SUCCESS STORY ON

PRODUCTION SHUTDOWN

Fast-Track Consult
on Qualification & Validation
for Increased Capacity
 With the expertise of the Biotech Quality Group (BQG),
a major pharmaceutical company successfully started up
a new production line, while dramatically shortening
the required shutdown period and achieving high compliance
in the quality and documentation requirements, following the
verification approach according to the ASTM E2500.
BACKGROUND

In pharmaceutical manufacturing, shutdown periods of production operations affect

time to market, manufacturing capacity, supply of product, manufacturing cost, and
profitability. Impacted stakeholders are the company and patients.

A major pharmaceutical company needed to increase the production capacity of

an antihemophilic factor, its flagship biotechnology product. In order to do so, the
company had to build a new production line, while shutting down the whole facility
until the new line (B) was up and running.

The pharmaceutical company hired the Biotech Quality Group (BQG) to shorten the
duration of the shutdown (i.e., complete stop of production operations) and ensure
proper start-up of the new line. As there is no substitute for the recombinant factor,
supply of the therapeutic biological is essential for patients with a severe disease.
This business case describes BQG’s successful trimming of the shutdown period by
using a dynamic approach, yet achieving high quality requirements.

CHALLENGE

Need for shorter duration of shutdown

The pharma company faced a tight deadline. To increase and continue the
supply of the market in recombinant antihemophilic factor, the pharmaceutical
company had to upgrade its production line A before its new line B was up
and running. The shutdown period originally was planned to be 36 weeks.
BQG’s ambition was to shorten the duration of the shutdown to reduce the
postponement of the therapeutic, which is key for patients with the severe
disease. Manufacturing cost of labor, equipment, and documentation, as
well as product revenue for the pharma company, also were impacted.
Therefore, trimming the shutdown period was essential.

BQG’S SOLUTION

Conduct fast-track project utilizing proprietary, ready-

to-use tools, templates, and processes and incorporating
ASTM E2500.

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Before any work could be done, BQG had to assess the readiness and
maturity of the pharma client to support a fast-track, ASTM E2500 based
project. A maturity assessment was performed by BQG following the
Apollo MaturityTM model designed specifically to measure the maturity of
verification practices. As a result of the assessment, a set of actions were
defined and implemented to ensure the client had the pre-requisites to use
BQG’s methodology.

BQG’s objective was to reduce the duration of shutdown from 36 to 20

weeks. The shorter shutdown period represented a 45% reduction of the
product’s time to market.

Finding a feasible solution was a challenge due to the following issues,

which had never been integrated into a single project before :

Drastic optimization of the schedule with all the stakeholders.

Change in shifts of pharma workers over several months.

Incorporation of a new qualification methodology :

the ASTM E2500.

Continuous follow-up/management of projects by advisors.

BQG commitment on results via a fixed-price contract.

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To realize the commissioning and the qualification of the production line of
the recombinant factor in maximum 20 weeks, BQG deployed a fast-track
project, including a complete package of BQG ready-to-use tools, templates,
and processes. BQG, whose advisors were located at the pharma’s facility
during the project, committed to achieving pre-defined results within a pre-
specified timeframe.

BQG adopted a dynamic qualification approach involving the ASTM E2500,

instead of the classical V-cycle qualification approach. The ASTM E2500 is
an innovative, risk-based and science-based approach to the specification,
design, and verification of manufacturing systems and equipment that have
the potential to affect product quality and patient safety. In collaboration with
all partners, the timeframe for the shorter shutdown period was agreed upon.

The project was accomplished in two phases :

A preparation and development phase involving commissioning,

1 writing the risk-based quality and performance documents
including product qualification, and preparing for the shutdown
period. This phase was conducted from July 2015 to January
2016. ASTM E2500 concepts were utilized. BQG’s staffing
involved 10 experts’ advisors in charge of the writing of protocols
and SOPs according to ASTM E2500 and the pre-writing of
reports. BQG partnered with a process engineering firm for the
planning, building, and installation, as well as collaborating with
the pharmaceutical client. Daily meetings and reports facilitated
communication between all involved parties.

A performance phase, including qualification of product and

2 execution documents, was accomplished, starting in February
2016 and ending in June 2016. BQG increased its staffing of
advisors to work on 4 fronts : automation, equipment, CIP/SIP and
project management. ASTM E2500 practices and daily meetings
and reports were implemented in partnership between BQG and
the pharmaceutical client.

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The steps for the shutdown of the line at the facility involved :

1 2 3
Building,
Decommissioning Modification
assembly, and
of some existing of some existing
construction of
installations. installations.
new installations.

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5 Standard
4 Bringing the
approach such
as Installation
shutdown into
Development Qualification
service during 3
of the cycles (IQ), Operational
8-hr shifts daily,
Clean-In-Place (CIP) Qualification (OQ),
including weekends,
and Sterilisation-In- Performance
in order to cover
Place (SIP). Qualification (PQ)
most of the possible
were replaced by
hazards.
ASTM fast track
practices.

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7
Verification of 9
CIP/SIP, and
Good Manufacturing
process, according
Practice (GMP) Shutdown
to the ASTM
operation procedures.
E2500 check
and change
mode.
management.

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Figure 1 summarizes the ASTM E2500 components for verification of GMP
operation and change management.
Figure 1: The specification, design, and verification process

Good engineering practice

Product
knowledge

Process
knowledge
Specification Acceptance
Requirements and design Verification and release Operation
Regulatory

Company
quality
Risk management

Design review

Change management

Figure 1: The specification, design, and verification process (source : ASTM E2500 – 07)

BQG utilized the following tools on the project :

BQG’s proprietary Quality Risk management tool, at the

heart of BQG’s verification approach.

Daily organizational meeting on qualification of installation

testing (QIT).

Turnover meeting for updating the next shift team.

Collaborative meeting with project leaders.

SharePoint, an internal website for sharing information

among the team.

Steerco (visual sharing of project information).

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Figure 2 displays the timeline for the various components of the project,
including :

Mechanical installation and passivation (cleaning process

for equipment).

Static SAT, installation validation, operational validation, and

validation of SIP and CIP.

SD of utilities.

Dynamic SAT, verification of operational validation (OV),

PQ, SIP PQ, build-up for release of product, and release.

Next batch of product.

Encountered issues:
18 weeks planned timeline

Mechanical installation/ SAT static/Verification SD Utilities SAT Dynamic/Verification Start of first campaign
Passivation INOV/Validation SIP and CIP OV/PQ
Steam
exchanger
TC2
explosion 01.03.2016 01.04.2016 01.05.2016 01.06.2016 01.07.2016
Air presence
in site steam
Condensate generator
presence
in steam Mechanical installation/ SAT static/Verification SD Utilities SAT Dynamic/Verification First lot
distribution Passivation INOV/Validation SIP and CIP OV/PQ SIP/PQ
line
20.8 weeks real timeline
Liberation Liberation
build up B12/B92

Figure 2 : Project Timeline

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 RESULT

Successful reduction of duration of shutdown to

20 weeks.

The following figure shows the status of specific accomplishments during the
project :

600

600 400
503 Deviations
Results
• 842 tests were conducted 417 200 174
400 141 CIP
• Right the first time: 600
38
- 83% of equipment tests
- 81% of CIP tests 200 0
- 47% of SIP tests 400
• Recorded and corrected:
- 342 differences in SAT 0
- 166 deviations 200 165
77

Equip. 0
51

SIP
77
Planned run
Executed run

Figure 3 : Results

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The project resulted in :

Revision of
Well detailed Good preparation
qualification
standard operating of requirement
procedures
procedures (SOP) of each SIP
according to ASTM
and CIP. protocol.
E2500 achieved in
record time.

Good anticipation Good

of redaction and collaboration
Preparation
approval of with the quality
of all reports.
protocols before the team during
execution phase. execution phase.

Successful
reduction of
shutdown All reports
duration to the produced.
project goal of 20
weeks.

IMPACT

Expertise in quality, project management, and teamwork resulted in a

dramatically shorter shutdown period, benefiting the pharmaceutical
company and patients.

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Successful accomplishment of the shorter shutdown period ensured :

Quicker start of next lot of product, thereby providing

higher capacity and faster time to market.

Continued supply of recombinant therapeutic, benefiting

patients and the pharma company.

Reduction in cost of manufacturing a biological.

Increased profitability (reduced cost and greater revenue)

for the pharma company.

BQG’s case study in qualification and verification demonstrates :

Achievement of planned goals in a fast-track project.

Teamwork and perseverance of all parties.

Favorable coaching of the client team by BQG.

BQG’s expertise in quality, verification, and project

management methods.

BQG’s maturity in collaborating with a commissioning firm

and consulting to pharmaceutical companies.

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