Continued Process Verification in

ALK A/S

How to handle part 3 of the validation life cycle?

Linda Bech Pihl, Senior chemist at ALK

Short presentation
M.Sc. Civilengineering, 1994-1999
Immunology Oct. 1993

2006 - ?? Test method validation 1999 - 2005

Test equipment qualification

2004 - 2013

Risk Assessment
Process validation Computer System Validation
Continued Process Verification

Process equipment qualification

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Companies

• 1994 - 2002 ALK A/S (Pharmaceutical)

• 2002 – 2006 Novo Nordisk A/S (Pharmaceutical)
• 2006 – 2010 Coloplast (Medical device)
• 2010 - ?? ALK A/S (Pharmaceutical)

• Six sigma black belt training completed 2009

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Process validation life cycle

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Guideline US - the beginning of CPV

Process Validation Guide, Jan-2011

“Process validation is the collection and evaluation of data from the
process design stage throughout production, which establishes scientific
evidence that a process is capable of consistently delivering quality
products”

The goal of the third validation stage is continual assurance that the
process remains in a state of control (the validated state) during
commercial manufacture

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf

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Guideline US
An ongoing program to collect and analyse product and process data that
relate to product quality must be established.

The data collected should include relevant process trends and quality of:
• incoming materials or components
• in-process material
• finished products.

The data should be statistically trended and reviewed by trained

personnel. The information collected should verify that the quality attributes
are being appropriately controlled throughout the process.

We recommend that the quality unit meet periodically with production staff to
evaluate data, discuss possible trends or undesirable process variation, and
coordinate any correction or follow-up actions by production.

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How to implement CPV?
US: Procedures should describe how trending and calculations are
to be performed and should guard against overreaction to an
individual event

A SOP must be established defining:

1. Prerequisite
2. State of control
Variation
Overreaction
Capability
3. CPV activities
Protocol
Sampling
Periodic assessment incl. participant
Report

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1. Pre-requsisties for CPV

• Risk assessment has been performed

• Control strategy has been written and approved
• Success full PPQ has been performed

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2. State of control - variation
Knowledge of process variation – common or special cause

• Common cause variability can be reduced, but can not be eliminated

• Special cause variability is based on special root causes and can be

eliminated. You might use 5 x WHY

Control Charts are the only tools to

differentiated between common and special
cause variability

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2. State of control - variation
11,5

A pattern that may be seen over time. 10,5

Data points
Center line
Example 1 shows a stable process without 9,5 LCL

any data points outside the limits and it 8,5

UCL
1 3 5 7 9 11 13 15
contains only common cause variation.
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Example 2 contains two data points outside 11 Data points

10 Center line
the limits and the cause leading to them 9 LCL

should be investigated. 8
UCL
1 3 5 7 9 11 13 15

Example 3 although all the data points are 11,5

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within the limits a trend is observed and the 10,5 Data points
cause of trend should be investigated 10 Center line
9,5 LCL

9 UCL

Prevent overreaction 8,5

1 3 5 7 9 11 13 15

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2. State of control - process capability
Process capability is the repeatability and consistency of a manufacturing
process relative to the requirements in terms of specification limits (LSL
and USL) of a product parameter. This measure is used to objectively
measure the degree to which a process is or is not meeting the
requirements.

Cp is a simple process capability index that relates the allowable spread of

the spec limits (difference between the USL, and the LSL) to the measure
of the actual, or natural, variation of the process, represented by 6 sigma
(σ), where sigma is the estimated process standard deviation.

The Cpk compares the distance of the mean of the process to the nearest
specification limit with the process variation, and any number above 1,33
illustrates that there are at least 3 standard deviations from the mean to
nearest specification limit.

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 3. CPV activities
The validated state obtained from the PPQ is to be maintained by a series
of activities during the period the product is on the market.

The key element of the CPV is documented reviews of the process

performance. Conclusions drawn from these reviews may lead to an
update of the CPV-protocol.

The documented reviews also give a documented evaluation of impact of

changes to the process and can identify opportunities for process
improvement together with PQR.

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3. CPV activities - protocol content
Purpose
Continual assurance that the process remains in a state of control (the
validated state) during commercial manufacture
Prerequisite
Finalized PPQ, Control strategy incl. risk assessment
Responsible
Production- establish protocol, statistically trained, prepare for CPV
meetings
QA – participate in CPV meetings, evaluate data, discuss possible trends
or undesirable process variation, and coordinate any correction or follow-
up actions
Interval
Periodically- based on a risk assessment

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3. CPV activities - protocol content
Method for detection variation and capability
Control charts, trend rules, Cpk calculation, inter and intra batch variation
- Start by defining which CPP’s, IPC’s and CQA’s are included
Data
Samples from incoming materials, In-process and finished product
Handling of observations
Use change request system implemented in the firm

Sampling
Define whether extended sampling are needed

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 3. CPV activities - protocol content
Practical example

Products, changes and Equipment, utilities

deviations, see section and facility, see section
CPV for XXX drug substance
10 9

Extended
Control charts, see SOP updates, see Holding time study,
sampling, see
section 12.1 section 12.2 see section 13.9
section 14

CPP, se section 11.1

IPC, se section 11.2

CQA, se section 11.3

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3. CPV activities - protocol content
Protocol example:
Section 9: Equipment, Utilities and facility

Equipment, Utility and facilities are not included in this CPV.

Manufacturing of XXX is a legacy process. Equipment was qualified at
retrieval [17;24;31] and yearly calibration and maintenance is performed
[25]. Further regular equipment reviews are performed [17;24;31].
Manufacturing takes place in existing facilities, qualification status can be
found in department validation plan [17;31]. The manufacturing environment
is in control in accordance with [18;19]. WFI and clean steam systems are
controlled, see [20]. Pressurized air is in control [21].
An overview of equipment, utility and facilities is listed in the control strategy
[11].

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3. CPV activities - protocol content
Protocol example
Section 10 - Product, Changes and Deviations
OOS/OOT, deviations and CC-cases related to the manufacturing
process are evaluated in the PQR [22;23], this is evaluated to be
sufficient for securing process control with regard to these parameters.

Evaluation of incoming source material is not part of the PQR, and hence
will be incorporated in the CPV. During yearly CPV all new batches of
source material must be listed [1].

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3. CPV activities - protocol content
Protocol example

• Section 14 – Extended sampling

• Describes in details extended sampling to perform during CPV (e.g
intrabatch variation)
• Section 13.9 - Holding time study
• During risk assessment and PPE work –inadequate holding time
studies (cGMP) were identified, this section describes how to
generate holding time data.
• Section 12.2 – SOP update
• During risk assessment and PPE work, the need for collection of
more parameters were identified. This section describes which
procedures to update to secure data collection going forward.

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 3. CPV activities - protocol content
Protocol example
Control charts – CPP’s (and IPC’s and CQA’s)

Process Process
Input Purpose of CPV Comment
Step Parameters
(1) In [5] a control limit of 15.56 – 16.38
Dissolution g SM was calculated, based on 25 Batch Size (input of
data points. This is as stated in [1] SM), see section 13.1
Batch size enough data for final control limit,
Report SOP update, see
(input of SM) hence purpose of CPV is to
implement control limits in section 12.2
manufacturing SOP’s, and as a Control Chart, see
control chart. section 12.1.
It’s a manual shaking, so enhanced
Stirring speed control will be added by including
SOP update, see
during Protocol check for everything is dissolved,
section 12.2
solution and no foam formation in
manufacturing SOP’s.

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 3. CPV activities - protocol content
Control chart example

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 3. CPV activities - report
Reporting – after each batch

Paper binder in production area – encompassing:

• Sheet for noting all batches including used source materials

• Print out of all control charts
• Test-sheets for extended testing
• Test-sheets for performed training

After each batch data are entered by hand in all control charts, and
sheets for noting batch numbers and source materials, double
control of entered data is performed.

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3. CPV activities - report
Yearly (only yearly for this product due to low manufacturing
frequency)

• Data from all year are entered into excelsheet.

• Data are reviewed and excelsheets are closed for changes (doc.
System)
• Updated control sheets are printed and replaces old control
charts

• CPV report form filled out.

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3. CPV activities - report
Strategy: Make it simple!!!!
The report must be written during the review meeting.

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3. CPV activities - report

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3. CPV activities - report
Recalculation of the final control limits is acceptable if all the
following conditions apply simultaneously:
• The change is positive e.g. tighter limits, higher yield, lower
impurity level
• The root cause is known and acceptable
• There is assurance that the change is going to be permanent
• At least 20 samples confirm the new process (NB! – 20
independent samples)

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Implementation of CPV
- Legacy processes
By Senior Chemist, Linda Bech Pihl, Global Product Support, ALK
What is a legacy process?

Legacy Process A process that has been in commercial use for more
than 2 decades, and where development
documentation according to current standards is not
available

Legacy Product A product that has been manufactured for commercial

use for more than 2 decades, and where product
development documentation according to current
standards is not available

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Challenge
inadequate

Lacking
X
Still expected to fullfill
demands
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Solution?

Use historical knowledge

• 30-40 years of manufacturing experience

• Approx. 20 years welldocumented

experience (In ALK)

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Solution – Drug Substance
Product Validation Plan (PVP) Crit. material

Crit. equipment
Risk
Assessment Crit. Controlled
(Patient safety) documents
CQA
PP
Severity
PPE (vers. 1)
CPP

Retrospective Control
Validation Strategy
(protocol and
report)
IPC
PPE (vers. 2)

CPV protocol and CPV report

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Learnings
• Ease the PQR process (data collection on-going)
• Ease the handling of deviations
• Increased process knowledge for responsible chemist in
production and QA
• Established system for handling of additional samples in a
validated process
• Process capability results have been an eye-opener

• Takes a lot of time to collect data and review data

• Difficult to use the results for process improvements

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Extra slides

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CPV versus on-going process verification
The term continued process verification is used in US and the term on-
going process verification is used in EU.

These terms are considered to be equal.

Ongoing process verification should be conducted

under an approved protocol and a corresponding
report should be prepared to document the results
obtained. Statistical tools should be used, where appropriate, to
support any conclusions with regard to the variability and capability
of a given process and ensure a state of control

Ongoing process verification should be used throughout the product

lifecycle to support the validated status of the product as
documented in the Product Quality Review. Incremental changes
over time should also be considered and the need for any additional
actions, e.g. enhanced sampling, should by assessed.

http://ec.europa.eu/health/files/eudralex/vol-4/2015-10_annex15.pdf
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2. State of control - variation
The typical form of a control charts sets control limits at plus/minus three standard
deviations.

Upper control limit (UCL) = mean + 3 x STD

Lower control limit (LCL) = mean - 3 x STD

That means if the process is in statistical control, the risk of a point falling outside the
limits by chance is 3 per 1000. The process is influenced by chance 99.73 % of all
results do fall within 3 STD

Setting control limits

• At the beginning of CPV there are typically not enough data to set the final
UCL and LCL, the obtained data from the batches produced after PPQ, are
evaluated against interim limits established in PPQ or similar
documentation.
• Interim UCL and LCL limits are recalculated with all data results for the
parameter until it is determined that there is enough data to set the final
limits. This will typically require >20 batches (historical and commercial).

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2. State of control - variation

Statistical rules for control chart

Aberration
or mean
One point is above UCL or below
1. shift.
LCL
Special
cause
Six points in a row, all Trend or
2.
decreasing or increasing drift
Nine points in a row on same
3. Mean shift
side of centerline
If one of this rules apply it indicates the presence of special cause
variability

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