition from a predominately SS facility

common today to a predominately SU facility of

the future, with a capital reduction of potentially

more than $100MM.

The value proposition for the widespread adoption of

the Buffer Stock Blending Skid approach was that it can

clearly tackle a bottleneck, creating opportunities for labor

reduction, reduced capital spend and a greener footprint.

As a BioPhorum member put it, it was “Not sustainable not

to do it.”

The benefits the Buffer Stock Blending System offers will be

explored further in the White Paper Addendum but include:

6.4.1 Operational

The key moving parts of the NIIMBL-BioPhorum Buffer

Stock Blending System will be the operator integration

with the WFI system and uninterrupted temperature,

pressure and flow of its supply. Stock solution change-out,

buffer recipe input/sequencing and troubleshooting will be

the only duties left to the operators. Ideally, a purification

process will progress from start to finish with no operator

intervention.


6.4.2 Speed to market

The open architecture and collaborative development

will help to improve the flexibility and performance of the

Buffer Stock Blending System. This approach will allow the

biomanufacturer’s facility development to take advantage

of the design development and could reduce the buffer

preparation area complexity of design and construction.

With a standard design approach biomanufacturers could

also simplify purchasing to a minimal number of buffer stock

blending systems.

6.4.3 Flexibility

The Buffer Stock Blending System design has been

conceived with performance and process flexibility in

mind. JIT delivery of buffers at various flow rates and

amounts allows users to create buffer as necessary, at a

higher speed, and with more flexibility in the production

scheduling process. Small batches can be produced thus

eliminating potential excess time, labor, and material. This

capability matches the needs of the Life Science industry

today, as personalized medicines become more popular

and inherently require less amounts of production material.

In addition, large batches of buffers can still be produced

to meet higher demands for traditional Biopharma

production. The range of buffer preparation scalability will

be significantly increased through the use of the buffer

stock blending system, making the system more adaptable

to varying processes.

The mechanical architecture and control system are open

source allowing for customizations for facility-specific user

requirements. Each manufacturing process and facility

is different, therefore consideration for such flexibility

and varying end-user requirements will be taken into

account throughout the design and build of the buffer

stock blending system. End-users will be able to tailor

the design of the skid to fit their individual needs in their

process and production facility. For example, future buffer

stock blending systems could be customized with more

buffer outlets to deliver buffer to several destinations,

such as single-use bag stations, holding tanks, or directly

to chromatography skids. Additionally, future systems

could also be customized to reduce the number of stock

solutions connections, thus reducing the footprint, cost, and

complexity. For any potential customizations, the system

and its application code will easily be able to be redesigned

and modified to accommodate.

6.4.4 Mobility

The skid design will be mobile for placement within a

facility. While the skid will be mobile some areas may

inaccessible after placement. Early facility planning

could optimize how the Buffer Stock Blending System is

integrated within a facility and the flexibility opportunities

that could arise.

The current assumption is that stock solutions may be

located in a ‘controlled not classified’ space while the Buffer

Stock Blending System will perform in a Class C or D space.

Future designs may make use of a modular facility design

with a standard buffer stock blending skid per scale of

operation in a lights-out, hands-off operation.

The opportunity to accelerate the pace of change in

the industry arises not only from the technical and

innovative development of a solution but the collaborative

and resultant open source approach this team have

adopted, demonstrating the value of leveraging industry

expertise to respond dynamically to evolving needs of the

biomanufacturing leaders and benefit patients.


6.5 Cost analysis and business caseThe BioSolve Process software application from Biopharm

Services has been used to construct a process model to

assess the impact of a buffer preparation philosophy on

facility design and operation for both intermediate (2,000L)

and large-scale (12,500L) manufacturing facilities for a wide

range of process titers.

The philosophies considered in the process model are:

• Preparation at a final-use concentration

(traditional)

• Buffer concentrates (in-line dilution)

• Buffer stock blending.

In the case of buffer stock blending, several scenarios are

considered in the assessment, such as whether the buffer

stock blending skid will be used on demand or to prepare

buffers ahead of time into intermediate storage systems.

Alternative strategies for the supply of stock solutions are

also considered, for example, whether to purchase them

ready-made or prepare them in-house.

Table 5 provides a high-level comparison of the three

preparation philosophies. For buffer stock blending,

the case of buffer stock blending on demand with the

preparation of stock solutions in-house is considered.

Further details on the process model assumptions

and output for the various scenarios can be found in

the BioPhorum paper The economic evaluation of buffer

preparation philosophies for the biopharmaceutical industry9

Table 5: Scale and impact comparisons of methodologies

Description 2,000 L scale 12,500 L scale

Trad

itio

nal

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Capital cost

Operating cost

Labor demand

Consumables cost

Footprint

Flexibility

Total cost of buffer

Net present cost

Key:

= High positive impact = Medium positive impact = Baseline = High negative impact


The process model offers significant insights into the

impact of a buffer preparation philosophy on capital

and operational expenditure. While the absolute values

presented in the economic evaluation will vary depending

on specific facility and process requirements, the relative

comparisons and general trends remain valid.

Overall, buffer stock blending on demand is demonstrated

to be the most flexible and cost-effective philosophy for

buffer preparation. The use of buffer stock blending to

prepare buffers ahead of time does not offer the same

advantages and is more comparable with the use of buffer

concentrates (in-line dilution).

For both intermediate and large-scale manufacturing,

buffer stock blending requires the highest initial

investment; however, this is offset by considerable

operational advantages, particularly in the labor demand

associated with buffer preparation. As the technology

develops, initiatives to reduce the equipment supply cost

will have a considerable impact on this initial investment

cost and consequently reduce the cost of producing

buffers even further.

While the results of the economic evaluation demonstrate

that buffer stock blending results in the highest capital

cost, it is worth noting that the scope of simulation is

limited to the direct production of stock solutions and

buffers only (results do not take raw material handling and

dispensing etc. into account due to capability of BioSolve).

The impact on overall capital investment (including

support areas such as weighing and dispensing) should

be evaluated in future studies to determine whether the

higher equipment cost will be offset by a further reduction

in facility capital.

Buffer stock blending is inherently flexible as a small

number of common stock solutions are used to prepare

a wide variety of buffers. Buffers may be prepared

on demand and connected directly to the process so

restrictions on minimum and maximum preparation and

hold volumes do not exist.

6.6 Buffer management concept for the futureA buffer preparation system of the future will most likely

skip buffer salt kitting, stock solution inventory and

possibly even buffer hold requirements to reduce the

operation to its minimal footprint. Buffer preparation

could be highly automated in closed systems in a

‘controlled not classified’ space. The NIIMBL-BioPhorum

Buffer Stock Blending System is a first step in developing

a more cost-effective automated buffer blending system

with less operator intervention and an open architecture.


7.0

Opportunities to maximize the benefits of the NIIMBL-BioPhorum Buffer Stock Blending Skid

blending skid. The water quality required in the makeup

of these stock solutions would also be critical from a

cost standpoint, with WFI and upstream processing-

purified water being the two options available. The

selection of water quality of the stocks would depend

upon a risk analysis from the end-user and application

of the final diluted buffer. Certain stocks (e.g. sugars)

could also be viral-inactivated with techniques such as

‘high temperature, short time’ to provide additional risk

mitigation in certain processes where specialized buffers

are needed. The edge of failure of these stock solutions will

be determined by the testing carried out on the NIIMBL-

BioPhorum Buffer Stock Blending System outlined in the

following sections.

Costs for in-house-made buffers will typically be lower

than outsourced buffers ($4–6/L vs $8–15/L); however,

these costs are offset by reduced complexity, reduced

EHS/compliance risk and ease of switching molecules and

operations. Reduced in-house QA/QC testing will enable

increased on-site effectiveness and reduce the burden

on testing low-priority or low-risk buffers. The costs that

would be added will be those for the storage of these pre-

made stocks and their management. However, these are

currently being managed, in some cases, by buffer vendors

with local storage facilities and at cGDP/cGMP facilities,

further increasing flexibility and de-risking the supply

chain. Standardized solutions across facilities will be

more economical but, since processes vary across/within

manufacturers, a site-by-site stock solution setup will be

required, at least in the near future.

7.1 Standard stock solutions enable outsourcing of stock solutionsThe process control method of the equipment using buffer

stock concentrates has dictated the quality and accuracy

requirements of the buffer stock solutions. A system that

has a pH or conductivity feedback loop can handle the

lower accuracy of buffer stock solutions due to its ability

to self-correct. However, these systems face hardware

constraints from sensor drift over time. The buffer stock

blending system described in this paper does not function

on a feedback loop and hence is dependent on very

accurate concentrated buffer stock component solutions

to delivery accurate recipes. Inaccurate stock solutions

can lead to unsustainable rejection rates, the disposal

of costly buffers and potential facility or process delays.

Outsourcing the manufacture of these stock solutions

would need to be combined with robust quality programs

between the stock vendors and end-users to ensure

minimal waste11. Harmonization between vendor test

methods, principal component analysis on stocks and raw

material data management will enable real time release of

buffer stocks and mitigate the risk of non-compliance.

Standard stock solutions will also need to be investigated

for stability and package shipping integrity to ensure

the safe delivery and optimum use with the Buffer Stock

Blending Skid. Stock solutions would need to have critical

quality attributes (such as pH, conductivity and sterility)

to ensure that the diluted and pH-adjusted buffers meet

the finished buffer specification from the buffer stock


7.2 Component standardization and innovationComponent standardization will play a critical part in

driving overall operational costs down for the Buffer Stock

Blending System. The major items that would benefit from

standardization include the types of concentrates, along

with standardized single-use packaging materials for the

concentrates and standardized connectors for the single-

use systems.

Stock solution delivery systems, such as single-use bags and

other containers, will benefit the most from standardization

in bag sizes and film types. Currently, single-use bags are

available from a variety of manufacturers in a variety of

sizes and configurations. However, from a buffer stock

standpoint, the size range for buffer stocks would typically

be between 100–1,000L per batch. For smaller facilities,

200L drum-sized containers would be ideal from an

operational standpoint and enable quick stock change-

outs and waste disposal. Larger mAb facilities would

need stock solutions to be supplied in 500L or 1,000L

pallet-sized containers to mitigate excessive change-outs

between production batches. Facilities with higher buffer

needs and stocks incompatible with single-use systems

might need stocks to be shipped in returnable containers,

such 375-gallon intermediate bulk containers, and totes,

to ensure daily supplies. The films used in the single-use

systems would need to have the requisite extractable-

leachable testing to prevent any quality issues10.

The current trend across single-use vendors seems to

highlight polyethylene-based films as a standard for the

delivery of most of the aqueous buffer solutions and stocks.

However, some of the more hazardous concentrated

buffer materials, such as glacial acetic acid, might require

development and implementation of fluoropolymer

films to ensure risk-free, long-term storage and shipping.

Standardization of secondary containers, such as drums

and pallets, would also enable simplification of warehouse

operations and UN/DOT/IATA compliance for shipping out

these stock solutions to customers.

Single-use assemblies used to ship and store liquid buffer

concentrates will need to have standardized external

asceptic connectors, which would enable end-users to

attach them to the buffer preparation skids. The main areas

of innovation would be in ensuring:

• Long-term stability of buffer concentrates to

enable flexibility in stocking

• Packaging strategies to ensure buffer stock

solution stability in standard shipping conditions,

including hazardous solutions

• Single-use aseptic connects/disconnects

• Enhanced instrumentation to allow for more

precise buffer parameters measurement to

help increase the effectiveness of the in-line

dilution process.

7.3 Logistics and supply chainThe logistics of running a mAb production facility using

the Buffer Stock Blending System revolve around the

management of the stock solutions. The purchasing

and stocking of these stock solutions are critical to the

continuous smooth operation of the facility. A good supply

chain strategy would be to ensure the selection of a

reliable buffer vendor(s) to ensure a robust and continuous

supply. Regional buffer stock concentrate generation

centers would need to be maintained to supply specific

facilities on demand and would help improve supply chain

security. A small on-site buffer preparation capacity might

be maintained to manufacture buffers in emergencies and

for complex buffer preparation. Campaign planning and

reserve management would be necessary, in collaboration

with vendors, to ensure that the concentrates are supplied

on time.

Figure 6 indicates the general relationship of the Buffer

Stock Blending System and the support pallets of stock

solution supply. It indicates the option of placing the stock

solutions in a separate environmental class space from the

operating system (as indicated by the blue bar).


Key to safe and compliant operations will be:

1. Communication from one area to another

containing stock solution staging and Buffer Stock

Blending System

2. Easy access to the stock solution warehousing

3. Access and Movement to all stock solution

positions for the supply and removal of new and

used stock solutions

4. Secondary containment of incompatible

stock solutions

5. Operator access to the stock solution supply

tubing and connection to the Buffer Stock

Blending System

6. Verification that tubing lengths are not

susceptible to collapse at supply flow-rates

7. Verification and documentation of the correct

stock solution placement and connection location

on the Buffer Stock Blending System

8. Tubing runways used to facilitate

error-free operation.

Figure 6: General buffer stock blending system configuration

WF tank

WFI pump

Panels

Stock solutionconnections




Stock solutionstations

BSB System


8.0

System adaptability

8.1 Stock Concentrate Handling Campaign planning and reserve management ensure

on demand concentrates are manufactured on time.

Since the accuracy of stock concentrates is critical,

harmonization between the QC testing and release

of the stock concentrates will be necessary across

suppliers and end-users. Increases in the efficiency and

reliability in the use of the buffer preparation skids can

be achieved through principal component analysis on

supplied stock concentrates.

8.2 Future drivers for the biopharma industry and its relevance to buffer managementThe BioPhorum Technology Roadmapping initiative

clearly identified four principal drivers for the future of

the biopharma industry with respect to biomanufacturing.

These include:

1. Speed: with the primary purpose of the biopharma

industry to serve patients, the speed-to-clinic and

speed-to-launch of lifesaving biologics is increasingly

relevant to our industry. Biomanufacturing often

becomes a critical path activity in bringing the drug to

the clinic or market and, therefore, any transformative

change that can cater to this need is expected to be

an enabler for the future. In the context of antibody

products, which are still expected to occupy a

significant percentage of future products, platform

processes have been well established and therefore

the process-related equipment and activities are well

defined from product to product and do not represent

a significant unknown. However, for each product,

the process itself has significant variability, both in

terms of titer and productivity, as well as the nature

and type of buffers and solutions to be utilized, and

hence remains a key unknown in every manufacturing

process. Enabling solutions that simplify and expedite

the implementation of new processes should result in

improved speed-to-clinic and speed-to-market.

2. Flexibility: multiple production platforms are

expected to be created as new product modalities

emerge. Building fixed infrastructure for different

product types is likely to be prohibitive, both from an

economic and flexibility standpoint. Thus, production

lines that can be reconfigured with relatively

little effort, time and cost to accommodate new

manufacturing methods and product types will prove

to be highly valuable. However, facility adaptability

places significant pressures on process support

areas, such as buffer preparation. Where traditional

preparation methods or buffer concentrates are

used, bottlenecks due to equipment and labor

constraints may easily develop. Buffer stock

blending is well placed to support flexible and

adaptable facilities as a small number of common

stock solutions are used to prepare a wide variety

of buffers in-line, on demand, thus buffer stock

blending is not limited by the same logistical issues

associated with traditional buffer preparation.

3. Cost: the reduction of cost can come through

consumables and equipment standardization,

reduced operational requirements and reduced

facility footprints.

4. Quality: as a flexibility requirement is removed, the

automation opportunities increase, while operator

intervention is decreased. With the design well

understood, the process quality improves.


9.0

Path to industry adoption

9.1 Reducing barriers to adoptionThe prototype will serve as a ‘proof of concept’ for the

buffer stock blending approach. There are many possible

developments once the base concept is proven. Once the

performance operations have been completed with the

prototype, the expansion, adaptability and performance

of the skid can be improved and tailored to different

manufacturing processes.

9.2 Scalable designThe scale of the buffer stock blending chosen for the

prototype was intermediate. Scale up or down should

be straightforward and a next-generation prototype will

prove the scalability of the technology.

9.3 Existing Product Adoption in legacy facilities and new facilitiesThe benefit for existing facilities would be the system

flexibility for buffer recipe modification. Increased flow-

rates could provide buffer preparation much faster than

conventional batch production, and buffer generation to

existing hold tanks for buffer top-off could greatly increase

the processing capacity. Note that a doubling of a column

volume has a minimal impact on the chromatography

skid and column, but the corresponding buffer volume

footprint has a significant impact on the buffer hold area.

9.4 Perceived risks and mitigation strategiesWe have highlighted some risks that may impact on

the system acceptance and we propose the following

mitigation strategies.

The unproven nature of our delivery to off-the-shelf

chromatography systems will be tested during prototype

testing. The performance during the chromatography

buffer switch-over must be proven, specifically for a JIT

operation. Also, the recovery and performance when

the chromatography and buffer stock blending system

operation is upset must be demonstrated to document the

events and establish that only quality buffer makes it to

the process in a JIT operation. From this testing mitigation

strategies can be identified.

The potential issue with instrument drift will be tested

over time, from the initial qualification through to

performance testing. Work-around modifications can be

made if the performance life of the instruments proves to

be restrictive.

The prototype has been designed based on some of the

most commonly used buffer recipes and is therefore

by design initially restrictive. From the baseline list of

buffers, new stock solutions may be added in time based

on performance data developed and this should help to

mitigate any perceived performance limits.

Operator safety risks with stock solution handling will

be mitigated through the testing phase with multiple

stock solution volumes required. Delivery of stock

solutions, stock solution hook-up, bag failure and

disposal requirements will all be reviewed to ensure an

ergonomic approach for system operators. Also, different

configurations of buffer stock supply will be considered to

anticipate the operational limitations and facility design

requirements in a GMP environment.


9.5DesignflexibilityThe prototype flexibility is limited to a conservative set of

parameters to not overcomplicate the ‘proof of concept’

(i.e. modest component list, ambient WFI, delivery manifold

with two connections, standard instrumentation and

cleaning/sanitization capability). Inherent in the design, is

the ability to supply buffer in a batch fashion to buffer hold

tanks and surge tanks, as well as direct delivery of buffers to

chromatography, filtration or diafiltration operations. The

supply of buffer stock solutions could be hard-piped from a

tank farm where stock solutions are held.

9.5.1Automationadaptabilityandflexibility

As mentioned in Section 1, the prototype will be open

source, such that all automation design documents

(including the user requirements specification, functional

design specification, software design specification,

hardware design specification, FAT protocols and

performance testing) will be available to promote the

adoption of the buffer stock blending system technology.

The controller and ‘human machine interface’ code will be

open source as well, and for this reason Configurable off

the Shelf Libraries and reports were used in programming.

The libraries are free and open to the public, therefore

only applicable software licenses for system functionality

would need to be purchased.

For prototyping and development, the system contains

a local historian server. However, it’s use may not be

necessary, as most end-users will typically have an existing

historian system in their site-automation architecture.

The electrical panel that houses the historian server can

easily be decoupled and removed from the system design.

Furthermore, the historian software can be omitted with

minimal impact on the software architecture and so reduce

the total cost of the system.

The system has been designed with a spool piece for future

addition of PAT, such as nuclear magnetic resonance

spectroscopy or near infrared spectroscopy. PAT software

for modeling can be added as a separate system or

integrated into the control system architecture. The new

technology can then be used to capture and model real-

time data to better control the buffer blending process

or increase buffer quality by more precisely determining

buffer compositions.

9.5.2 Future buffer stock blending system capabilities

The development of more versatile designs will follow

once we have learned from the prototype performance

and established a flexible design basis. The addition of

system-temperature control to accommodate WFI-

system delivery variations such as WFI loop cold drops,

hot-WFI supply, and 5ºC cold-WFI supply). The addition

of on-board 0.2µm filtration for integration into existing

production facilities. Increasing the number and types of

the buffers that can be made through working with buffer

supply manufacturers to increase the number of stock

solutions available. The current system flow-rate is tied

to line sizes and production capacities of a given column

size range. Increasing the system flow-rate will require

modest design changes to accommodate larger flow-rates

and larger stock solution stations around the buffer stock

blending system. In the future, the buffer stocks could

even come from a tank farm.


10.0

System commissioning and qualification

10.1 Factory acceptance testing performancetospecificationFactory acceptance testing (FAT) will be executed

to challenge the design specification document and

functional specification. The protocol for the execution

of the FAT will be written by the skid manufacturer. The

performance of the FAT will be at the vendor’s facility

and executed by the BioPhorum team. Some of the

specifications that the FAT will test are listed below:

1. Cleaning function

2. WFI-flushing function

3. System-purge function

4. WFI-module testing

• Tank level

• Alarms

• Maintain tank level with varied flow

• Air blow-down

5. Stock pumps

• High-flow and low-flow for each pump

• Alarms

• Maintain flow-rate

6. pH range

7. Conductivity range

8. Control-screen testing and alarm testing.

10.2 Extended factory acceptance testing The extended FAT testing will act as an extension of

the initial FAT, in which the protocol will be written and

executed by the BioPhorum team. The extended FAT will

use one of the most common buffer solutions in biological

research, phosphate-buffered saline. The extended FAT

will use sodium chloride, potassium chloride, sodium

phosphate and potassium phosphate stock solutions to

make 1x, 5x and 10x phosphate-buffered saline buffers.

The stock buffer pumps’ flow-rates will be varied to test

the flow-rate range of each pump. Varying the different

pumps will demonstrate the system’s capabilities to

meet the buffer specifications at different flow-rates and

concentrations. While a series of buffer recipes linked

together is a capability of the skid, the extended FAT will

test a recipe input for a single buffer. Linking buffer recipes

together will be tested during the realization testing at the

University of Delaware.


10.3 Realization testing The realization testing will provide an opportunity to test

beyond the designed capabilities of the skid and enable

additional ‘stress’ testing to the FAT and extended FAT.

It will be performed at the University of Delaware and will

be planned and executed by the BioPhorum team. It will

test and capture the full capabilities of the buffer stock

blending system and will use a limited number of stock

buffers, see list below, to make a wide variety of 1, 5 and

10x buffers for a standard biologic purification process.

After establishing the capability of the skid to accurately

make a multitude of different buffers, linking of multiple

buffer recipes will be tested. The team will link a series of

buffers together that will represent making the buffers

in real-time and directing them in-line into a purification

process. Lastly, the realization testing will execute some

contingency testing that will include (but is not limited to)

multiple flow-rates, back-pressure on the system, pauses

during a recipe and recovery when going in- and out-of-

specification. Throughout the realization testing, data will

be collected to observe the skid’s accuracy and precision

in meeting the final buffer specifications, the time it takes

to meet the different buffers’ specification, the time it

takes to make the buffer and the amount of buffer that

goes to waste.

Stock buffers used during realization testing are:

1. Sodium phosphate monobasic

2. Sodium phosphate dibasic

3. Sodium chloride

4. Sodium acetate

5. Glacial acetic acid

6. Tris HCl

7. Tris base

8. Sodium hydroxide

9. Ammonium sulfate.

10.4 Packaged installation, operation, and performance qualificationsAfter rigorous testing and performance refinements, the

development of standardized installation, operation and

performance testing protocols may help to facilitate the

use the Buffer Stock Blending System in industry. These

protocols will be developed for use with the buffer stock

blending system to facilitate the system qualification

testing. A more general outline for performance

qualification testing will be provided so that modifications

can be made for specific application needs. The document

will be a starting place for specific performance testing

required by independent users.


11.0

Future improvements and applications

11.1 Extension of the conceptThe concept of making buffers and solutions from their

primary stocks is the basis of the design of the system

being demonstrated in this project. This concept, while

currently being demonstrated with a typical mAb process

platform buffer system, is not limited to this system and

can be readily extended to any process or unit operation

that requires buffers or solutions as demonstrated in

Section 10.

It should be feasible to extend the use of this system to any

process modality. Buffer and solution preparation for:

1. Production of microbial- or yeast-

derived products

2. Production of gene therapy products

3. Production of RNA, plasmid DNA and

related products

4. Production of therapeutics from non-

recombinant systems, such as blood products, etc.

5. Production of non-therapeutic products including

food, beverage and cosmetics

6. Production on non-protein products, including

small-molecule drugs and other chemical

purification systems.

In each of the above applications, the underlying benefit

is the reduction in equipment footprint and storage

systems, as well as increasing flexibility by being able

to produce multiple different solutions within the same

system. It is clear that the components and the quality

requirements of each of these applications are likely to be

different and may require a redesign, but the underlying

concept of mass composition-based solution preparation

is central to the simplification and accuracy of the system,

and the universality of the application. Small-volume

preparations could be made at a buffer supply house in

aliquots produced from a single buffer stock blending

operation. The industrialization of the buffer supply would

add value in instances where the buffers are stable and of

a shippable size.

11.1.1 Use in non-product manufacturing applications

Buffers and solutions, while typically manufactured in

biologics manufacturing facilities, may often be standalone

products. For example, with the advent of extensive

single-use manufacturing facilities, buffers and solutions

are often bought vs made in-house. The vendors supplying

these buffers typically produce them in large quantities and

package them for shipping. Such large-scale production of a

variety of buffers is another potential use for a buffer stock

blending system, where the vendor could make the stock

solutions and use them to make the 1x buffers to package

and ship. As previously state, there are tremendous savings

in labor costs when using the Buffer Stock Blending Skid.

The skids ability to accurately control based on mass-flow

controls ensures consistency from batch to batch, which is a

critical requirement for vendors supplying these solutions.

11.1.2 Use in non-manufacturing facilities

Buffers and solutions are highly universal and in every

regulated industry where accurate control of composition

is required, therefore making the buffer stock blending

concept applicable, with significant cost savings. For

example, in the food industry, or other industries where

large amounts of buffers are required on a real-time basis,

the buffer stock blending skid should provide a huge

advantage over batch preparation.


11.1.3 Additional capabilities in buffer design and process development

The buffer stock blending system is readily adaptable for

use in development laboratories where a multitude of

different buffers and buffer compositions are required

daily. For example, in scouting buffers for process

development, it is often required to make the same

buffer with a different pH or salt concentration. Once

a generic recipe is created with a buffer stock blending

system, it is possible to create variants of such a recipe

with different salt concentrations. In a development

setting, it is also possible to add calculations to design

these buffers so the recipe generation can be in-silico,

resulting in automatic preparation of buffers with varying

pH and salt concentrations. Using this concept, opens up

the possibility to automate the scouting of a column step,

evaluating different columns, pH and salt conditions on a

laboratory-scale system that has a laboratory-scale buffer

stock blending connected to the system.

Alternately, the laboratory-scale buffer stock blending

system can be used to make batch buffers, which a scientist

could use as input for the chromatography system. Such a

system can make the buffers automatically 24x7 and fill into

storage bottles. This also represents a very valuable use

case, as often the time of a highly valuable scientist is spent

in making buffers for such experiments.

11.1.4Expansiontofacility-widefluid-management system

The buffer stock blending system establishes the ‘proof

of concept’ for an on-demand, automated solution

preparation system. Once established, this concept can

be extended to a facility-wide operation, where a set of

stock solutions are connected to a set of pumps, that can

be operated independently (or in a combination of two

or more) to generate any solution needed at any point in

the facility. Such a distributed system can produce the

buffers or solutions needed at any point-of-use through

pre-programmed recipes and automated operations. For

example, a system with eight pumps could be setup with

multiple point-of-use outlets such that, while a set of three

pumps is making a buffer for one point-of-use, a set of two

pumps could be making a hydroxide solution and a set of

three pumps could be making a different buffer. When

needs change, a set of four pumps could make a buffer, a

set of two pumps could make a solution and the remaining

pumps could be making another solution. Such a distributed,

dynamic system then can be designed to cater to the needs

of an entire process.

In this use case, process operations essentially

become ‘clients’ to the fluid-management system. A

chromatography cart, a filter cart and an ultrafiltration cart

could be connected to the points-of-use to consume the

buffers/solutions that are required.

Such a system will provide the highest equipment-utilization

efficiency in a plant, eliminating the need for individualized

fluid-management systems per unit operation.

11.2 Integration in other facility conceptsThe buffer stock blending system will be versatile as to the

location and integration within a facility. The ideal design

will be to place the system remotely to the controlled

production space and make the operation self-contained

without the need for continuous operator intervention

and management. Location of the system on the floor

above the production floor as well as in adjacent spaces

to the production area can help to reduce the buffer

transfer distance . The control platform is designed for easy

integration to many of the configurations currently in use

and is potentially applicable to a modular delivery or super-

skid approach. Existing plants may use the buffer stock

blending system to expand buffer preparation areas.

The buffer stock blending system design is intentionally

planned to be a more complex design (JIT buffer to

chromatography). In the future, a simpler task such as

caustic supply for 0.1 N, 0.5 N, 1.0 N sodium hydroxide

plant-wide or rapid batch buffer production can be

developed from the prototype lessons learned.


11.3 Enabling process analytical technologies and other advanced control strategiesOne of the most significant limitations for enabling PAT for

downstream processes is the ability to dynamically change

the process parameters that depend on the buffers used.

For example, for an ion exchange step, if it is determined

that dynamically changing the pH and conductivity of

the buffer is required to achieve the required process

performance or product quality, changing the buffers with

batch preparation systems is not feasible. On the other

hand, the recipes for many of the pH and conductivity

variants can be stored in the buffer stock blending system

and can be deployed in real-time upon determining that

a different buffer is required for the specific batch (e.g.

when reacting to an upstream variability). Such a system

can represent a very practical PAT application without the

need for any sophisticated analytical technologies.

This ability to dynamically change the buffers (coupled

with the ability to change product loading on columns and

the real-time detection of impurities during processing)

can be readily coupled to create a truly adaptive process

control strategy. Without the use of a buffer stock blending

system, such a comprehensive control is challenging. In

this aspect, the buffer stock blending concept overcomes

the significant limitations of the in-line dilution systems, as

well as the other buffer-preparation systems, where the

accurate compositional control is not possible.

11.4 Large and small-scale – other roadmaps scenariosThis paper has discussed typical mAb buffer needs from

2,000L to 12,500L bioreactor scales. It is clear from the

concept and design that the system is only limited by the

pumps and mass-flow meters with respect to throughput.

Fortunately, the pump and mass-flow technologies are

readily scalable and have been commercialized. The smaller-

scale systems can also benefit from the robust and accurate

piston-pump technologies that are available, obviating the

need for mass-flow controllers that are sometimes needed

for real-time control.

Many other industries could benefit from this system,

each with their own design challenges, e.g. cell therapy,

gene therapy, viral vector production, vaccine, plasma

fractionation, oligonucleotide, etc. While each will require a

step-by-step evaluation, it is anticipated that in every case

where dilute buffers are used in processing the buffer stock

blending concept should be a very attractive option.

11.5 Continuous DSPContinuous DSP represents one of the best use cases

for the buffer stock blending system. Continuous DSP

requires a new paradigm for buffer preparation and hold.

In traditional batch processing, each skid is idle during

some part of a batch, allowing time for buffer preparation.

In continuous DSP, all skids are running continuously, with

no open window for supplying new buffer. The BSB skid

can address this challenge, as it can very rapidly deliver

buffer with minimal change-over time between the next

buffer supplied. This rapid delivery, coupled with a buffer

top-off strategy for refilling buffer bags during a batch, can

enable buffer supply in a continuous DSP operation.

11.6 Modular and mobile Buffer stock blending presents the best opportunity to

achieve a modular and mobile facility6. The buffer stock

blending concept could be extended to achieve a distributed

fluid-handling system. In this scenario, every unit operation

is a ‘plug-and-play’ device that connects to the appropriate

point-of-use on the fluid-management system.

Alternately, the buffer stock blending concept could be used

to create a modular buffer/solution manufacturing facility,

which can produce all the buffers needed for processing as a

standalone module. Such a modular facility can be designed

on a platform basis to cater for a wide range of buffers and

solutions, with the ability to dynamically change the set of

buffers produced from campaign to campaign by simply

changing out the stock solutions.

A standardized buffer stock blending system could be

designed for a modular system and this could add design

opportunities by placing the buffer stock blending system

in the interstitial or second-floor space. This would

consolidate the production-floor footprint and move

closed-system buffer production to a lower-cost space.

By modularizing the buffer stock blending and stock

solution needs, plug-and-play capabilities could facilitate

the utilization of the system. Perhaps, when the acceptance

of filtered-WFI generation gains acceptance, the

incorporation of WFI in the buffer stock blending system

may reduce costs


12.0

Linkages to other roadmap projectsLinks to related TRM workstreams are presented below and cover process enhancements (e.g. a new cell harvest approach) as well as digital data requirements (e.g. release of formulated buffer for DSP processes).

12.1 In-line/out-line monitoring and real-time releaseThe buffer skid is designed to include monitors measuring

pH and resistance, and to confirm that the final formulation

was prepared correctly. If the buffer formulation falls

outside of specifications, it is automatically dumped

(to waste) and will not proceed to the appropriate DSP

equipment. The skid is designed to reduce the amount of

release testing. Quality control testing for buffer stock

components managed by the appropriate raw material

management group. Process validation will confirm that no

additional testing is required for the buffer usage.

The real-time release team can help enhance the system

by providing additional means of releasing the buffers and

solutions. An ideal scenario would be to completely avoid

any in-house testing of the concentrates through the use

of Raman or other analytics, such that the composition and

identity of the solution are ensured in real-time.

12.2 Continuous DSP The buffer stock blending concept enables continuous

DSP. However, for the full potential to be achieved, the

continuous DSP process equipment has to be redesigned

as current designs still rely on unit operation-based design

with integration to enable communication between the

steps. An ideal system would be a truly integrated design

with the fluid-management system being at the center

of the process and the unit operations being ‘clients’ to

the fluid-management system. Such a system is ideal for

continuous DSP.

The use of the buffer skid enables the development of

continuous DSP when previous steps may require buffer

formulations that can be addressed by the skid real-time

and at the volumes required to proceed. Further, use of

the skid will eliminate the need for hold steps, as required

buffers are immediately formulated and delivered to the

next process step.


12.3 Standard facility designWith the use of the skid, facility design will benefit through

eliminating, or greatly reducing, the size of buffer suites and

hold tanks the buffer skid’s footprint is small thus, allowing

transfer to various locations within the production facility.

The mobility of the buffer stock blending system is also

advantageous to a modular design and any repurposing of

a modular space. This concept supports the new modular

design approach described in the BioPhorum Technology

Roadmap, Modular and Mobile chapter6.

12.4 Plug-and-playThe buffer stock blending system is designed with

ANSI/ISA-88 (S88) standard methodology for batch

process control, enabling a logical and modular

structure to the automation code. The system uses

a controller-based batch engine to sequence the

equipment phases, which direct equipment modules

to perform specific process steps to blend stock

solutions into a desired buffer. By utilizing the S88

concepts of the process model, the physical model

and the procedural control model, the system fits into

modern batch-control systems at drug manufacturing

sites. The batch solution provided is scalable and

flexible such that it can be utilized as standalone

equipment (single-unit control) or integrated into a

site’s existing distributed-control system and batch

strategy for multi-unit operations. By following the S88

methodology, the buffer stock blending system will

be in a good position to adopt new standards, such as

the new BioPhorum plug-and-play interface standard

that is being developed at the time of authoring this

white paper. The overall objective of the plug-and-play

group is to integrate unit operations in an overlying

distributed-control system, while reusing as much of

the existing code and architecture as possible, thereby

saving cost, integration and validation efforts but

remaining a flexible system.

12.5HarvestclarificationPost-upstream processing, the amount of cell debris and

other contaminants will increase as a result of the high cell

densities involved in manufacturing. This will impact on the

volumes of buffers being formulated, which may change

biological oxygen demand needs.


13.0

ConclusionThe introduction of a buffer stock blending system has promising results in many applications of automated buffer preparation. Reducing the buffer preparation time and footprint, as well as improving the buffer consistency and quality, can facilitate standardization of the buffers commonly utilized in biological production. The prototype being developed is designed for some of the more aggressive applications, such as the JIT delivery of buffer to the process stream. Preliminary information from this testing may help to clarify the needs of future systems for facility capacity upgrades and continuous processing developments, and may help quantifysomeofthepotentialcostbenefits.

Expectations from the initial testing are the proof of the mass-flow blending approach,

the ability for an open design plug-and-play application through the OPC communication

platform and the development of a set of recipes of standard buffer formulations to

provide a starting point for the expansion of the buffer library. It is recommended

that aggressive expansion of the buffers and future applications are developed as the

prototype’s initial testing data is collected. The industry is also expected to drive some of

the future developments identified, such as on-board filtration, temperature control and

decoupling both the cleaning and sanitizing agent supply and the buffer stock blending

system distribution module.

©BioPhorum Operations Group Ltd | December 2019 NIIMBL-BioPhorum Buffer Stock Blending System 46

Appendix

DesignspecificationforautomatedbufferstockblendingThis is the design specification produced for the RFP to find a vendor to fabricate the skid. The design review stage delivered a

functional specification that will be made available when the prototype project outcome and data is published in Q1 2020.

User Requirements Specification

TITLE: Buffer Stock Blending Skid User Requirement

Doc. Number: BSB-101 Revision: 0 Date: Nov 20, 2018 Page: 1 of 27

Buffer Stock Blending Skid

User Requirement Specification Document History

Version No. Date: Reason For Issue:

Rev A 10-19-17 1st Draft for Discussion

Rev B 10-30-18 2nd Draft for Review

Rev C 11-14-18 Final Draft

Rev 0 11-20-18 For Procurement




CONTENTS 1.0 INTRODUCTION ............................................................................................................................................. 3

1.1 System Scope .................................................................................................................................................. 3 1.2 Purpose.............................................................................................................................................................. 3 1.3 System Boundaries ........................................................................................................................................ 3 1.4 Reference Norms and Standards................................................................................................................ 4 1.5 Abbreviations and Definitions ..................................................................................................................... 5

2.0 OPERATION REQUIREMENTS ......................................................................................................................... 6 3.0 CONTROL SYSTEM REQUIREMENTS ............................................................................................................... 8

3.1 Control System General Requirements .................................................................................................... 8 3.2 Operator Interface Requirements ............................................................................................................... 9 3.3 Electronic Record and Reporting Requirements ................................................................................. 10 3.4 Security Requirements ................................................................................................................................ 11 3.5 Alarms/Error Handling Requirements ..................................................................................................... 13 3.6 Calculations and Algorithms ..................................................................................................................... 14

4.0 MECHANICAL REQUIREMENTS ..................................................................................................................... 15 4.1 General Mechanical Requirements .......................................................................................................... 15

5.0 SAFETY REQUIREMENTS ............................................................................................................................. 17 5.1 General Safety Requirements .................................................................................................................... 17

6.0 EQUIPMENT TESTING .................................................................................................................................. 18 6.1 Testing Requirements.................................................................................................................................. 18

APPENDIX A – Vendor Documentation Requirements (VDR) List ................................................................... 19 APPENDIX B – Buffer List ................................................................................................................................. 23 APPENDIX C – Components List ...................................................................................................................... 24 APPENDIX D – P&ID ......................................................................................................................................... 27




1.0 INTRODUCTION

1.1 System Scope The system described in this URS is a Buffer Stock Blending (BSB) Skid, Equipment Number: BSB-101. The BSB system is designed to provide buffers or solutions to the process directly and shall utilize concentrated inlet stock salt solutions (referred to as “stocks”) to prepare various conditioned final solutions. The solutions shall be prepared by blending at most 4 stock solutions through metered flow through pumps. Inlet valves connected to each pump will provide for 4 stocks to be connected. Stocks will be supplied to the skid from owner supplied flexible hoses and bags or tanks. The blended outlet from the pumps shall be mixed, monitored and diverted through outlet valves to process or waste as needed. The system shall be connected to an external Water-for-Injection loop system with point of use cooler, and a skid mounted WFI break tank with level control will be used to segregate the BSB from the WFI system. The entire system shall include cleaning functionality using either hot water or a sanitizing solution. The system shall be designed to be directly connected to process equipment such as a chromatography column or a filtration system, or to directly fill buffer bags. The system shall operate in an automated manner and be able to blend and supply a series of solutions sequentially with minimal operator intervention. Solution recipes shall be stored and reused. The data shall be collected to a database system. The system shall be designed to be directly translatable to producing a GMP compliant system, including data integrity, etc. A listing of targeted buffers that the system should be able to provided are included in Appendix B. 1.2 Purpose To design a Buffer Stock Blending (BSB) system that handles sequential buffer preparation and delivery of process buffers from concentrated stock solutions. System utilization will be intended for use in new construction as well as facility retrofits for increased capacity. 1.3 System Boundaries The system boundaries are provided on the P&ID included in Appendix D as well as in the system components list included in Appendix C for all system valves, instrumentation, tanks, specialty piping components, pumps, etc.




1.4 Reference Norms and Standards

Type Codes

Hygienic design ASME BPE

Mechanical design EN ISO 12100:2010

Pressure vessel design ASME Section VIII, Division 1

Welding requirements AWS B 2.1, ASME Section II Part C

Electrical design UL508A / EN 60204-1:2006

EMC EN 61236-1:2013

Ingress Protection IP65, NEMA 4X

Automation GAMP 5

C&Q ASTM E2200

Compressed Air Quality ISO 8573.1 Class 1,2,1

Security CFR Part 11

ANSI American National Standards Institute

NEMA National Electrical Manufacturers Association ST – National Institute of Science and Technology

OSHA – U.S. Occupational Safety and Health Administration

IEEE Institute of Electrical and Electronics Engineers

NEC National Electrical Code

NFPA 79 Electrical Standard for Industrial Machinery




1.5 Abbreviations and Definitions

Terms & Abbreviations:

Definition:

ACD Aseptic Connection Device

API Active Pharmaceutical Ingredient

ASME BPE American Society of Mechanical Engineers Bioprocessing Equipment Standard

CFR Code of Federal Regulations

cGMP Current Good Manufacturing Practices

COC Certificate Of Conformance

DCS Distributed Control System

DP Differential Pressure

EU European Union

E-Stop Emergency Stop

FAT Factory Acceptance Test

FDA Food and Drug Administration

FIT Filter Integrity Test

FS Functional Specifications

GA General Arrangement

GAMP5 Good Automated Manufacturing Practice 5

HMI Human Machine Interface

ISO International Standard Organisation

I/O Input / Output

ID Identification

IQ Installation Qualification

µm Micrometer

NEMA National Electrical Manufacturers Association

No. Number

OQ Operation Qualification

PA Process Air

P&ID (or PID) Piping and Instrumentation Diagrams

PLC Programmable Logic Controller

RTD Resistance Temperature Detector

RTM Requirements Traceability Matrix

S/N Serial Number

SAT Site Acceptance Test

SCADA Supervisory Control And Data Acquisition

SDS Software Design Specifications

SIP Sterilization In Place

Buffer Solution Outlet buffer/ blended solution

Stock Solution Starting inlet solution

TC Sanitary triclamp fitting

TCU Temperature Control Unit

TBA To Be Agreed

TBD To Be Determined

UPS Uninterruptible Power Supply

URS User Requirement Specifications

USP 88 Class VI United States Pharmacopeia Biological Reactivity Testing Level VI

VIT Vendor Internal testing

WFI Water For Injection




2.0 OPERATION REQUIREMENTS

2.1 Operation Requirements Will Comply

Will Not Comply

Comments

Item: Description:

2.1.1 One (1) Buffer Preparation Skid shall be provided as a part of this scope of work.

2.1.2 The system shall be capable at a minimum of generating all of the identified buffers to the required specification (as listed in Appendix B) on a mass flow basis.

2.1.3 The equipment shall have a capacity for buffer delivery range of 5 – 60 L/min at ambient temperature.

2.1.4 The buffer specification (Flow, pH, Conductivity) must be achieved in 30 seconds or less.

2.1.5 The system must ensure that any produced buffer which is outside of the specified release criteria is diverted directly to waste. No out of specification buffer is to be sent to process.

2.1.6 The system shall be capable of generating a pre-defined sequence of buffers (and associated routes). The system shall be capable of automatically cycling through the pre-defined sequence incorporating any necessary cleaning steps in between.

2.1.7 The skid shall be able to accept an input for a buffer recipe (including process and purge/ flush volume requirements), flowrate and maximum pressure from an external control system.

2.1.8 A Break Tank (minimum working volume of 50L) shall be provided on the WFI Inlet.

2.1.9 x Break tank is to be equipped with a dedicated heat-traced 0.2 micron rated vent filter to maintain low bioburden conditions.

2.1.10 Break tank is to be equipped with a rupture disk / pressure safety device with burst detection.

2.1.11 WFI inlet to the break tank shall be provided with a removable spray device to enable full coverage of the vessel head during sanitization.

2.1.12 z Level in the Break Tank shall be measured within the range (0-50L) with an accuracy of ±1L.

2.1.13 Pressure in the Break Tank shall be measured within the range (0-100psig) with an accuracy of ±0.1psig.

2.1.14 The system shall be capable of receiving Hot WFI (< 95° C) and Ambient WFI (18 - 30° C)

2.1.15 A flow range of 1 - 60 L/min with an accuracy of ±0.2% is to be provided for the combined WFI pump / flow meter configuration.

2.1.16 The system shall include four stock solution inlet lines each with four inlet connections.





Will Not Comply

Comments

Item: Description:

2.1.17 There shall be two High Flow (3-15 L/min) and two Low Flow (0.05 – 3.5 L/min) pumps provided for Stock Solutions.

2.1.18 A minimum flow accuracy of 0.2% (or better) of target flow is to be provided on each combined pump / flow meter configuration.

2.1.19 The system shall allow for a minimum of four connections to be made to each pumps using inlet valves and piping manifolds.

2.1.20 It shall be possible to flush each Stock Solution inlet directly to drain.

2.1.21 The system shall include an inline static mixer after the four stock solution inlet lines that allows for removal / replacement of the internal mixing element.

2.1.22 The skid shall include 2 outlet valves to enable collection of final buffers. The system shall be connected to downstream storage bags/tanks.

2.1.23 A sample point shall be incorporated into the skid for non-routine sampling.

2.1.24 A single (pressurized) waste connection is to be provided on the system.

2.1.25 The drain design shall ensure that cross-contamination between the various stock solution inlets is not possible.

2.1.26 The design of the equipment shall allow for all process contact surfaces to be fully cleaned in place (using an automated sequence).

2.1.27 The system shall include a pressure transmitter after the static mixer.

2.1.28 Pressure shall be measured within the range (0-60psig) with an accuracy of ±0.1psig.

2.1.29 The system shall include a conductivity meter with temperature compensation.

2.1.30 Conductivity shall be measured within the range (0-200mS/cm) with an accuracy of ±0.5mS/cm.

2.1.31 The system shall include temperature measurement from the conductivity meters.

2.1.32 Temperature shall be measured within the range (0-100°C) with an accuracy of ± 0.5°C.

2.1.33 v The system shall include two pH meters, one dedicated to high salt buffers and one to low salt buffers.

2.1.34 pH shall be measured within the range (3-9) with an accuracy of ±0.05 with temperature compensation.

2.1.35 The system shall be able to be stored liquid full in a suitable bacteriostatic fluid which shall be easily rinsed using a pre-use flush cleaning sequence.

2.1.36 The cleaning functionality shall provide for an initial WFI rinse discharging straight to drain.





Will Not Comply

Comments

Item: Description:

2.1.37 The cleaning functionality shall provide for either a Hot WFI or Sodium Hydroxide (max. 1N) intermediate rinse.

2.1.38 The system shall include a resistivity meter to confirm acceptable cleaning has been achieved (WFI quality).

2.1.39 The cleaning functionality shall provide for a final WFI rinse discharging straight to drain.

2.1.40 The cleaning initial, intermediate and final rinse flow and time parameters shall be able to be stored locally and have the capability of transfer to an external SCADA / data historian.

3.0 CONTROL SYSTEM REQUIREMENTS

3.1 Control System General Requirements

3.1 Control System General Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.1.1 The equipment control system shall be designed and tested in accordance with GAMP 5 and be shall be compliant with 21 CFR Part 11 and EU Annex 11 requirements.

3.1.2 The equipment shall be provided with a local PLC and controls.

3.1.3 The system shall enable communications with an external DCS.

3.1.4 The system should have the ability to add in the future additional interfaces such as sensors (20% spares for the future).

3.1.5 The system should have the ability to connect and/ or interface with external data sources.

3.1.6 The HMI operator interface shall be a PC based system.

3.1.7 A method for back up of data to be provided.




3.2 Operator Interface Requirements

3.2 Operator Interface Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.2.1 The HMI shall display an equipment process flow scheme displaying device status and process parameters for operator reference during processing.

3.2.2 The open/closed status of valves shall be displayed.

3.2.3 The run status of pumps shall be displayed.

3.2.4 It shall be possible to see when there is an alarm.

3.2.5 It shall be possible to configure user access.

3.2.6 It shall be possible to display numerical Process values.

3.2.7 It shall be possible to display status of devices.

3.2.8 It shall be possible to manually execute recipes.

3.2.9 It shall be possible to manually operate all devices in maintenance, and supervisor mode.

3.2.10 It shall be possible to use retrieve batch reports and trend process values

3.2.11 It shall be possible to generate reports.

3.2.12 It shall be possible to set flow rate.

3.2.13 It shall be possible to select inlets.

3.2.14 It shall be possible to totalize Inlets.

3.2.15 It shall be possible to divert the outlet to collection of drain.

3.2.16 It shall be possible to select outlet.

3.2.17 No process data shall be stored on the PLC.

3.2.18 The HMI shall be used for data logging of the recorded process parameters. Data logging intervals for each parameter shall be user selectable.

3.2.19 A database should be provided on the industrial computer / HMI which shall be archive data for a minimum of 100 runs.

3.2.20 The HMI shall be a touch screen for operator actions.

3.2.21 The HMI shall allow the following: A. To Start / Stop a Recipe B. To Allow Input Of Operator Password. C. To Allow Creation, Editing And Deletion Of Recipes. D. To Allow downloading of Recipes To The PLC. E. To Acknowledge And Reset Equipment Alarms. F. To Allow Error Recovery In The Event Of Equipment Failure.




3.2 Operator Interface Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.2.22 The equipment shall be provided with a maintenance mode. Maintenance mode shall allow the following to be undertaken as a minimum:

A. To Allow Jog Of All Equipment Drives. B. To Allow Operation Of All Components manually C. Select specific maintenance recipes for draining, cleaning, rinsing, etc. D. Instrument Calibration.

3.2.23 The following push button controls shall be provided as a part of the HMI to allow operation of the equipment:

A. Start button B. Stop button C. Reset button D. Pause or Hold button

3.2.24 The HMI shall provide a printable version of the batch reports and reference data.

3.3 Electronic Record and Reporting Requirements

3.3 Electronic Record Requirements Will Comply

Will Not Comply

Comments

Item:

3.3.1 The system shall provide a batch report at the completion of a solution run and keep track of each batch lot number, stock lot numbers used.

3.3.2 The system shall track the lot numbers for all stock solutions and have materials traceability for production buffer solutions.

3.3.3 The system shall maintain all maintenance set point values.

3.3.4 The system shall maintain all operations set point parameters.

3.3.5 The system shall maintain an Alarm and paused system log.

3.3.6 The system shall maintain an audit trail of all user actions.

3.3.7 The system shall provide the capability to review the audit trail on the screen and have screen print capability.

3.3.8 The audit trail shall have the capability to be filtered on any of the data fields contained in the acquired information. Any filters applied shall be shown when the audit trail is displayed or printed.

3.3.9 Upon completion of a batch the system shall automatically generate a process report.

3.3.10 Process reports shall be secured against alteration.




3.3 Electronic Record Requirements Will Comply

Will Not Comply

Comments

Item:

3.3.11 The following shall be recorded for the batch records: A. Batch Information shall be shown on the header section of each page

including at a minimum: File Name, Batch Number, Recipe Name / Information, Buffer Name, Batch Start / End Time.

B. Lot numbers for all stock solutions C. Critical process parameters (pH, Conductivity, flowrates, temperature,

etc.) D. Alarms

3.4 Security Requirements

3.4 Security Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.4.1 The HMI PC system shall utilize password control to access functionality. to meet the following requirements as a minimum:

A. The security system shall employ two identifiers for each user - username and password. User name shall be unique to one individual and never be reused.

B. The password shall not be readable on the display when entered. C. Password aging shall be used and be configurable. D. The security system shall have a minimum of 4 security levels. E. Login and Logout capability shall be available from all screens except

displayed forms. F. The passwords shall be a minimum of 6 characters in length. G. The software shall start up with no user logged on, or default to a system

user that prohibits any control functions. H. A user shall be logged on to perform any control. Viewing of screens can

be performed without a user logged on. I. If there is no activity by the current user logged on for 10 minutes (or

another desired configurable period) then an auto logout shall be executed.

3.4.2 Four levels of security shall be provided – Operator, Supervisor, Maintenance, and Administrator.




3.4 Security Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.4.3 The Operator user shall be permitted to undertake the following: A. View production settings and batch records. B. Acknowledge the informative message boxes. C. Documentation of recipe selection via an assigned report number D. View the screens of the recipe editor, run the selected recipe. E. View alarm log, acknowledge and reset alarms. F. View batch data. G. Complete actions such as Recipe Select, Start, Stop, Pause, etc.

3.4.4 The Maintenance user shall be permitted to undertake the following: A. View production settings and batch records. B. Acknowledge the informative message boxes. C. Sensor calibration D. Functional testing E. Setup the PID loop parameters and engineering parameters.

3.4.5 The Supervisor user shall be permitted to undertake the following: A. View production settings and batch records. B. Acknowledge the informative message boxes. C. Create, edit, save or delete a batch recipe to / from the database. D. Download the selected recipe to PLC. E. Setup the PID loop parameters and engineering parameters. F. Execute error recovery. G. Modify the system date & time. H. Copy those alarm and historical data files generated by the skid. I. Configure and save the tag group to show the historical data in table. J. Export the alarms, events, audit trails, historical data or historical trend

data.

3.4.6 The Administrator user shall be permitted to undertake the following: A. All of the above for Supervisor, Operator and Maintenance B. Access the system and security configuration




3.5 Alarms/Error Handling Requirements

3.5 Alarms/Error Handling Requirements Will Comply

Will Not Comply

Comments

Item: Description:

3.5.1 Once an alarm is activated it shall be displayed on the HMI for the user. The user shall need to acknowledge the alarm. If the alarm is still active when acknowledged then the alarm text color shall change. The alarm shall remain on the screen while it exists.

3.5.2 The most current alarms shall be displayed in a banner at the bottom of each of the HMI screens.

3.5.3 It shall be possible to set alarm for WFI break tank level.

3.5.4 It shall be possible to set alarm for Conductivity.

3.5.5 It shall be possible to set alarm for pH.

3.5.6 It shall be possible to set alarm for pressure.

3.5.7 It shall be possible to set alarm for improper valve positions.

3.5.8 It shall be possible to set alarm for temperature.

3.5.9 It shall be possible to set alarm for flow deviation.

3.5.10 It shall be possible to set alarm for flow totalizers.

3.5.11 The following alarm groupings shall be provided on a PLC level: A. Critical B. Non- Critical

3.5.12 Alarms shall be capable of the follow levels A. High High B. High C. Low D. Low Low

3.5.13 Critical alarmed actions shall be logged and traceable in historical batch records.




3.6 Calculations and Algorithms

3.6 Calculations and Algorithms Will Comply

Will Not Comply

Comments

Item: Description:

3.6.1 Once an alarm is activated it shall be displayed on the HMI for the user. The user shall need to acknowledge the alarm. If the alarm is still active when acknowledged then the alarm text color shall change. The alarm shall remain on the screen while it exists.

3.6.2 Parameter sampling rate will be measured every 0.1 seconds and recorded every 1 seconds. The intent is to ensure that out of specification material is diverted to drain.

3.6.3 Flow rate, pH and conductivity criteria will be provided for each recipe and the criteria will be applied in a cascaded manner, meeting the flow rate first and then meeting the pH and conductivity criteria. When all the criteria have been met and stably maintained for a user defined duration (seconds), the flow will be directed to process.

3.6.4 Programming should be provided to allow for a filtering approach, such as moving average over a user defined duration (seconds), to determine an out of specification condition and to direct the flow to waste.

3.6.5 A minimum of 100 recipes will be available in stored status with ability for the PLC to hold 20 active recipes.

3.6.6 Recipe provided by the user will contain the mass fraction of each component in the final solution. The HMI /PLC code will determine the flow rates based on the Stock concentration (provided by the user) and the target total mass flow rate.

3.6.7 Stock solution concentration and location of each connected stock will be provided by the user and should be stored and the amount decremented based on totalizer value. The remaining amount of the stock should be tracked and alarmed for the user to replace the bag/tank. A new recipe shall not be able to start and should alarm if there is not sufficient stock solution to complete the recipe

3.6.8 Every recipe that is used for making a solution will be locked. Edits will be saved as new recipe.




4.0 MECHANICAL REQUIREMENTS 4.1 General Mechanical Requirements

4.1 General Mechanical Requirements Will Comply

Will Not Comply

Comments

Item: Description:

4.1.1 All materials of construction used in the equipment shall be designed and constructed to be suitable for operating temperatures of 2 - 100°C.

4.1.2 The equipment shall be ergonomically designed to allow for ease of operation and maintenance.

4.1.3 All metallic product contact surfaces shall be mechanically polished to 20 in RA,

followed by electropolishing.

4.1.4 The Supplier shall provide material certification data for all materials that comes in direct contact with stock solutions and buffers.

4.1.5 The Supplier shall provide documentation certifying that all materials used in any component which contacts liquid or gas that ultimately will contact the buffer or the buffer environment, meets or exceeds the minimum requirements as set forth in these specifications and referenced standards.

4.1.6 The systems support vessel, control cabinet and exterior framing shall be will be constructed of 304L stainless steel or better.

4.1.7 All components shall be of a hygienic design and meet the minimum requirements of ASME BPE.

4.1.8 All wetted components and materials of construction must be reviewed for materials compatibility with all stock solutions included in the Appendix B buffer list.

4.1.9 The systems wetted parts which are plastic shall be compliant with USP Class, VI requirements. Documentation shall be provided for extractables from the supplier and should meet the “Standardized Extractable Protocol for Single Use Systems in Biomanufacturing” Pharmaceutical Engineering Nov-Dec2014 as authored by BPOG

4.1.10 All components are to be free of animal derived materials. Certification to confirm is required.

4.1.11 All elastomers used shall comply with FDA guidelines.

4.1.12 All materials of construction shall be nonporous, non-shedding, smooth surfaced, and shall be free from cracks, crevices, and ledges.

4.1.13 Exposed painted surfaces shall not be permitted on the equipment.




4.1 General Mechanical Requirements Will Comply

Will Not Comply

Comments

Item: Description:

4.1.14 During manufacture, the Supplier shall be responsible for protecting all exposed / finished surfaces of the equipment from mechanical damage.

4.1.15 All bearings shall be pre lubricated, sealed and require no external lubrications. Where external lubricants have to be used (with the written approval of the Purchaser), no leakage of lubricants shall be permitted.

4.1.16 All internal corners of the skid shall be rounded for easy cleaning (Min. radius on all corners shall be ½”).

4.1.17 All welding shall be performed by certified welders in accordance with applicable codes and ASME BPE Standard. All Welds shall be polished smooth.

4.1.18 All operator interface features for equipment adjustment shall be clearly identified with permanent labels. The labels shall not be affected by the routine cleaning of the equipment.

4.1.19 The equipment shall be constructed to enable ease of installation, disassembly for maintenance, servicing and cleaning.

4.1.20 Any item requiring maintenance shall be arranged in a manner that will allow easy access and removal / repair.

4.1.21 All sensors with displays shall be located at the perimeter of the equipment. If a display cannot be located in this manner it shall be arrange in a way that will allow easy viewing from the equipment perimeter.

4.1.22 All instruments and devices shall be tagged with stainless steel tags and secured using chains.

4.1.23 The equipment exterior shall be cleaned and/or sanitized periodically. All materials of construction for the equipment shall be compatible with and shall not absorb the following common pharmaceutical process equipment cleaning and sanitizing agents. Including (but not limited to): Sporklenz, IPA, LPH, VHP, Vesphene, and WFI.

4.1.24 The system should operate on 60 Hz power.




5.0 SAFETY REQUIREMENTS

5.1 General Safety Requirements

5.1 Safety Requirements Will Comply

Will Not Comply

Comments

Item: Description:

5.1.1 Power loss recovery shall be to a safe state.

5.1.2 The system must be Lock Out Tag Out (LOTO) ready.

5.1.3 The equipment shall be provided with emergency stop buttons in all potential operator areas. The emergency stop buttons shall be highly visible and readily accessed without obstruction from each potential operator interface. When activated, the emergency stop button shall terminate the operation of the equipment immediately and where appropriate stored energy shall release. (Emergency Stop Strategy should be explained by the system supplier and agreed with the operators, during design phase)

5.1.4 Pressing E-Stop shall stop all active devices.

5.1.5 The emergency stop shall be of a “push/pull mushroom head” design with cover that prevents accidental actuation and shall be readily accessible from all normal working locations. A manual reset shall be provided.

5.1.6 Electrical panels shall include an approved locking disconnecting means for all electrical sources and be capable of being secured in the zero energy state.

5.1.7 In the event of an emergency stop affecting the function / restart of the equipment, the HMI / PLC system shall be provided with manual error recovery mechanisms to allow the equipment to be reset to its starting position.

5.1.8 After emergency stops and cycle stops, the restart of the equipment shall be manually initiated. Automatic restart of the equipment shall not be permitted.

5.1.9 Equipment noise levels shall not exceed 80 decibels 3 feet from the equipment.

5.1.10 General guarding design shall prevent personnel from reaching above, under, through or over guards to contact or reach a hazard area/zone.

5.1.11 All access panels shall be interlocked to prevent operation of the equipment if they are open or incorrectly secured.

5.1.12 Each pump shall be equipped with a pressure switch to enable a high pressure critical alarm that stops the pump.

5.1.13 Where applicable material Safety Data Sheets shall be provided with all oils, chemical and cleaning materials provided by the Supplier to operate or clean the equipment.




6.0 EQUIPMENT TESTING

6.1 Testing Requirements

6.1 Factory Acceptance Testing Requirements: Will Comply

Will Not Comply

Comments

Item:

6.1.1 The Supplier shall provide the necessary utilities to allow the equipment to be operated at production conditions during the FAT.

6.1.2 The Supplier shall calibrate all instruments on the equipment before the FAT commences.

6.1.3 The FAT shall be executed to a Purchaser prepared FAT Protocol.

6.1.4 The FAT may take up to 1 week of testing to complete

6.1.5 All programming shall be complete and ready to run at FAT. Skid should be able to be run not only in manual mode, but also all PID loops tuned, and recipe(s) built and run at FAT.




APPENDIX A – Vendor Documentation Requirements (VDR) List

Required with

Quote

Data for Approval

Data for FAT Required for ETOP

Will Comply

Will Not Comply

Comments

Item Data and Drawings Required Y/N Y/N WKS ARO

Y/N WKS PFAT

Y/N

A Drawings

A-1 General Arrangement Drawings N Y 4 Y 0 AS

A-2 Flow Diagrams or P&IDs Y Y 4 Y 0 AS

A-3 Schematic Piping Diagrams N Y 4 Y 0 AS

A-4 Foundation Diagrams, Loading Requirements and Seismic Design

N Y 4 Y 0 AS

A-5 Catalog Information of Supplied Components Y N N/A N N/A Y

A-6 Detail/Shop Drawings for Components N Y 8 Y 0 AS

A-7 Variable Frequency Drive (VFD) Data Sheet N Y 4 Y 0 AS

A-8 Power and Control Panel Drawings N Y 4 Y 0 AS

A-9 Power and Control Wiring & Pneumatic Diagrams and Schematics

N Y 4 Y 0 AS

A-10 Instrument Installation Details N Y 8 Y 0 AS

A-11 Assembly and/or Arrangement Drawings N N N/A Y 0 AS

A-12 Instrument Location Drawings N Y 8 Y 0 AS

A-13 Instrument Loop Drawings N Y 8 Y 0 AS

A-14 System (Skid) Interconnection Details N Y 4 Y 0 AS

A-15 Spray Ball Map N Y 4 Y 0 AS

B Schedules

B-1 Preliminary Production Schedule Y N N/A N N/A N

B-2 Wt List of Fabricated Parts for Erection, Unit Shipping wt., Erected wt.

N Y WS N N/A N

B-3 Installation and Start-up Plan N N N/A Y 0 AS

C Calculations and Data Sheets

C-1 Utility Requirements N Y 4 Y 0 AS

C-2 Allowable Moments and Forces on Nozzles N Y 8 Y 0 AS

C-3 ASME Code or Applicable Design Code Calculations N Y 8 Y 0 AS




Required with

Quote

Data for Approval


Will Comply

Will Not Comply

Comments


Y/N WKS PFAT

Y/N

C-4 Equipment Calculations and Performance Curves (including instruments, equipment, and specialty devices)

N Y 8 Y 0 AS

D Lists and Indices

D-1 Recommended Spare Parts List N N N/A Y 0 AS

D-2 Bill of Materials (Parts List w/part numbers) N Y 4 Y 0 AS

D-3 Drawing List N N N/A N N/A N

D-4 Instrument List N Y 4 Y 0 AS

D-5 Equipment List N Y 4 Y 0 AS

D-6 Valve List N Y 4 Y 0 AS

D-7 I/O Schedule N Y 4 Y 0 AS

D-8 Alarm and Interlock List N Y 4 Y 0 AS

D-9 List of Special Tools for Maintenance and/or Operation

N N 8 Y 0 AS

D-10 Product Contact Materials-Parts List N Y 4 Y 0 AS

E Manuals and Reports

E-1 Installation, Operation and Maintenance Manuals N N N/A Y 0 AS

E-2 Leak Test Reports N Y PFAT Y 0 AS

E-3 ASME or Applicable Design Code Certificates/Stamps/Reports

N N N/A Y 0 AS

E-4 Inspection Report N N N/A Y 0 AS

E-5 Factory Calibration Certificates (NIST traceable) for Instruments

N N N/A Y 0 AS

E-6 Passivation Procedure N N N/A Y 0 AS

E-7 Riboflavin Procedure N N N/A Y 0 AS

E-8 Cleaning Procedure N N N/A Y 0 AS

E-9 Vendor's QA/QC Plan N N N/A Y 0 AS

E-10 Boroscope Inspection Report and Video Documentation of Hygienic Welds

N N N/A Y 0 AS

E-11 Surface Finish Report N N N/A Y 0 AS

E-12 Electropolish Report N N N/A Y 0 AS




Required with

Quote

Data for Approval


Will Comply

Will Not Comply

Comments


Y/N WKS PFAT

Y/N

E-13 Passivation Report N N N/A Y 0 AS

E-14 Calibration Instructions with Instrument Ranges, Accuracies and Tolerance

N N N/A Y 0 AS

E-15 Cleaning Report N N N/A Y 0 AS

E-16 Filter Certifications N N N/A Y 0 AS

E-17 VFD Configuration Files N N N/A Y 0 AS

F Welding File Documents

F-1 Weld Records (weld map, weld log, examination & inspection log)

N N N/A Y 0 AS

F-2 Welding Procedure Specification (WPS) N N N/A Y 0 AS

F-3 Procedure Qualification Record (PQR) N N N/A Y 0 AS

F-4 Welder Performance Qualification (WPQ) N N N/A Y 0 AS

F-5 Purge Gas Certificates N N N/A Y 0 AS

F-6 Weld Machine Calibration Reports N N N/A Y 0 AS

F-7 Welding Operator Performance Qualification (WOPQ) N N N/A Y 0 AS

F-8 Material Test Report (MTR) N N N/A Y 0 AS

F-9 Weld Coupons/Logs N N N/A Y 0 AS

F-10 Weld Wire/Rod Material Datasheets N N N/A Y 0 AS

F-11 Weld Examiner/Inspector Qualification N N N/A Y 0 AS

G General Documents

G-1 Functional Design Specification (FDS) N N N/A Y 0 AS

G-2 Hardware Design Specification (HDS) N N N/A Y 0 AS

G-3 Software Design Specification (SDS) N N N/A Y 0 AS

G-4 Software Source Code/Ladder Logic N N N/A Y 0 AS

G-5 FAT Protocol N N N/A Y 8 N

G-6 Executed FAT Protocol N N N/A N N/A Y / WS




ABBREVIATIONS NOTES PFAT Prior to FAT 1. All submittals must be marked with the Project Name, POFAT Post FAT Purchase/Contract Order Number and VDR Item Code. PS Post Shipment WS With Shipment or at time of shipment 2. All documents shall be submitted in native format ARO After Receipt of Order (.xls, .dwg, .doc, CAD, etc., preferred) and/or PDF AS "as built" P Print (Hard copy) 3. All documentation is to be as complete as possible for review E Electronic copy prior to customer FAT.




APPENDIX B – Buffer List

Buffer Stock 1 Stock 2 Stock 3 Stock 4 Stock 5 Stock 6 pH WFI

50mM Sodium Phosphate 2M Sodium Phosphate

Monobasic 3M NaOH 7.4 Yes

50mM Sodium Phosphate, 500mM NaCl

2M Sodium Phosphate Monobasic

3M NaCl 3M NaOH 7.4 Yes

50 mM Sodium Phosphate, 3 M Ammonium Sulfate


4M Ammonium Sulfate

3M NaOH 7.0 Yes

50 mM Sodium Phosphate, 1 M Ammonium Sulfate


4M Ammonium Sulfate

3M NaOH 7.0 Yes

50 mM Sodium Phosphate, 0.250 M Ammonium Sulfate


4M Ammonium Sulfate

3M NaOH 7.0 Yes

50 mM Acetic Acid 3M Acetic Acid 3.1 Yes

0.1 M Acetic Acid 3M Acetic Acid 5.0 Yes

1.5 M Acetic Acid 3M Acetic Acid Yes

50 mM Tris-Acetate, 50 mM NaCl 3M NaCl 2M Tris 3M Acetic Acid 8.0 Yes

50 mM Sodium Acetate, 50 mM NaCl 3M NaCl 3M Acetic Acid 3M NaOH 5.0 Yes



0.1 N NaOH, 0.1 M NaCl 3M NaCl 3M NaOH Yes

0.1 M NaOH 3M NaOH Yes

0.5 M NaOH 3M NaOH Yes

1.5 M Tris base 2M Tris Yes

50 mM Sodium Acetate, 2% Benzyl Alcohol

Yes




APPENDIX C – Components List




APPENDIX D – P&ID


References

1 This work was performed under financial assistance award 70NANB17H002 from the U. S. Department of Commerce,

National Institute of Standards and Technology

2 Biomanufacturing Technology Roadmap, First Edition. BioPhorum. 2017.

3 Levine L. Perspectives on Continuous Processing. BPI Boston. Sept 2017.

4 A Single-use Strategy to Enable Manufacturing of Affordable Biologics. Comput Struct Biotechnol J. 2016. 14: 309–318.

5 Fabbrini D, Simonini C, Lundkvist J, Carredano E and Otero D. Addressing the Challenge of Complex Buffer Management An

In-Line Conditioning Collaboration. BioProcess International, 15(11), pp. 43-46. 2017

6 Biomanufacturing Technology Roadmap, First Edition, Modular and Mobile Chapter. BioPhorum. 2017.

7 Matthews T, Bean B, Mulherkar P and Wolk B. An Integrated Approach to Buffer Dilution and Storage. Pharma

Manufacturing. Accessed 2018 https://www.pharmamanufacturing.com/articles/2009/046/

8 Malone T and Li M. PAT-Based In-Line Buffer Dilution: Serving the Paradigm of Quality By Design. BioProcess International

8(1):40-49. January 2010.

9 The economic evaluation of buffer preparation philosophies for the biopharmaceutical industry BioPhorum, 2019.

10 BioPhorum Extractable and Leachable Paper. BioPhorum. 2016.

11 https://bioprocessintl.com/2016/outsourcing-buffer-preparation-activity-increasing/


Acronyms Definition

DSP Downstream processing

FAT Factory acceptance testing

cGDP Current good design practice

cGMP Current good manufacturing practice

JIT Just-in-time

mAb Monoclonal antibody

NIIMBL National Institute for Innovation in Manufacturing Biopharmaceuticals

PAT Process analytical technologies

WFI Water for injection

Acronyms


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DisclaimerThis document represents a consensus view, and as such it does not represent fully the internal policies of the contributing companies.

Neither BioPhorum nor any of the contributing companies accept any liability to any person arising from their use of this document.

The views and opinions contained herein are that of the individual authors and should not be attributed to the authors’ employers.