Q12 Technical and Regulatory
Considerations for Pharmaceutical
Product Lifecycle Management
Annex

This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person andis not binding on FDA or the public. You can use an alternative approach if it satisfies therequirements of the applicable statutes and regulations. To discuss an alternative approach,contact the FDA staff responsible for this guidance as listed on the title page.

For questions regarding this draft document contact (CDER) Mahesh Ramanadham 301796-3272 or (CBER) Ingrid Markovic 240-402-8115.

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINETechnical and Regulatory Considerations for Pharmaceutical
Product Lifecycle Management
Annex

Q12
Draft version
Endorsed on 16 November 2017
Currently under public consultation

At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate
ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory
authorities of the ICH regions for internal and external consultation, according to nationalor regional procedures.

TABLE OF CONTENTS
ANNEX I: ECs – ILLUSTRATIVE EXAMPLES................................................................. 1
Annex I A: Chemical Product ...................................................................................... 2
Annex I B: Biological Product ..................................................................................... 5
ANNEX II: PACMP – ILLUSTRATIVE EXAMPLES ......................................................... 9Annex II A: PACMP Example 1 .................................................................................. 9Annex II B: PACMP Example 2 ................................................................................ 12
ANNEX III: PRODUCT LIFECYCLE MANAGEMENT DOCUMENT –ILLUSTRATIVE EXAMPLE .................................................................................... 15

1

ANNEX I: ECs – ILLUSTRATIVE EXA/MPLES 1

2

Identification of Established Conditions for the Manufacturing Process

345The examples provided below are intended for illustrative purposes and only suggest how
the ECs concept could be applied using the development approaches described in ICH Q12
Guideline Chapter 3.2.3.1.

6
7

The examples describe the relevant reporting categories for changes to the ranges of the
manufacturing process parameters, controls or equipment referenced in the tables.

8910This demonstrates that increased knowledge and understanding (e.g., enhanced
development approaches) lead to reduction of uncertainty and improved management of
risk. As a result, ECs could become less extensive and reporting categories more flexible.

11

For example:

12
13
14
15

-

Enhanced knowledge may lead to a reduction in uncertainty demonstrating that an
initially determined CPP does not have a direct impact on a CQA. Therefore, it
could be classified as either a KPP (impact on process consistency) or a processparameter (PP).

16
17

-

Risk management activities could lead to downgraded reporting categories e.g.,change to CPP could be downgraded from prior approval to notification.

18
19
20
21
22
23
24
25

-

Where the performance-based approach is used, some process parameters may not
be classified as ECs due to assurance of quality being provided by online
monitoring. In this circumstance the typical operating conditions for processparameters is provided as supportive information. During manufacture, the processparameters may be adjusted to deliver the expected outcome. The risks related tothe inline PAT (Process Analytical Technology) tests, e.g., NIR, should beappropriately managed throughout the lifecycle. The inline PAT tests are
considered ECs.

26
27
28
29

For the parameter-based approach where there is limited process understanding, if specificECs were not proposed by the MAH then regional regulations would be followed for
managing post-approval changes. This is illustrated in the examples for comparative
purposes.

30
31

A holistic view of the manufacturing process and overall control strategy is necessary when
considering ECs, as the output of one unit operation is the input for a subsequent operation.

32

1

This Annex document is intended to be considered in conjunction with the ICH Q12 Core Guideline
being simultaneously published for comment.
1

33

Change Reporting Categories:

34

Prior Approval (PA) – PAS, Type II, PCA, etc.

35

Notification Moderate (NM) – CBE 30, Type IB, MCN, etc.

36

Notification Low (NL) –AR, Type IA, MCN etc.

37

Not Reported (NR)38

Annex I A: Chemical Product

39

Process Flow

40
Components- API- Excipient #1- Excipient #2- Excipient #3

Process Step
Powder Blending

Roller Compaction

41
42

2

Subsequent StepsPowder Blending Unit Operation
Comments/Justification

Acceptable ranges and reporting categories(White boxes are ECs, and grey ones are not ECs.)

Output Performance
MeasureEquipment and Parameters

Input Materials

Parameter

Parameter BasedApproachEnhanced
Approach

Performance BasedApproach

API PSD

20-50um(PA)5-200um(NM)

5-200um(NM)

API Moisture

<1.0%
(NM)

<1.0%
(NL)

<1.0%
(NL)

Excipients #1-3
Specification

Pharmacopeial

Pharmacopeial

Pharmacopeial

Equipment type

Diffusion blender(V-blender)(PA)

Diffusion blender(V-blender)(NM)

Diffusion blender(V-blender)
(NM)

Scale
>10x

200kg
(NM)

200kg
(NL)

200-600kg(NL)

Blend Speed

20rpm
CPP
(NM)

10-20rpm
KPP(NL)

15 rpm
(NR)

20 minutes
CPP
(NM)

15-25 minutes
KPP
(NL)

20 minutes(NR)

Homogeneity
methodNot Tested

Not Tested

NIR online analyser(PA)

Homogeneity

Not Tested

Not Tested<5% RSD
IPC(NM)

Blend Time

Refer to section 3.2.P.2. for detailed justification and experimental data

API moisture and Pharmacopeial specifications for excipients 1-3 are ECs in all cases.
Excipient specifications managed in line with the Pharmacopoeia. Equipment type is an
EC in all cases.

3

Enhanced Approach
API Moisture has limited impact on quality demonstrated within the ranges explored.
Particle size distribution (PSD) of API demonstrated no impact on dissolution orabsorption. DoE studies showed no significant impact on blend uniformity for 5-200um
PSD of API. This allows reduction in reporting type for API moisture or PSD.
Understanding of variability of blending on product performance allows reduction inreporting type. Knowledge of the impact of scale on blending may allow downgradingof the reporting category (See 3.2.P.2). Homogeneity (blend uniformity <5% RSD) isrequired for assurance of quality in the next manufacturing step. Experimental studies
identified the range of blend speeds and times utilised without significant impact onblend uniformity as confirmed by successful process demonstration. Blending
parameters being defined as ECs means homogeneity is not routinely measured but
confirmed by end-product testing.
Performance Based Approach
Using a performance-based approach (online NIR analyser) in the control strategy
allows homogeneity confirmation in real-time. Use of the NIR analyser with feedback
to blending operating parameters minimises the need to rely on blend speed and time toensure process control. Therefore, these parameters are not ECs. The NIR method andblend homogeneity specification are ECs. Enhanced understanding of blending andoutput measurement allows for a wider range of manufacturing scale. Typical operating
conditions for blend speed and time described in Module 3.2 is supportive informationand monitored to assure performance.

Roller Compaction Unit Operation:
Acceptable ranges and reporting categories(White boxes are ECs, and grey ones are not ECs.)

Input
Materials

Parameter

Parameter BasedApproachEnhanced Approach

Performance BasedApproachfrom blending
operationfrom blending
operationfrom blending
operation

CPP
(NM)

KPP
(NL)

(NR)

Roller Speed

8rpm
CPP
(NM)

4-10rpm
KPP
(NL)

7rpm
(NR)

Ribbon Density
MethodNot Tested

Not Tested

NIR online analyser(PA)

Ribbon density (solid
fraction)

Not Tested

Not Tested

0.7-0.9 gcm-3
IPC
(PA)

Powder Blend

Output performancemeasureEquipment and Parameters

Equipment typeRoll gap

Roller compaction
force

Comments/Justification
Refer to section 3.2.P.2. for detailed justification and experimental data

Enhanced Approach
Understanding of the inter-relationship between roll force/gap and roll
speed allows for consistent process operation in achieving a target
ribbon density. This provides the optimal input for the subsequent
Roller compactor with Roller compactor with Roller compactor with milling operation. Following milling, granules with the desired particle
10cm rolls
10cm rolls
10cm rolls
size distribution, flow and compressibility characteristics are generated.
(PA)
(NM)
(NL)
These quality attributes verified following the milling operation
3mm
2-4mm
3 mm
minimise the need for output performance measurements in the roller
CPP
KPP
(NR)
compaction operation. Expanded knowledge from experimental studies
(NM)
(NL)
allows definition of operating ranges and lower reporting categories tobe proposed.
-1
-1
-1
8kNcm
5-10kNcm
7.5kNcm4

Performance Based Approach
Using a performance based approach (online NIR analyser) in thecontrol strategy allows ribbon density to be confirmed in real-time.
This allows more flexibility in the type of roller compactor equipment
and operating conditions. These output measurements ensure process
performance and acceptable ribbon quality attributes. Online
measurement of a defined ribbon density with feedback to roller
compactor operating parameters reduces variability and ensures lot to
lot uniformity of granules for compression. Typical operating
conditions are described in Module 3.2 as supportive information andmonitored to assure performance.

Annex I B: Biological Product
EXAMPLE FOR BIOLOGICAL PRODUCTFLOW DIAGRAMWORKING CELL BANK↓
Seed train↓
N-1 bioreactor↓

The following monoclonal antibody
example illustrates how, in a future state,established conditions could be defineddifferently in terms of acceptable ranges,
extent of parameters included in ECs, andreported depending on their related risk
and development approaches. This
example will focus on 4 steps: seed train,
production culture, low pH and anionexchange chromatography.

Production Cultures↓
Harvest↓Affinity Chromatography↓
Low pH(viral inactivation)↓
Cation Exchange Chromatography↓
Anion-Exchange Chromatography↓
Viral filtration↓
Ultrafiltration↓
Diafiltration↓
DRUG SUBSTANCE

5

Unit
operation

Acceptable ranges and reporting categories(White boxes are ECs, and grey ones are not ECs.)
Input/Output

Viable celldensity at thaw

input

pH

Duration

Seed train

Input X

Comments
Parameter BasedApproachEnhanced Approach

Performance
Based Approach≥1.0 x106 cells/mL≥1.0 x106 cells/mL≥1.0 x106 cells/mL

KPP (NL)

KPP (NL)PP

6.5 − 7.5

6.5 − 7.5

6.5 − 7.5

KPP (NM)KPP (NM)PP

20 - 28 hours

12 - 48 hours

12 - 48 hours

KPP (NM)PP (Monitored)PP

Enhanced Approach :Interaction of inputs on outputs were studied through multivariate analyses. No product is produced
at this step, and thus the direct impact of PP on CQA cannot be studied for this step (i.e., no CPP
identified).

###

###

###

KPP (NM)KPP (NM)

PP

≥ 70%

≥ 70%

IPC (NM)(Monitored)

6≥ 5 x10 cells/mL≥ 5 x10 cells/mL

IPC (NM)(Monitored)

The impact of inputs on outputs were not studied. Minimal value is needed to ensure proper seedingof subsequent bioreactors. Viable cell density, pH, duration and input X are considered KPP as they
are important to ensure process consistency as it relates to product quality.
Viable cell density is tested as output; lower reporting (NL) is proposed.

≥ 70%

outputCell viability

Cell density

6

Parameter Based Approach:Interaction studies shows that a viable cell density at thaw, pH and input X needs to be controlled
within tight ranges to ensure proper output (classified as KPP). Duration does not require tightcontrol.

IPC inline
automatic
counting (NM)≥ 5 x106 cells/mL

Based on the process understanding, outputs of this step are not considered EC, but are internallymonitored.

IPC at-line NIR(NM)

Performance Based Approach:In addition to the study performed for enhanced approach parameer based:

Output Y

###

###

###

IPC (NM)(Monitored)

IPC (NM)- Outputs of this step were linked to subsequent steps,- Inline tests are used to control outputs in a real time manner; inline test equipment is considered EC
(PA).

6

Unit
operation

Acceptable ranges and reporting categories(White boxes are ECs, and grey ones are not ECs.)
Input/Output

Inoculum Cell
Density

Comments
Parameter BasedApproachEnhanced Approach

Performance
Based Approach

4.0-6.0 x105 cells/mL

2.0-8.0 x105 cells/mL

Controlled by
MSPC

KPP (NM)PP

37.0 − 38.0°C

36.0 − 39.0°C

CPP (PA)CPP (NM)

Enhanced Approach:
Similar DOEs as described for seed train step were performed. These studies showed that:

Input- Temperature and input Z can impact CQAs (classified as CPP)
Temperature

###

###

CPP (PA)CPP (PA)

≥ 70%

≥ 50%

IPC (NM)(Monitored)

IPC inline
automatic
counting (NM)≥ 4.0 g/L

≥ 4.0 g/L

Predicted throughprocess model

IPC inline HPLC(NM)

Controlled byMSPC

Downgraded reporting for Temperature is proposed (NM) because statistical models predict thatwhen operating beyond the tested acceptable ranges, CQAs would remain within their acceptancecriteria.

≥ 50%
Viability at
harvestTiter≥ 4.0 g/L
IPC (NM)

outputProduction bioreactor (XXX L)

Input Z

- Inoculum cell density (tested at wider ranges than traditional parameter based approach) do not
impact CQAs and process consistency.

Controlled by
MSPC

Performance Based Approach:In addition to parameter based:- Outputs of this step were linked to subsequent steps- Inline tests are used to control outputs in a real time manner- Relevant inputs are monitored through Multivariate Statistical Process Control (MSPC) defining aprocess signature that is not considered EC.

2.0-5.0%
G0-F
oligosaccharide(CQA)

Microbiologicaltests- Inputs are adjusted realtime based on a model accounting for the inline measurements of outputs.

IPC inline UPLC
UV/MS

Included in release
specification

Included in release
specification

###

###

###

IPC (PA)

IPC (PA)

IPC (PA)(CQA not includedin specification)(PA)

7

(White boxes are ECs, and grey ones are not ECs.)
Input/Output

18°C − 23°C

15°C − 25°C

15°C − 25°C

CPP (PA)CPP (PA)CPP (PA)pH

2.0 – 4.0

2.0 – 4.0

2.0 – 4.0

CPP (PA)CPP (PA)CPP (PA)

120 -240 min

120 -360 min

120 -360 min

CPP (PA)CPP (PA)CPP (PA)

6.0 − 8.0 mS/cm

6.0 − 8.0 mS/cm

6.0 − 8.0 mS/cm

CPP (PA)CPP (PA)PP

Feedstock
Conductivity

Input

Feedstock pH

Resin age

Input XX
Bioburden

Endotoxin
outputPerformance BasedEnhanced Approach
Approach

Operatingtemperature

Incubation time

Anion-Exchange Chromatography

Comments
Parameter BasedApproach

Input

Low pH

Unit
operation

Acceptable ranges and reporting categories

HCP
(CQA)

CQA XXX

Performance based approach is not applicable due to intrinsic viral safety risk (i.e., meaningful
output cannot be tested); Such situation should follow parameter based or enhanced approach.

Enhanced Approach:- Scale down studies demonstrate that feedstocks conductivity, pH, resin age and input XX can
impact CQA and are considered CPP.

4.8 – 5.2

4.5-5.5

4.0-6.0

CPP (PA)CPP (PA)PP≤ 20 cycles, ≤ 3 yrs≤ 100 cycles, ≤ 3 yrs≤ 100 cycles, ≤ 3 yrs

CPP (PA)CPP (NL)PP- Ongoing validation protocol includes time points beyond the claim of 100 cycles up to 3 years
for the resin age. A downgraded reporting (NL) is proposed to extend the maximum number ofcycle / lifetime in accordance to validation protocol.

###

###

XX

Performance Based Approach:

CPP (PA)CPP (PA)PP

In addition to parameter based:≤ 10 CFU/10 mL≤ 10 CFU/10 mL≤ 10 CFU/10 mL

IPC (PA)

IPC (PA)

IPC (PA)≤ 5 EU/mL≤ 5 EU/mL≤ 5 EU/mL

IPC (NM)

Monitored

Monitored

Tested in DS
specification

Predicted throughprocess model≤ 100 ppm

Tested in DS
specification

Predicted throughprocess model- Outputs of this step were linked to subsequent steps- Inline tests are used to control outputs in a real time manner- Inputs are adjusted realtime based on a model accounting for the inline measurements of
outputs.

IPC inline UPLCUV/MS (PA)
Inline IPC (PA)8

43

ANNEX II: PACMP- ILLUSTRATIVE EXAMPLES

44
45
46
47
48
49
50
51
52
53

The examples provided below are intended to illustrate the range of PACMPs that are
possible for a given type of change. They are not intended to serve as a binding templateand other approaches may also be acceptable. The first example below outlines a protocol
for a single change (a manufacturing site change) to a single product. The second example
outlines a protocol for multiple changes (multiple manufacturing site changes) that could
be implemented for multiple products. These examples are not intended to suggest that the
only type of change appropriate for inclusion in a PACMP is a manufacturing site change.
As described in ICH Q12 Guideline Chapter 4, in order to meet expectations regarding
continuous improvement of the product and process, many other quality-related changes
may be suitable for inclusion in a PACMP.

54

Annex II A: PACMP Example 1

55

Alternative manufacturing site for a small molecule drug substance56

Outline for Step 1 Submission

57

1. Introduction and Scope

58
59
60

This PACMP is intended to allow for the addition of an alternative manufacturing site forthe manufacture, testing, and release of the drug substance for a small molecule solid oral
drug product.

61
62
63
64

Based on the risk management activities described below, the implementation of thischange in Step 2 is proposed to be reported in a submission type that is a lower category
than currently provided for in existing regulations or guidance, or a submission typeeligible for accelerated review timelines, depending on regional requirements.

65

2. Quality Risk Management (QRM) Activities

66

QRM is conducted for the proposed alternative site and includes:

67
68
69
70
71
72

o Identification and assessment of the potential risks associated with theproposed change, as well as the activities proposed to mitigate each risk;o Accounting for known elements of the process, such as robustness, existing
controls, and potential impact on product quality; ando Incorporating prior knowledge gained from development and commercial
manufacturing experience.

73

3. Acceptance criteria

74

Based on the risk assessment, the following acceptance criteria should be met:

75
76
77
78

•

In a comparative batch analysis, three consecutive batches of drug substancemanufactured at the alternative manufacturing site should meet approved
specification to demonstrate equivalence to batches manufactured at the currently
approved site.

9

79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100

Other conditions to be met prior to implementation:
•

•

•
•
•
•
•
•

Stability studies will be initiated immediately on a suitable number of commercial
scale batches of drug substance manufactured at the alternate manufacturing siteand drug product manufactured with drug substance produced at the alternate
manufacturing site. Stability data are to be reported to the regulatory authority
subsequent to implementation of the new site according to regional requirements.
Alternative manufacturing site to have acceptable compliance status for small
molecule drug substance manufacturing; depending on the region, this may be
indicated by the last GMP inspection with acceptable outcome, through a valid
GMP certificate, or other appropriate documentation (e.g., Qualified Person
declaration).
Alternative manufacturing site to use similar manufacturing equipment orequipment with the same type of material of construction.
Technology transfer and process qualification to be completed.
No change to synthetic route, control strategy, impurity profile, or physicochemical
properties.
No change to any specification or analytical method for starting material orintermediates.
No change in analytical methods or specification for release and stability testing for
drug substance manufactured at the alternative site.
Any additional regional requirements.

10

101

Summary of Step 1 and Step 2 Submissions
PACMP
Component

PACMP Step 1 Contents(registration/approval of
protocol)Defined scope and limitations

PACMP Step 2 Contents(change implementation)

QRM

Description of QRM activities
and summary of risk
assessment

Confirmation that previously
conducted risk assessment
has not changed; or, if new
information is available that
impacts the risk assessment,
an updated risk assessment isprovided

Acceptance criteria

Tests and studies to be
performed; description of any
other criteria to be met,
including plans to reportoutcomes from ongoingstability testing

Data demonstrating that
acceptance criteria are met;
confirmation that othercriteria are met. Updated
CTD sections for S.2.1
Manufacturer(s) of Drug
Substance and S.4.4 Batch
Analyses for Drug
Substance.

Overall Strategy(Scope andLimitations ofproposed change)

102

11

Demonstrate requirements ofscope are met

103

Annex II B: PACMP Example 2

104

Manufacturing Site Transfers of Biotech Drug Substances

105

Proposed Outline for Step 1 Submission

106

1. Introduction and Scope

107
108
109
110
111
112
113
114
115

The primary objective of this expanded PACMP is to support the mobility across biologic
drug substance manufacturing sites, i.e., the transfer of one or multiple products from one
donor site to one or more recipient site(s), including CMOs (sites already licensed withappropriate inspection record), thereby reducing the number of regulatory submissions ofsimilar content and driving consistency. The expanded PACMP effectively leverages
concepts of Quality Risk Management and ICH Q9. Typical process adaptations linked toscale and equipment differences at the donor and recipient site(s) are in scope of the
protocol (e.g., change in raw material sourcing) whereas the scope excludes opportunistic
significant process changes (e.g., changes to increase productivity/yield).

116

2. Quality Risk Management (QRM)

117

QRM is performed for each individual site transfer, and includes:

118
119
120

•

Identification, scoring, and documentation of the potential hazard and harm
associated with each manufacturing unit operation and process change, as well as
the prevention and detection controls

121
122

•

Accounting for known elements of the process, such as robustness, existing
controls, and potential impact on product quality

123

3. Comparability/Acceptance Criteria

124

The overall comparability plan in line with ICH Q5E comprises the following elements:

125
126
127

•

The drug substance meets all release and in-process specifications, as well ascomparability acceptance criteria (e.g., tolerance intervals [TI, 95/99]) derived
from the entire manufacturing history.

128
129

•

Analytical profiles from selected characterisation tests of post-change material areconsistent with pre-change material in side-by-side comparison.

130
131

•

Process performance attributes, e.g., cell culture performance, purification process
yields, and impurities levels, are comparable between donor and recipient site.

132•

Planned process validation at the recipient site.

133•

Drug Substance degradation studies consistent with pre-change material.

134

12

135

4. Site-specific Considerations

136a) Site Risk

137
138
139
140
141
142
143

A risk assessment for the receiving site will be conducted by the MAH at the time of
implementation. The risk assessment includes the GMP compliance status and should also
include factors such as facility experience, process knowledge, and any additional regional
assessments such as QP declaration. The outcome of the risk assessment will indicate to
the MAH whether a site inspection by the competent regulatory authority may be needed
and whether additional data to support the change should be generated (e.g., site-specificstability data).

144b) Process Validation

145
146
147
148
149

An overview of the process validation project plan and validation master plan for the sitetransfer in accordance to the current PQS system should be provided (at step 1). A summaryof validation studies performed to support the site transfers, e.g., studies adopted fromdonor site and new studies at the recipient site are part of the step 2 implementation
submission.

150
151
152
153

The number of proposed validation batches should be based on the variability of theprocess, the complexity of the process/product, process knowledge gained during
development, supportive data at commercial scale during the technology transfer and theoverall experience of the MAH.

154c) Stability

155
156
157
158

Stability studies are traditionally rate-limiting to site transfer timelines; following
successful demonstration of comparability by analytical characterisation methods,
including accelerated and/or stress stability studies (see ICH Q12 Guideline Chapter 8.2.),
can leverage tiered regulatory submission reporting categories and commitments.

159

13

160
161

Summary Expanded PACMP Step 1 submission and proposed outline for Step 2
submission
Component

Step 1 contents(registration of protocol)

Step 2 contents (change
implementation)

Overall Strategy(Scope andLimitations)Defined scope andlimitations

Demonstrate requirements of scope met,
including process changes associatedwith transfer

QRM

Description of QRM
program and approach to sitetransfer risk assessment

Documented risk control strategy andexecuted risk management reportsummary

Comparability &Stability

Comparability plan, realtime stability commitments
and acceptance criteria(product-specific)

Data demonstrating that acceptancecriteria are met

Process
Validation

Overview of validation
program

Summary of facility/equipment
differences and applicable validation;
validation summary data support theprocess, facility/equipment, and method
transfer

Site risk

Description of site inspection
risk assessment

Outcome of site inspection risk
assessment defines actual change
submission requirements

162

14

163
164

ANNEX III: PRODUCT LIFECYCLE MANAGEMENT DOCUMENT ILLUSTRATIVE EXAMPLE

165

Example for a Solid Dosage Form Tablet X (small molecule)

166
167
168

The following example for drug product illustrates how MAH can present the elements of
ICH Q12 Chapter 5 in the PLCM document. Other approaches and formats can be used as
appropriate.

169
170
171
172
173

Figure 1 presents the current Flow Diagram the drug product Manufacturing Process for
Tablet X. For purposes of this example, the flow diagram is limited to the dry blending
and roller compaction operations within the manufacturing process using an enhanced
approach. The table elaborates the details of the specific established conditions for these
operations, the change reporting categories, and associated PACMPs and commitments.

174

Note: This example is not intended to describe the ECs identification process.

175

Summary of Product Control Strategy

176
177
178

Tablet X is an immediate-release, film-coated tablet containing 100 mg of API Y,
manufactured via a standard batch manufacturing process. Description of Manufacturing
Process and Process Controls is typically described in section P.3.3 of Module 3.

179
180

The drug product has been developed following an enhanced development approach, using
the science- and risk-based principles described in ICH Q8(R2), Q9, and Q10.

181
182

Figure 1

Partial Flow Diagram of the Manufacturing Process for Tablet X

183
Components- API- Excipient #1- Excipient #2- Excipient #3

Process Step
Powder Blending

Roller Compaction

184

15

Subsequent Steps

185
CTD
SectionSection Title

Established Conditions
Note that identification andjustification of ECs are presented
in the relevant section of CTD

Reporting Category
when making achange to theEstablished
Condition

3.2.P
3.2.P.3.3

Description of
Manufacturing
Process and Process
Controls - Unit
Operations
Input Material - API PSD

Notification Moderate

5-200um
Input Material – API Moisture
Powder Blending
Operation

Notification Low<1.0%
Excipients Specification

By regional
requirement

Pharmacopeial

16

PACMP or Post-approval CMC
Commitment, if applicable

CTD
SectionSection Title

Established Conditions
Note that identification andjustification of ECs are presented
in the relevant section of CTD

Equipment Type

Reporting Category
when making achange to theEstablished
Condition

PACMP or Post-approval CMC
Commitment, if applicableNotification Moderate

Diffusion blender (V-blender)
Scale

Notification Low

200kg
Blend speed

PACMP included in the MAA for
expanded range for scale to besubmitted as a Notification Low

Notification Low

10-20rpm
Blend time

Notification Low

15-25 minutes

Equipment Type

Notification Moderate

Roller compactor with 10cm
rolls

17

CMC commitment to monitor
dissolution performance for 10
batches manufactured at upper endof blend time range due to potential
over lubrication at the proposedcommercial scale (200kg).

CTD
SectionSection Title

Established Conditions
Note that identification andjustification of ECs are presented
in the relevant section of CTD

Roll Gap
Roller Compaction
Operation

Reporting Category
when making achange to theEstablished
Condition
Notification Low

2-4mm
Roller Compaction Force

Notification Low

5-10kNcm-1
Roller Speed

Notification Low

4-10rpm
186

18

PACMP or Post-approval CMC
Commitment, if applicable