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Transfer of A Manufacturing Process: Case Study Solid Dosage Transfer Within Technical Operations

This document provides an overview of a case study for transferring a manufacturing process for a solid dosage form from a sending unit to a receiving unit. Key aspects summarized include: 1) The product is highly potent and explosive, requiring a detailed transfer process. 2) Statistical process control was used to evaluate the process variability and capability. Process parameters like dissolution and content uniformity showed good control. 3) A cross-functional project team from both companies managed the transfer, which included technology transfer, process validation activities, and establishing process and analytical method control. 4) Risks around regulatory expectations, process improvements, and facility readiness were addressed during the transfer planning and execution. The receiving unit established significant controls and

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100% found this document useful (1 vote)
363 views28 pages

Transfer of A Manufacturing Process: Case Study Solid Dosage Transfer Within Technical Operations

This document provides an overview of a case study for transferring a manufacturing process for a solid dosage form from a sending unit to a receiving unit. Key aspects summarized include: 1) The product is highly potent and explosive, requiring a detailed transfer process. 2) Statistical process control was used to evaluate the process variability and capability. Process parameters like dissolution and content uniformity showed good control. 3) A cross-functional project team from both companies managed the transfer, which included technology transfer, process validation activities, and establishing process and analytical method control. 4) Risks around regulatory expectations, process improvements, and facility readiness were addressed during the transfer planning and execution. The receiving unit established significant controls and

Uploaded by

tvvsagar
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Transfer of a manufacturing process:

Case study ~ Solid dosage transfer


within technical operations
Ian Flawn Orpana
QPharma AB, Sweden

Overview of Product
Product fitted into therapeutic area
Purchased from big pharma
Product:
Highly potent
Explosive
Traditional production

Fig. 1. Schematic of manufacturing operation

Project history/setup
Due diligence
1 day to technically review process
Statisical process control (SPC) to determine variation
Robustness of process

Clarification of scope

Bulk: Transferred CH to UK
Bulk: UK site produced small quantity of batches
Packaging outsourced to TPM
Other sites involved due to regulatory demands of
certain countries

Selection of TPM
Initial overview communication
Showing show stopper issues
No confidentiality agreement
Explosive, potent, volumes, major
process/analytical equipment, bulk volumes &
packaging forms & splits
Proof needed of EU GMP licence

TPMs selected
Knowledge from RUs people
Conferences
Web sites

Detailed scope for TPM


Table of Contents
1
Scope............................................................................................................................ 2
2
Introduction................................................................................................................... 4
3
Tendering Phases........................................................................................................ 5
4
Historical TPM Site GMP Compliance........................................................................ 7
5
Forecast........................................................................................................................ 9
6
Manufacturing ............................................................................................................14
7
Manufacturing Equipment list....................................................................................19
8
Packaging...................................................................................................................20
9
Process Improvements..............................................................................................25
10 Technology Transfer..................................................................................................28
11 Stability .......................................................................................................................39
12 Analytical Testing.......................................................................................................41
13 Logistics......................................................................................................................45
14 Safety..........................................................................................................................46
15 Supporting Activities ..................................................................................................48
Appendices..........................................................................................................................51
(A) GMP Compliance..........................................................................................................51
(B) Preferred suppliers .......................................................................................................51
(C) Manufacturing documents/specifications....................................................................52
(D) Equipment Guidance....................................................................................................52
(E) Packaging specifications..............................................................................................52
(F) Ferring Technology Transfer Guideline.......................................................................53
(G) EMEA Process Validation Guidance document.........................................................53
(H) Process validation.........................................................................................................53
(J) Other manufacturing issues..........................................................................................53
(K) Stability Guidelines .......................................................................................................54
(L) Material Safety Data Sheet...........................................................................................54
(M) Analytical methods API.............................................................................................54
(N) Analytical methods Excipient....................................................................................54
(O) Final Product testing.....................................................................................................54
(P) Ferring SPC Guideline..................................................................................................55
(Q) Draft Agreements .........................................................................................................55
(R) Forecast spreadsheet...................................................................................................56
(S) Sampling Plan ...............................................................................................................56

Criteria for selection


Decision making
technique
Kepner Tragoe
Musts
EU GMP licence
Wants
Rank wants
multiply by
TPMs response

Criteria used

Commitment to quality
Flexibility
Reputation
Scope of resources
(people, equipment,
facility)
Price
Honesty
Financial standing

Experiences
 Spent 6 months finalising TPM
selection process
 TPM pulled out from selection
process on last day
 Serious GMP failure during selection
process
TPMs pulled out immediately giving
clear rationale of why

Project Team
Makeup

Cross functional
Inter company
Intra company
Multi cultural
Multi experienced (high
& low)

Communication
High visibility with Sending
& Recieiving Units
Web/phone meetings
gotomeeting.com

Minutes of meeting &


email confirmation
Central customer
electronic file directory

Project Management tools


Adopted structured approach to Project

Risks
Regulatory approach PAT vs traditional approach
Traditional approach

Process improvements
Minimise for reduction in regulatory effort
Technical report to support all changes
Changes made where significant cost saving could be realised

Review of regulatory file


Identify discrepencies of SU procedures

Timeline of transfer
Build up of safety stock from SU

RU building new production area


Perform number of GMP audits

Process Understanding
Historical review
Used during due diligence
Basis for writing Process Validation

Statistical Process Control


Identify if the process is in control or not
In statisitcal control ~ repeatable & predictable

Determine capbility of process


Process is centred of target (Cp Cpk)
Robust or not (Cp > 1.33)

Examples of parameter assessment

Conclusion & Recommendations


Final product
parameter
Loss
on
drying

 

HIGH

Friability

 

LOW

Mean weight




 
 

LOW
MEDIUM

Strength (g)
b
c
c

Dissolution

Content
of
Uniformity
Assay

Degradation
substances




 
 

Conclusions
Perform the LOD test on the tablets during
compression or a soon after compression as possible.
Recommend that this parameter be kept as a in process
control but is discarded as a final product release
parameter
Process shows excellent control.
The dissolution methodology has two additional steps if
S1 fails, with S2 and then S3 (if S2 fails) tests
becoming active.
During the process validation
attention should be made to distribution of active and
the performance of the dissolution method. This should
be cited within the process validation protocol.

LOW to
MEDIUM




LOW

Process demonstrates good control.

LOW

Process demonstrates good control.

LOW

This is an observation only, it cannot be confirmed


statistically due to low sample numbers.
impurity a no further action

 

Risk

HIGH

impurity b & unknown substances - Contact with


Novartis is recommended to determine any abnormal
situations. This parameter should be evaluated further
during process validation

LOW

Process demonstrates good control.

Process / Procedural changes (1/2)


LOD tested during production
Change of milling technology

Guidance for Industry, SUPAC-IR/MR: Immediate Release and Modified Release


Solid Oral Dosage Forms ~ Manufacturing Equipment Addendum

Process / Procedural changes (2/2)


Removal of in process dissolution
SU performed IPC, x3 hardness & perform
dissolution test
Historical review identified suitable hardness
specification, with confidence that dissolution
would pass

Removal of Industrial Methlylated Spirits


(IMS)
Under direction from regulatory authorities
IMS contains wood derivative

Transfer Process (1/3)


Training from SU
personnel
Developed checklist
based upon ISPE
checklist ~ to gather
all info
Formal anlaytical
method transfer
Placebo batch
Trained
operators/technical
support & RU people
Review 1st BMR

Transfer Process (2/3)


Bracketing review
Lower strength
Similar manufacturing process (1 part)
g API quantities

Upper strength
Similar manufacturing process (2 part)
g API quantities

Historical review
Good degree of statisitcal control
Robust

Conclusion
Lower strength (x1 ag & x2 bg) = 3 batches
Upper strength (x1 cg & x2 dg) = 3 batches

Main events of transfer process (3/3)

Structure of transfer protocols (1/3)


~ Preliminary activities

Review of historical data


BMR update ~ perform LOD testing during compression

MISSED: Review of regulatory file against BMR and analytical


methods
Sampling plans
Rationale derived from SPC
20 sampling occasions with no understanding of process, this may be
reduced to 10 if good data exists

Structure of transfer protocols (2/3)


~Transfer tests acceptance criteria
RU ~ Process in statistical control

RU ~ Meeting release specifications

WEIGHT_EUR_PH
Indivi d.
140

USL

135

130

O
O
O
O
O

ucl

O
O
O

O
O
O

O
O
O

O
O
O

O
O
O
O

O
O
O
O

O
O
O

O
O
O

O
O
O

O
O
O
O
O

O
O
O
O

O
O

O
O

O
O

O
O

O
O
O

O
O

O
O
O
O

O
O
O

cl
Target

O
O

lcl
125

LSL

120
SAMPLE_POINT:
Individ.:
USL: 139.5

cl: 129.8
LSL: 120.1

13

ucl: 133.43

lcl: 126.17

Target: 129.8

17

21
* Rule violation
Subgrp Size 5

RU similar to SU process

Assess of pack performance

Structure of transfer protocols (3/3)


~ Non conformance & further actions

BMR update ~ increase in frequency


of hardness/thickness testing
BMR update ~ reduction in frequency
of friability testing
Low assay ~ monitor future batches
to determine if process is statistically
different than SU

Validation Report

People issues

Language
Cultural
Experience
Technical
Communication
High turnover of people

Responding & communication of changes

Presentation to steering group each month


Budget set following review of TPMs
Close and honest relationship with TPM
Scope clearly identified in contracts
Fact: No matter how well initial risks are
envisaged, project will throw up unplanned
events:
Project team needs to react professionally to
minimise impact

Maintenance of product
Routine management of
TPM
Customer & TPM
All key functions
represented
QC, QA, Logistics,
TechOps, Srn Manager

Guest members
Regulatory, R&D

Meetings
Customer ~ monthly
Customer/TPM ~ yrly
(low)

Fixed agenda

Issues

Packaging
 Yield ~ high # batch changes
 Artwork ~ did not appreciate
complexity
 Scope poorly defined for TPM

Marketing
 Closer, better and flexible
understanding of their needs

Project Management
 Late start to project

Transfer strategy
Well defined and good use of
SPC in understanding the
process being transferred

Project team
Well supported by
management
Team worked well
understanding each others
roles and expertise

Analytical methods
 Significant amount of
variation associated to
methods
 Timelines and effort needed
to perform testing
Excellent support from R&D
Maintenance

Budget and timelines


Set with data not gut feeling

Selection of TPM
TPM honest, ethical &
trustworthy

References
Article or book
Title
Sampling- procedures and charts for
inspection by variables for percent
nonconforming
Control charts - General guide and
introduction
Control charts for arithmetic average
with warning limits

Reference and/or
Year
IS0 3951:1989 (E)
IS0 7870:1993(E)
ISO 7873:1993(E)

Acceptance control charts

ISO 7966:1993(E)

Shewhart control charts

IS0 8258:1991(E)

SPC in the Office, A Practical Guide


to Continuous Improvement
Understanding Statistical Process
Control
Deming Out of the Crisis
Statistical Quality Control Handbook

2000
1992
1982
1984

Author
International
Standard
International
Standard
International
Standard
International
Standard
International
Standard
Mal Owen and John
Morgan
Wheeler, D. J. and D.
S. Chambers
W. Edward
Western Electric

ISPE Good Practice Guide:


Technology Transfer Mar 2003

Thanks
QPharma: R&D, Logistics, Regulatory,
Marketing, QA & Technical groups (D, CH, DK)
RU & SU ~ Confidential

Contact details
ifo@qpharma.se
end

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