Q12 Technical and Regulatory 
Considerations for 
Pharmaceutical Product 
Lifecycle Management  
 
 
Annexes
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2021 
ICH
    
Q12 Technical and Regulatory 
Considerations for 
Pharmaceutical Product 
Lifecycle Management  
 
Annexes 
Guidance for Industry 
 
 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
  
May 2021 
ICH
  Contains Nonbinding Recommendations 
 
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.  
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  ILLUSTRATIVE EXAMPLES (ANNEX I) ................................................................... 1 
A.  Identification of Established Conditions for the Manufacturing ProcessChemical 
Medicinal Product (Annex IA) ..................................................................................................... 3 
B.  Identification of Established Conditions for the Manufacturing ProcessBiological 
Medicinal Product (Annex IB) ...................................................................................................... 7 
C.  Identification of Established Conditions for Analytical Procedures (Annex IC) ................... 14 
D.  PACMP Example 1 (Annex ID) .................................................................................................. 17 
E.  PACMP Example 2 (Annex IE) .................................................................................................. 19 
F.  Product Lifecycle Management DocumentIllustrative Example (Annex IF) ..................... 21 
II.  STRUCTURED APPROACH TO ANALYTICAL PROCEDURE CHANGES 
(ANNEX II)...................................................................................................................... 23 
i  Contains Nonbinding Recommendations 
 
Q12 Technical and Regulatory Considerations for Pharmaceutical 
Product Lifecycle Management  
Annexes 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  ILLUSTRATIVE EXAMPLES (ANNEX I)2 
 
The examples provided in sections I.A through I.F of the ICH Q12 Annexes are mock examples 
provided for illustrative purposes.  They only suggest how the tools described in sections III, IV, 
and V of the ICH Q12 guidance could be applied, and should not be used as a template or the 
sole basis for a regulatory submission.  In addition, the reporting categories, as described in 
section II of the ICH Q12 guidance, may differ across regions depending on regional legislation; 
the nature of the product; and the Marketing Authorization Holders (MAHs) demonstrated 
understanding of the product, process, and analytical procedure.  
 
Table 1: Terminology Used in Examples 
ICH Terminology  Regional Terminology 
Prior approval (PA)  PAS, Type II, PCA, etc. 
Notification moderate (NM)  CBE 30, Type IB, MCN, etc. 
Notification low (NL)  CBE 0, AR, Type IA, MCN, etc. 
Not reported (NR)   
 
 
1 This guidance was developed within the Expert Working Group (Quality) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been subject to 
consultation by the regulatory parties, in accordance with the ICH process.  This document has been endorsed by the 
ICH Steering Committee at Step 4 of the ICH process, November 2019.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory members of the ICH regions. 
 
2 This guidance is intended to be considered in conjunction with the ICH guidance for industry Q12 Technical and 
Regulatory Considerations for Pharmaceutical Product Lifecycle Management ([May 2021), which is being 
simultaneously published as a final guidance.  We update guidances periodically.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.   
 
  1  Contains Nonbinding Recommendations 
 
Sections I.A and I.B: Identification of Established Conditions for the Manufacturing 
Process 
 
The examples in sections I.A and I.B of the ICH Q12 Annexes illustrate how the development 
approaches described in section III.B.3.a of the ICH Q12 guidance could be applied.  The 
examples describe different development approaches and resulting control strategies to illustrate 
how they influence the identification of Established Conditions (ECs) and reporting categories.  
Marketing Authorization Applications could consist of a combination of these approaches.  
 
These examples demonstrate that increased knowledge and understanding gained from 
progressively more extensive 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.   
 
For example: 
 
  Enhanced knowledge may lead to a reduction in uncertainty, demonstrating that a 
material attribute or process parameter initially considered potentially critical in a 
minimal approach is not actually criticali.e., does not have an impact on product 
quality and, therefore, is not an EC. 
 
  Risk management activities could lead to different reporting categoriese.g., a change 
from prior approval (PA) to a notification for a change to a critical process parameter 
(CPP).  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 process parameters are provided 
as supportive information.  During manufacture, the process parameters may be adjusted 
to deliver the expected outcome.  The risks related to the in-line Process Analytical 
Technology (PAT) tests (e.g., near infrared (NIR)) should be appropriately managed 
throughout the lifecycle.  In-line PAT tests used for quality control are considered ECs. 
 
A holistic view of the manufacturing process and overall control strategy is necessary when 
considering ECs since the output of one unit operation is the input for a subsequent operation. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
   
  2  Contains Nonbinding Recommendations 
 
A.  Identification of Established Conditions for the Manufacturing ProcessChemical Medicinal Product (Annex 
IA) 
 
Table 2: Powder Blending Unit Operation 
Acceptable Ranges and Reporting Categories  
(White boxes are ECs and grey boxes are not ECs.) 
  Parameter 
Minimal Parameter-Based  Enhanced Parameter-Based 
Performance-Based Approach  
Approach  Approach  
2050 um  5200 um  5200 um 
     
API PSD 
als    Tighten (NL)  Tighten (NL)  Tighten (NL) 
ri        
e
t
a Widen (PA)  Widen (NM)  Widen (NM) 
M
t  <1.0%  (NR)  (NR) 
u API Moisture 
np   (NM) 
I
Excipients #13  Pharmacopoeial  Pharmacopoeial  Pharmacopoeial 
     
Specification 
Diffusion mixing  Diffusion mixing  Diffusion mixing 
Operating Principle 
(PA)  (PA)  (PA) 
s 
r
e V-blender  V-blender  (NR) 
t Equipment Type 
e
m (NM)  (NL) 
a
r 200 kg  200 kg  200600 kg 
a
d P S  cale  Increase >10x (NM)  Increase >10x (NL)  Increase >10x (NL) 
n
a 20 rpm  Design space consisting of   15 rpm 
t 
n
e Blend Speed  CPP  blend speed: 1020 rpm  CPP 
m
p (NM)  blend time 1525 minutes  (NR) 
i
qu 20 minutes  CPP  20 minutes 
E
Blend Time  CPP  (NM)  CPP 
(NM)  (NR) 
                                Continued
  3  Contains Nonbinding Recommendations 
 
Table 2 continued: Powder Blending Unit Operation 
Acceptable Ranges and Reporting Categories  
(White boxes are ECs and grey boxes are not ECs.) 
  Parameter 
Minimal Parameter-Based  Enhanced Parameter-Based 
Performance-Based Approach  
Approach  Approach  
Homogeneity  HPLC    NIR online analyzer 
e 
put  manc sure  M  ethod Principle  (NM)  Not tested  (PA) 
ut or ea Homogeneity  <5% RSD    <5% RSD 
O f M
r
e Acceptance Criteria  IPC  Not tested  IPC 
P
(NM)  (NM) 
 
   
  4  Contains Nonbinding Recommendations 
 
Comments/Justification 
 
For this example, discussion and justification for selected parameters are provided to illustrate 
concepts in section III.B.3.a of the ICH Q12 guidance.  EC refers to the identification of ECs; 
reporting refers to the assessment of the appropriate reporting category. 
 
Excipient specifications are ECs and managed in line with the pharmacopoeia.  Equipment 
operating principle is an EC in all cases.  
 
Minimal Parameter-Based Approach 
 
  Active pharmaceutical ingredient (API) particle size distribution (PSD) 
 
  EC: The impact of the PSD of the API on blend homogeneity and dissolution could 
not be excluded during development.  PSD was not studied outside the range of 20
50 m; this range is an EC. 
 
  Reporting: The impact of a change outside this range on blend homogeneity and 
dissolution is unknown, and the risk to product quality is potentially high.  As a 
result, any future change outside the range would be reported as PA, supported by 
appropriate studies and data.  Changes to tighten the EC range based on knowledge 
gained during the commercial phase (e.g., better process control observed at tighter 
ranges) are considered low-risk and reported as notification low (NL). 
 
  API Moisture 
 
  EC: The impact of API moisture content on blend flowability, which impacts content 
uniformity, could not be reasonably excluded during development and has not been 
further studied in detail.  The set point value is based on a limited amount of 
development and manufacturing data.  API moisture content is therefore considered 
an EC. 
 
  Reporting: A change in this EC is considered moderate risk since downstream 
processing involves a power-assisted feeder in the tablet press which mitigates the 
risk of content uniformity failure.  The change is reported as notification moderate 
(NM). 
 
  Blend Equipment 
 
  EC: Only one type of blending equipment (V-blender) was considered in 
development.  Due to limited knowledge, blender type is considered an EC. 
 
  Reporting: A change in this EC is considered moderate risk and therefore is reported 
as NM. 
 
 
  5  Contains Nonbinding Recommendations 
 
 
  Blend Speed and Time 
 
  EC: Blend speeds and times used have not been studied in detail beyond the set points 
described.  The set point values are based on a limited amount of development and 
manufacturing data.  Therefore, the set points and the homogeneity specification are 
considered ECs. 
 
  Reporting: When assessing the risk of changing set points for these parameters, it was 
demonstrated that detection mechanisms are sufficient to capture disturbances in 
homogeneity.  Therefore, changes in these process parameters and specification are 
reported as NM.   
 
Enhanced Parameter-Based Approach 
 
  API PSD 
 
  EC: The impact of PSD of API on blend homogeneity and dissolution was well 
understood.  Design of Experiments (DoE) studied PSD within 5200 um.  API PSD 
was confirmed as having no impact on dissolution.  The proposed control range for 
PSD of 5200 m maintained adequate homogeneity.  Compared to the minimal 
approach, a wider PSD range is the EC. 
 
  Reporting: Enhanced knowledge gained from studying a wider range led to a 
reduction in uncertainty regarding the impact of changing the EC and a better 
understanding of the risk related to homogeneity.  A change to increase the range 
beyond that studied is considered a moderate risk and reported as NM.  Changes to 
tighten the EC range based on knowledge gained during the commercial phase (e.g., 
better process control observed at tighter ranges) are considered low-risk and reported 
as NL. 
 
  API Moisture 
 
  EC: API moisture has been studied in detail and demonstrated to have no impact on 
flowability and content uniformity within the ranges explored.  API moisture content 
is not an EC. 
 
  Blending Equipment 
 
  EC: The impact of different equipment types within the same operating principle on 
blend quality was studied and no significant impact was observed.  Due to this 
enhanced knowledge, the EC is focused on blending principle rather than specific 
type of equipment. 
 
  6  Contains Nonbinding Recommendations 
 
  Reporting: Enhanced understanding regarding the impact of different blending 
equipment reduced uncertainty regarding the impact of changing blender type on 
blend homogeneity.  A change is considered low-risk and is reported as NL. 
 
  Blend Speed and Time 
 
  EC: Enhanced understanding of blending parameter variability on homogeneity 
allows ranges for blend speed and blend time (i.e., design space established across 
these two parameters) that maintain adequate product quality and offer more 
operational flexibility than set points.  The ranges studied for both parameters are 
considered to be ECs.  The EC for blend homogeneity testing seen in the minimal 
approach is not an EC in this approach as a result of enhanced knowledge about the 
risk of blend segregation gained through homogeneity assessment and stratified 
sampling during development. 
 
  Reporting: Changes outside of the design space established for blend speed and time 
are considered moderate-risk and reported as NM. 
 
Performance-Based Approach 
 
It is assumed that a performance-based approach is developed on the basis of an enhanced 
approach.  The same relationships among material attributes, equipment, process parameters, and 
product quality as outlined above for the enhanced parameter-based approach apply.  However, 
some of the ECs are different as a result of a performance-based control strategy. 
 
Using a performance-based approach (online NIR analyzer) in the control strategy allows 
homogeneity confirmation in real time.  Use of the NIR analyzer with feedback to blending 
operating parameters minimizes the need to rely on blend speed and time to ensure blend 
homogeneity.  Therefore, these CPPs are not ECs.  The NIR method and blend homogeneity 
specification are ECs.  Enhanced understanding of blending and output measurement allows for a 
wider range of manufacturing scale.  Typical operating conditions for blend speed and time, 
described in Module 3.2, are supportive information and monitored to assure performance. 
 
B.  Identification of Established Conditions for the Manufacturing Process
Biological Medicinal Product (Annex IB) 
 
The following monoclonal antibody example illustrates how ECs and reporting categories could 
be defined differently depending on the related risk and development approaches used. 
 
This example will focus on two steps: production culture and anion-exchange chromatography. 
 
   
  7  Contains Nonbinding Recommendations 
 
Figure 2: Monoclonal Antibody Example 
FLOW DIAGRAM   
   
WORKING CELL BANK   
   
Seed train   
   
N-1 bioreactor   
   
Production Culture   
   
Harvest   
   
Affinity Chromatography   
   
Low pH    
(viral inactivation) 
   
Cation Exchange Chromatography   
   
Anion-Exchange Chromatography   
   
Viral filtration   
   
Ultrafiltration   
   
Diafiltration   
   
DRUG SUBSTANCE   
 
   
  8  Contains Nonbinding Recommendations 
 
Table 3: Production Culture (XXX L) 
n  Acceptable Ranges and Reporting Categories  
o
nit ati Input/Output  (White boxes are ECs and grey boxes are not ECs.) 
Uer Minimal Parameter- Enhanced Parameter- Performance-
p
O Based Approach  Based Approach   Based Approach 
Controlled by 
4.0-6.0 x105 cells/mL  2.0-8.0 x105 cells/mL 
Inoculum Cell  MSPC 
PP   PP  
Density  PP  
(NM)  (NR) 
(NR) 
Controlled by 
t  37.0  38.0C  36.0  39.0C  MSPC  
u
p Temperature  CPP   CPP  
n CPP  
I (PA)  (NM) 
(NR) 
Controlled by 
###  ### 
MSPC 
Input Y  CPP   CPP  
CPP  
(PA)  (PA) 
(NR)  
 50% 
 70%   50% 
IPC in-line 
Viability at Harvest  IPC   (Monitored)  
automatic counting 
(NM)  (NR) 
(NM) 
 4.0 g/L 
 4.0 g/L   4.0 g/L 
Predicted through 
Titre  IPC   IPC in-line HPLC  
process model  
(NM)  (NM) 
t   (NR) 
u
p
t 2.0-5.0% 
u
O IPC in-line UPLC 
G0-F 
Included in release  Included in release  UV/MS 
Oligosaccharide 
specification  specification  (CQA not included 
(CQA) 
in specification)   
(PA) 
## CFU/mL  ## CFU/mL  ## CFU/mL 
Bioburden  IPC   IPC   IPC  
(PA)  (PA)  (PA) 
 
Minimal Parameter-Based Approach 
 
  EC 
 
  Process development is minimal.  Due to a lack of supporting justification, most 
parameters are considered ECs and ranges are narrow. 
 
  The bioburden test is considered an EC as the production culture step presents a 
known risk of microbial growth if contaminated. 
  9  Contains Nonbinding Recommendations 
 
 
  Reporting 
 
  A change of inoculum cell density is medium-risk, taking into account that control of 
viability and titre takes place for this step.  The change is reported as NM. 
 
  Considering that the impact of temperature and input Y was not studied, and that 
literature suggests potential impact of these parameters on a critical quality attribute 
(CQA), changes to these parameters are considered high-risk.  These changes are 
reported as PA. 
 
  A change in the bioburden test or results is considered high-risk, considering the 
severity of microbial contamination at that stage.  The change is reported as PA. 
 
Enhanced Parameter-Based Approach 
 
  EC: CQAs have been identified and DoE studies for selected CQAs show that: 
 
  Temperature and input Y can impact the CQA G0-F at a different magnitude (high 
impact for input Y and low-to-moderate impact for temperature); these are considered 
ECs. 
 
  Inoculum cell density does not impact CQAs and is not considered an EC. 
 
  Linkage studies demonstrate the lack of impact of viability at harvest on CQAs when 
reduced to 50%.  Process characterization studies demonstrate that viability at harvest 
is maintained above 70% when the CPPs (temperature and input Y) are maintained 
within the proposed ranges.  Viability at harvest is not considered an EC. 
 
  Titre is predicted through a process model.  With this knowledge, cell viability at 
harvest and titre are not considered ECs. 
 
  Bioburden test is considered an EC as the production culture step presents a known 
risk of microbial growth if contaminated. 
 
  Reporting: Risk management activities have been performed and concluded that: 
 
  A change to input Y is considered high-risk because input Y has been shown to have 
a high impact on G0-F.  The change is reported as PA. 
 
  A change in temperature is considered moderate-risk given the low-to-moderate 
impact on G0-F.  The change is reported as NM. 
 
  A change in bioburden test or limit is considered high-risk given the severity of 
microbial contamination at that stage.  The change is reported as PA. 
  10  Contains Nonbinding Recommendations 
 
 
Performance-Based Approach 
 
  EC 
 
  In-line tests are used to control outputs in real time.  In-line tests are considered to be 
ECs. 
 
  Relevant inputs are monitored through Multivariate Statistical Process Control 
(MSPC) defining a process signature that is not considered an EC. 
 
  Inputs are adjusted in real time based on a model accounting for the in-line 
measurements of outputs.  Inputs are not considered ECs as the outputs of the step 
(titre and G0-F level) are assured by in-line testing. 
 
  The bioburden test is considered an EC as the production culture step presents a 
known risk of microbial growth if contaminated. 
 
  Reporting 
 
  Changes of viability and titre tests are assessed as moderate-risk since CQAs are not 
directly impacted.  These changes are reported as NM. 
 
  A change to G0-F test or ranges is assessed as high-risk because this attribute is not 
tested in the drug substance specification.  The change is reported as PA. 
 
  A change in the bioburden test or results is considered high-risk given the severity of 
microbial contamination at that stage.  The change is reported as PA. 
   
  11  Contains Nonbinding Recommendations 
 
Table 4: Anion Exchange Chromatography 
n  Acceptable Ranges and Reporting Categories  
o
nit ati Input/Output  (White boxes are ECs and grey boxes are not ECs.) 
Uer Minimal Parameter- Enhanced Parameter- Performance-
p
O Based Approach  Based Approach   Based Approach 
Feedstock  6.0  8.0 mS/cm  6.0  8.0 mS/cm  6.0  8.0 mS/cm 
Conductivity  CPP  CPP   CPP  
(PA)  (PA)  (NR) 
Feedstock pH  4.8  5.2  4.5-5.5  4.0-6.0 
CPP   CPP   CPP 
(PA)  (PA >5.5)  (NR) 
t 
u (NM <4.5) 
p
n
I
 100 cycles,  3 
 20 cycles,  3 yrs 
 100 cycles,  3 yrs  yrs 
Resin Age  CPP 
PP   PP  
   (PA) 
(NL)  (NR) 
 
 
CPP   CPP   CPP  
Input Z 
(PA)  (NM)  (NR) 
Bioburden   10 CFU/10 mL   10 CFU/10 mL   10 CFU/10 mL 
IPC   (Monitored)    (Monitored)  
(NL)  (NR)  (NR) 
 5 EU/mL   5 EU/mL   5 EU/mL 
Endotoxin  IPC   (Monitored)   (Monitored)  
t 
u (NL)  (NR)  (NR) 
p
t
u Host Cell Protein  Tested in DS  Predicted through   100 ppm 
O
(HCP)  specification  process model  IPC in-line UPLC 
(CQA)  UV/MS  
(PA) 
CQA X  Tested in DS  Predicted through  In-line IPC  
specification  process model  (PA) 
 
Minimal Parameter-Based Approach 
 
  EC 
 
  Process development is minimal.  The impact of inputs on CQAs has not been 
studied.  Due to the lack of knowledge, all inputs are considered to be ECs as they 
can potentially have impact on CQAs. 
 
  Output (i.e., bioburden and endotoxin) are considered ECs as they have potential 
impact on product quality. 
 
  12  Contains Nonbinding Recommendations 
 
  HCP and CQA X are part of drug substance specifications and are not tested at this 
stage.  HCP and CQA X are not considered ECs for this step. 
 
  Reporting 
 
  Considering the lack of understanding of the impact of inputs (feedstock conductivity 
and pH, resin age, and input Z) on CQAs, changes to these inputs are considered 
high-risk.  These changes are reported as PA. 
 
  Changes to bioburden and endotoxin limits are considered low-risk as these are 
further tested in subsequent steps.  These changes are reported as NL. 
 
Enhanced Parameter-Based Approach 
 
  EC 
 
  Studies on scale-down models demonstrate that feedstock conductivity and pH as 
well as input Z can impact CQAs (HCP and CQA X) and are considered CPPs. 
 
  Resin age, which has been studied for up to 100 cycles and up to 3 years, did not 
show any impact on CQAs.  Impact on CQAs cannot be excluded when the range is 
further extended.  Resin age is considered an EC. 
 
  HCP and CQA X are not considered ECs as multivariate studies demonstrated that 
they remain within their acceptance criteria when feedstock conductivity and pH as 
well as input Z are maintained within the studied ranges. 
 
  Bioburden and endotoxin are not considered ECs for this step, taking into 
consideration testing of the attributes in several of the subsequent process steps, but 
are monitored. 
 
  Reporting: Risk management activities have been performed and concluded that: 
 
  Extension of resin age is considered low-risk, taking into account the ongoing 
validation protocol, which includes time points beyond the claim of 100 cycles/3 
years.  This change is reported as NL. 
 
  Change to feedstock conductivity is considered high-risk because it can impact HCP 
and CQA X.  This change is reported as PA. 
 
  Change to feedstock pH is considered high-risk when increased beyond 5.5 and is 
reported as PA.  This change is considered moderate-risk below 4.5 and is reported as 
NM. 
 
  13  Contains Nonbinding Recommendations 
 
  A change to input Z has a moderate impact on HCP and CQA X.  This change is 
reported as NM. 
 
Performance-Based Approach 
 
  EC: In-line tests are used to control outputs (i.e., HCP and CQA X) in real time.  Inputs 
are adjusted in real time based on a model accounting for the in-line measurements of 
outputs.  In-line tests are considered ECs. 
 
  Reporting: The control strategy relies on the in-line tests to ensure that HCP and CQA X 
remain within acceptable ranges.  Changes to these in-line tests or ranges are assessed as 
high-risk and are reported as PA. 
 
C.  Identification of Established Conditions for Analytical Procedures (Annex 
IC) 
 
The following is an example to illustrate how ECs could be presented for an analytical 
procedure, acceptance criteria, and testing facility, along with their suggested reporting 
categories.  This example considers an analytical procedure (capillary electrophoresis) for a 
biological drug substance (non-glycosylated recombinant protein) referred to as Illustropin, 
using a minimal development approach validated in accordance to ICH Q2.  To better illustrate 
the example, the change categories, conditions, and data requirements are according to the World 
Health Organization (WHO) guidelines on procedures for changes to approved biotherapeutic 
products.  The actual reporting categories and data requirements may differ for a particular 
product and by region. 
 
The information summarized in the table below provides guidance on:  
 
  The conditions to be fulfilled for a given change to be classified as moderate or minor (if 
any of the conditions outlined for a given change are not fulfilled, the change is assessed 
and, if appropriate, the next higher reporting category may be usedfor example, if any 
conditions recommended for a low-quality change are not fulfilled, the change may be 
considered to be a moderate-quality change). 
 
  Adequate scientific data and justification should be provided to support a given change. 
 
Table 5: Moderate or Minor Changes 
Reporting  
  All Items Listed are ECs  (as example referring 
to WHO) 
Measurement of Purity: Determination of charged variants of  NM 
Method  active substance by capillary electrophoresis (nonreduced)  Conditions:  None 
and corrected relative-area %.  Supporting Data:15 
Continued 
 
 
  14  Contains Nonbinding Recommendations 
 
Table 5 continued: Moderate or Minor Changes 
Reporting  
  All Items Listed are ECs  (as example referring 
to WHO) 
Illustropin Reference Standard:  NL  
Test 
Concentration of test solutions and reference standards: 1  Conditions 14 
Solutions 
mg/ml Illustropin in water  Supporting Data:1, 4, 
5 
Suitable capillary electrophoresis system 
 
Suitable spectrophotometric detector 
Equipment  Capillary:  
Material: Uncoated fused silica capillary diameter  = 50 m 
Size: Effective length = at least 70 cm 
Chemicals (pharmacopoeial quality)  NL  
Separation buffer (CZE): 13.2 g/l solution of ammonium  Conditions 14 
phosphate adjusted to pH 6.0 with phosphoric acid filtered  Supporting Data:1, 4, 
Rinsing agents: 1M sodium Hydroxide, water, 0.1M sodium  5 
hydroxide   
Instrument parameters 
Detection: 200 nm (UV) 
Electric field strength: 217 V/cm 
Temperature: 30 C 
Sample analysis 
Injection test solution (a) and the reference solution;  
Condition 
injection for at least 3 s then CZE buffer injection for 1 s 
Separation: Separation buffer at both ends of the capillary 
Sample storage at 4C during analysis 
System conditioning 
Preconditioning: 
At least 20 min. 1M sodium hydroxide 
At least 10 min. water 
At least 20 min. separation buffer 
Between-run rinsing:  
0.1M sodium hydroxide at least 2 min. 
Separation buffer at least 6 min. 
Specificity: The electropherogram obtained is similar to the  NL 
electropherogram of Illustropin supplied with Illustropin  Conditions 1-4 
System 
reference; 2 peaks (I1, I2) eluting prior to the principal peak  Supporting Data:1, 4, 
Suitability 
and at least 2 peaks (I3, I4) eluting after the principal peak are  5 
clearly visible   
Continued 
 
 
 
 
   
  15  Contains Nonbinding Recommendations 
 
Table 5 continued: Moderate or Minor Changes 
Reporting  
All Items Listed are ECs 
  (as example referring 
to WHO) 
Deamidated forms: Maximum 5.0%   Widening: NM 
Any other impurity: For each impurity, maximum 2.0%  Conditions:  None 
Acceptance  Total: Maximum 10.0%.  Supporting Data:1, 5, 
Criteria  6 
  Narrowing: NL 
Conditions:  2, 7 
Supporting Data:1 
  NM 
Conditions: None 
Site  Supporting Data: 7, 8 
Transfer  NL 
Conditions: 4-6 
Supporting Data: 7, 8 
 
Table 6: Conditions To Be Fulfilled To Implement the Change at the Corresponding 
Reporting Category 
1  There is no change in the limits/acceptance criteria outside the approved limits for the approved 
assays used at release/stability. 
2  The method of analysis is the same and is based on the same analytical technique or principle (for 
example, change in column length or temperature, but not a different type of column or method) 
and no new impurities are detected. 
3  The modified analytical procedure maintains or improves the performance parameters of the 
method. 
4  The change does not concern potency testing. 
5  No changes made to the test method. 
6  The transfer is within a facility approved in the current marketing authorization for the 
performance of other tests. 
7  The change does not result from unexpected events arising during manufacture (for example, new 
unqualified impurity, change in total impurity limits). 
 
Table 7: Supporting Data (Documentation to Be Submitted) 
1  Updated drug substance specifications 
2  Copies or summaries of analytical procedures if new analytical procedures are used 
3  Validation/qualification results if new analytical procedures are used 
4  Comparative results demonstrating that the approved and proposed analytical procedures are 
equivalent 
Continued 
 
 
 
 
  16  Contains Nonbinding Recommendations 
 
Table 7 continued: Supporting Data (Documentation to Be Submitted) 
5  Justification for the proposed drug substance specification (for example, tests, acceptance criteria, 
analytical procedures) 
6  Documented evidence that consistency of quality is maintained 
7  Information demonstrating technology transfer qualification for the non-pharmacopoeial assay or 
verification for the pharmacopoeial assay 
8  Evidence that the new company/facility is compliant with good manufacturing practices (GMPs) 
 
D.  PACMP Example 1 (Annex ID) 
 
The examples in sections I.D and I.E are intended to illustrate the range of Postapproval Change 
Management Protocols (PACMPs) that are possible for a given type of change.  They are not 
intended to serve as a binding template, and 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 section IV of the ICH Q12 guidance, in order to meet expectations 
regarding continual improvement of the product and process, many other quality-related changes 
may be suitable for inclusion in a PACMP. 
 
Alternative Manufacturing Site for a Small Molecule Drug Substance 
 
Outline for Step 1 Submission 
 
(1) Introduction and scope 
 
This PACMP is intended to allow for the addition of an alternative manufacturing site for the 
manufacture, testing, and release of the drug substance for a small-molecule, solid oral drug 
product.  
 
Based on the risk management activities described below, the implementation of this change 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 type eligible for accelerated 
review timelines, depending on regional requirements. 
 
(2) Quality risk management (QRM) Activities: QRM is conducted for the proposed 
alternative site and includes:   
 
  Identification and assessment of the potential risks associated with the proposed 
change as well as the activities proposed to mitigate each risk 
 
  Accounting for known elements of the process, such as robustness, existing controls, 
and potential impact on product quality 
 
  17  Contains Nonbinding Recommendations 
 
  Incorporating prior knowledge gained from development and commercial 
manufacturing experience 
 
(3) Acceptance Criteria: Based on the risk assessment, the following acceptance criteria 
should be met: 
 
  In a comparative batch analysis, three consecutive batches of drug substance 
manufactured at the alternative manufacturing site should meet approved 
specification to demonstrate equivalence to batches manufactured at the currently 
approved site. 
 
  Other conditions to be met prior to implementation: 
 
  Stability studies are initiated immediately on a suitable number of commercial-
scale batches of drug substance manufactured at the alternate manufacturing site 
and 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. 
 
  The alternative manufacturing site has acceptable compliance status for small-
molecule drug substance manufacturing; depending on the region, this may be 
indicated by the last GMP inspection with an acceptable outcome, through a valid 
GMP certificate, or other appropriate documentation (e.g., Qualified Person 
declaration). 
 
  The alternative manufacturing site uses similar manufacturing equipment or 
equipment with the same type of material of construction. 
 
  The technology transfer and process qualifications are completed. 
 
  No change to synthetic route, control strategy, impurity profile, or 
physicochemical properties. 
 
  No change to any specification or analytical method for starting material or 
intermediates. 
 
  No change in analytical methods or specification for release and stability testing 
for drug substance manufactured at the alternative site. 
 
  Any additional regional requirements.  
 
   
  18  Contains Nonbinding Recommendations 
 
Table 8: Summary of Step 1 and Step 2 Submissions 
PACMP Step 1 Contents 
PACMP Step 2 Contents 
PACMP Component  (Registration/Approval of 
(Change Implementation) 
Protocol) 
Overall Strategy (Scope  Defined scope and limitations  Demonstrate that the requirements 
and Limitations of  of the scope have been met 
Proposed Change) 
QRM  Description of QRM activities  Confirmation that previously 
and summary of risk assessment  conducted risk assessment has not 
changedor, if new information is 
available that impacts the risk 
assessment, an updated risk 
assessment has been provided  
Acceptance Criteria  Tests and studies to be  Data demonstrating that 
performed; description of any  acceptance criteria are met; 
other criteria to be met,  confirmation that other criteria 
including plans to report  have been met; updated 
outcomes from ongoing stability  information in Common Technical 
testing  Document (CTD) S.2.1, 
Manufacturer(s) of Drug 
Substance, and S.4.4, Batch 
Analyses for Drug Substance  
 
E.  PACMP Example 2 (Annex IE) 
 
Manufacturing Site Transfers of Biotechnological Drug Substances 
 
Proposed Outline for Step 1 Submission 
 
(1) Introduction and scope 
 
The primary objective of this expanded PACMP is to support mobility across drug substance 
manufacturing sitesi.e., the transfer of one or multiple products from one donor site to one or 
more recipient site(s), including Contract Manufacturing Organizations (sites already licensed 
with appropriate inspection records), thereby reducing the number of regulatory submissions of 
similar content and driving consistency.  The expanded PACMP effectively leverages concepts 
of QRM and ICH Q9.  Typical process adaptations linked to scale and equipment differences at 
the donor and recipient site(s) are within the 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). 
 
(2) Quality Risk Management (QRM) Activities: QRM is performed for each individual site 
transfer, and includes: 
 
  19  Contains Nonbinding Recommendations 
 
  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 
 
  Accounting for known elements of the process, such as robustness, existing controls, 
and potential impact on product quality 
 
(3) Comparability/Acceptance Criteria: The overall comparability plan in line with ICH Q5E 
comprises the following elements: 
 
  The drug substance meets all release and in-process specifications as well as 
comparability acceptance criteria (e.g., tolerance intervals (TI, 95/99)) derived from 
the entire manufacturing history. 
 
  Analytical profiles from selected characterization tests of post-change material are 
consistent with pre-change material in side-by-side comparison. 
 
  Process performance attributes (e.g., cell culture performance, purification process 
yields, impurity levels) are comparable between donor and recipient site. 
 
  Process validation is planned at the recipient site. 
 
  Drug substance degradation studies are consistent with pre-change material. 
 
(4) Site-specific considerations 
 
  Site risk 
 
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 (e.g., 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-specific stability data). 
 
  Process validation 
 
An overview of the process validation project plan and validation master plan for the site transfer 
in accordance with the current Pharmaceutical Quality System should be provided (at step 1).  A 
summary of validation studies performed to support the site transferse.g., studies adopted from 
the donor site and new studies at the recipient siteare part of the step-2 implementation 
submission. 
 
The number of proposed validation batches should be based on the variability of the process, the 
complexity of the process/product, process knowledge gained during development, supportive 
data at commercial scale during the technology transfer, and the overall experience of the MAH. 
  20  Contains Nonbinding Recommendations 
 
 
  Stability 
 
Stability studies are traditionally rate-limiting to site transfer timelines; following successful 
demonstration of comparability by analytical characterization methods, including accelerated 
and/or stress-stability studies (see section IX of the ICH Q12 guidance) can leverage tiered 
regulatory submission reporting categories and commitments.  
 
Table 9: Summary Expanded PACMP Step 1 Submission and Proposed Outline for Step 2 
Submission 
Step 1 Contents (Registration 
Component  Step 2 Contents (Change Implementation) 
of Protocol) 
Overall Strategy  Defined scope and limitations  Demonstrate that the requirements of the 
(Scope and  scope have been met, including process 
Limitations)  changes associated with the transfer 
QRM  Description of QRM program  Documented risk control strategy and 
and approach to site transfer  executed risk management report summary 
risk assessment 
Comparability and  Comparability plan, real-time  Data demonstrating that acceptance criteria 
Stability  stability commitments and  are met  
acceptance criteria (product-
specific) 
Process Validation  Overview of validation  Summary of facility/equipment differences 
program  and applicable validation; validation 
summary data support the process, 
facility/equipment, and method transfer 
Site Risk  Description of site inspection  Outcome of site inspection risk assessment 
risk assessment  defines actual change submission 
requirements 
 
F.  Product Lifecycle Management DocumentIllustrative Example (Annex IF) 
 
The following example for drug product illustrates how an MAH can present the elements of 
section V of the ICH Q12 guidance in an initial Product Lifecycle Management (PLCM) 
document.  Other approaches and formats can be used as appropriate.  This example follows the 
Enhanced Parameter-Based Approach from section I.A of the ICH Q12 Annexesspecifically, 
the example for identifying ECs for a Solid Dosage Form Tablet X (small molecule). 
 
ECs defined in section I.A of the ICH Q12 Annexes are presented in the table below with 
additional illustrative ECs; a PACMP; and a postapproval chemistry, manufacturing, and 
controls (CMC) commitment.  This table should not be seen as an exhaustive list of ECs.  It is 
  21  Contains Nonbinding Recommendations 
 
recognized that other Common Technical Document (CTD) sections containing ECs, or ECs 
within a CTD section, as outlined in Appendix 1 of the ICH Q12 guidance may be included in a 
PLCM document.  Additional unit operations (roller compaction, tabletting, and film-coating) 
are listed for illustrative purposes, but their ECs and reporting categories are not described.  
Similarly, although only the PSD attribute is included in this table, the entire drug substance 
specification would be provided in an application. 
 
In this example, where the MAH proposes to follow regional regulations and guidance for a 
change to a particular EC, the reporting category has been left blank.  
 
Table 10: Presentation of the Elements of Section V of the ICH Q12 guidance in an Initial 
PLCM Document 
Established Conditions  Reporting Category When 
CTD Section  (Note that identification and justification of EC is  Making a Change to the 
presented in the relevant section of CTD)  Established Condition 
3.2.S.4.1  Input materialAPI PSD (5  200 um)  Tighten (NL) 
 
Widen (NM) 
3.2.P.3.1  Drug product manufacturing sites (including those   
for testing, primary and secondary packaging, 
device assembly for drug product-device 
combination products) 
3.2.P.3.2  Drug product batch formula (qualitative and   
quantitative) 
3.2.P.3.3  The manufacturing process consists of the   
following sequence of unit operations:   
   
1. Powder blending 
2. Roller compaction 
3. Tablet compression 
4. Film-coating  
  1. Powder blending    
   
The active substance and three excipients are mixed 
together.  The following process parameter are 
defined as ECs. 
  Operating principle: Diffusion mixing  PA 
  Equipment type: V-blender  NL 
  Scale: 200kg  NL 
Continued 
   
  22  Contains Nonbinding Recommendations 
 
Table 10 continued: Presentation of the Elements of Section V of ICH Q12 guidance in an 
Initial PLCM Document 
Established Conditions  Reporting Category When 
CTD Section  (Note that identification and justification of EC is  Making a Change to the 
presented in the relevant section of CTD)  Established Condition 
  Design space for blending process parameters  NM 
Blend speed: 1020 rpm 
Blend time: 1525 minutes 
  2. Roller compaction    
  3. Tablet compression    
  4. Film-coating    
3.2.P.3.4  Design space for blending process parameters  NM 
Blend speed: 1020 rpm 
Blend time: 1525 minutes 
3.2.P.4  Input materialExcipients #1 specification   
(pharmacopeial) 
3.2.P.4  Input materialExcipients #2 specification   
(pharmacopeial) 
3.2.P.4  Input materialExcipients #3 specification   
(pharmacopeial) 
 
Table 11: PACMP and Postapproval CMC Commitment 
CTD Section 
PACMP or Postapproval CMC Commitment (If Applicable) 
Referenced 
PACMP included in the Marketing Authorization Application for expanded 
3.2.P.3.3 
range for scale 
CMC commitment to monitor dissolution performance for 10 batches 
3.2.P.3.3  manufactured at upper end of blend-time range due to potential 
overlubrication at the proposed commercial scale (200 kg) 
 
 
II.  STRUCTURED APPROACH TO ANALYTICAL PROCEDURE CHANGES 
(ANNEX II) 
 
Principles for Analytical Procedure Changes 
 
MAHs are expected to maintain existing analytical procedures for authorized products and 
ensure that these are kept up-to-date.  These analytical procedures can relate to the drug 
substance(s) and drug product.  The intent of this approach is to incentivize structured 
implementation of at least equivalent analytical procedures that are fit for purpose.  An approach 
wherein specific criteria are defined for changes to analytical procedures used to test marketed 
products is described below.  If this approach is followed and all criteria are met, the analytical 
  23  Contains Nonbinding Recommendations 
 
procedure change can be made with immediate or other post-implementation notification, as 
appropriate, to the relevant regulatory authorities.   
 
This approach does not apply in the following situations: 
 
  Procedures where the acceptance criteria do not adequately reflect the complex 
information provided by the method; in particular, procedures for which only a subset of 
the characteristics are identified and specified (e.g., test for identity by peptide map, 
assay for complex drug substances) or where the specified acceptance criteria include a 
general comparison to a reference standard beyond specified characteristics (e.g., 
comparable to reference standard, such as for naturally derived products, biotechnology 
products) 
 
  Change(s) to a test method based on a biological/immunological/immunochemical 
principle or a method using a biological reagent (e.g., bioassay, binding assay, enzyme-
linked immunosorbent assay (ELISA), testing for viral adventitious agents) 
 
  Changes to models and multivariate methods (model maintenance for multivariate 
models is not considered to be a change) 
 
  Changes to analytical procedures (methods) described in pharmacopoeial monographs 
 
It is important to note that with the exception of the above exclusion criteria, all other methods 
are in scope, including those used for biotechnological/biological products.  
 
In order for this approach to be used, the following should be met: 
 
  The physicochemical basis and the high-level description of the current method and the 
intended method should be the same (e.g., reversed-phase chromatography with 
ultraviolet (UV) spectroscopic detection). 
 
  The acceptance criteria of the validation protocol of the current method can be applied to 
the proposed method as well. 
 
  Validation results should demonstrate that the intended method is equivalent to or better 
than the current method. 
 
  Test results obtained using the current method and intended method should be equivalent 
to each other.  This should be assessed in two ways.  First, the intended method should 
give an equivalent outcomei.e., the same conclusion will be made, regardless of 
whether the data was obtained by the current or the intended method.  Second, the 
validation protocol should contain explicit criteria that compare results obtained using the 
current and proposed method.  See step 2 below for further details. 
 
  24  Contains Nonbinding Recommendations 
 
  System suitability requirements should be established for the revised method to 
ensure the same effectiveness and day-to-day performance of the revised method 
compared to the current method. 
 
  Acceptance criteria changes (e.g., total impurities, potency) should not be introduced 
using this mechanism unless tighter/more restrictive acceptance criteria are introduced, or 
they are allowed by existing regional regulations. 
 
  Toxicological or clinical data are not warranted as a result of the method change.   
 
If these criteria are met, the methods are equivalent, and changes can be made with immediate or 
other post-implementation notification, as appropriate, to regulatory authorities. 
 
Structured Approach for Analytical Procedure Changes 
 
  Step 1: Evaluate the physicochemical basis of the method (the mode) and the method 
description.  When two or more techniques are used together (e.g., high-performance 
liquid chromatography (HPLC) with UV and mass spectrometry (MS) detection), each 
technique should be included in the method description.  The current and intended 
method (and its mode(s)) should have the same scientific basis and principles.  Changes 
between different modes (e.g., reversed phase to normal phase liquid chromatography) 
are not in the scope of this guidance. 
 
  By way of example, the following changes could be acceptable: 
 
  A change to a liquid column chromatography method where the mode of 
separation remains the same (e.g., reversed phase to reversed phase, size 
exclusion to size exclusion, etc.) 
 
  A change to an electrophoretic method where the mode of separation and method 
description remains the same (e.g., reduced to reduced, nonreduced to 
nonreduced, etc.) 
 
  A change to a pure spectroscopic or chemical/physical property method where 
principle remains the same (e.g., UV to UV, refractive index to refractive index, 
differential scanning calorimetry (DSC) to DSC) 
 
  This approach can be applied to other methods as appropriate. 
 
  Step 2: A prospective analytical validation protocol should be prepared and approved 
internally by the company.  It should be based on a comparison of the current and 
intended method, knowledge of the original validation protocol, and regulatory 
expectations.  The validation should assure that the intended method will be fit for its 
intended purpose and should contain at least the following: 
 
  25  Contains Nonbinding Recommendations 
 
  The principles of ICH Q2 should be followed to validate the intended method.  All 
validation characteristics relevant to the type of method being validated should be 
executed as described in ICH Q2. 
 
  The validation protocol should include, at minimum, the tests used to validate the 
current method and all other relevant tests in ICH Q2 or as required for the analytical 
method type.  For example, if specificity, linearity, precision, and accuracy were 
assessed during validation of the current method, then specificity, linearity, precision, 
and accuracy should also be included in the validation of the intended method.  The 
protocol acceptance criteria should reflect current expectations for method 
performance, be justified scientifically, and not be less stringent than those used for 
the validation of the current method. 
 
  The validation should demonstrate that the intended method is at least equivalent to 
the current method using parallel testing of an adequate number of samples of 
appropriate concentration based on the intended use of the method.  The assessment 
of equivalency should include the requirement that the new method not lose any 
meaningful information provided by the current method.  In addition, the same 
conclusion should result when assessing data from the same samples tested using the 
current and intended methods. 
 
  If there is a switch from manual to automated methods, the validation should also 
assess the impact of any related changes in critical reagents, reference standards, or 
software. 
 
  The protocol should also contain the detailed operating conditions of both the current 
method and the intended method to assure the changes being made are clear. 
 
  Step 3: Consider the system suitability criteria that exist in the current method, if any, and 
determine, based on method development data and any additional knowledge gained from 
commercial production, the system suitability criteria aspects that should be part of the 
intended method.  System suitability in this context includes all criteria used to evaluate 
the day-to-day performance of the method when used for routine testing. 
 
  Step 4: Execute the validation protocol and compare the results to the predetermined 
acceptance criteria.  If all criteria are met, the method is considered acceptable for its 
intended use.  If any criterion is not met, the change in method is outside the scope of this 
approach and should not be implemented. 
 
  Step 5: Consider new product information, if any, identified as a result of a change in the 
context of the current regulatory filing.  If new or revised acceptance criteria (e.g., total 
impurities, potency) are required based on results obtained during method validation, this 
structured approach may not be used, unless it is allowed by existing regional regulations.  
In addition, this approach may not be used if toxicological or clinical data are needed as a 
result of the method change.  Thus, the method change should have no impact on the 
safety, efficacy, purity, strength, identity, or potency of the product. 
  26  Contains Nonbinding Recommendations 
 
 
  Step 6: Prepare a written summary report documenting the outcome of the validation 
versus the protocol criteria. 
 
  Step 7: Follow the internal change process as defined within the companys 
Pharmaceutical Quality System to implement the change. 
 
  Step 8: Unless new information is identified as a result of this process (see step 5), 
provide a post-implementation notification of the method change to the regulatory 
authority after the change is implemented as per regional reporting requirements.  This 
may include the updated method description, the protocol, and the summary report of the 
validation. 
 
  Step 9: Complete post-change monitoring.  The companys change control system (refer 
to Appendix 2 of the ICH Q12 guidance) should explicitly identify and document a 
mechanism to assure the change was effective and had no unintended consequences.  The 
outcome of the assessment should be documented with a conclusion indicating the 
acceptability of the change. 
 
  Step 10: All information related to the method change should be available for verification 
during regulatory inspection. 
  27