Republic of the Philippines  
Department of Health  
FOOD AND DRUG ADMINISTRATION  
 
Civic Drive, Filinvest City, Alabang 1781 Muntinlupa, Philippines  
Trunk Line +63 2 857 1900  Fax +63 2 807 0751  
Website: www.fda.gov.ph  Email: info@fda.gov.ph  
 
  
 
 
 
 
     PHILIPPINE VARIATION GUIDELINE  FOR     
       BIOLOGICAL PRODUCTS  
 
Version 1.0 
16 March  2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
2  
PURPOSE  
 
This handbook was created to provide guidance specific to vaccine and biotherapeutic  products.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
3  LIST OF CONTENTS  Page 
no. 
I INTRODUCTION  8 
II SCOPE OF THIS GUIDELINE  8 
III DEFINITION  8 
III.a Major Variation (BMaV)  8 
III.b Minor Variation (BMiV -PA) 8 
III.c Minor Variation ( BMiV -N) 8 
IV PROCEDURE  8 
V CHANGES LEADING TO A NEW PRODUCT REGISTRATION  9 
VI OTHERS  9 
SECTION 1: CHANGES TO APPROVED VACCINES  
I. CHANGES TO ANTIGEN/DRUG SUBSTANCE  
A General Information   
A1  Change in the name of the antigen  11 
B Manufacture   
B2 Change to a drug substance manufacturing facility  11 
B3 Change to the antigen fermentation, viral propagation or cellular  propagation 
process  12 
B4 Change to the antigen purification process  13 
B5 Change in scale of the manufacturing process  13 
B6 Change in supplier of raw materials of biological origin  13 
B7 Change in source of raw materials of biological origin  13 
B8 Introduction of reprocessing steps  13 
B9 Change to the cell banks  15 
B10 Change to the seed lots  15 
B11 Change in cell bank/seed lot testing/storage site  15 
B12 Change in cell bank/seed lot qualification protocol  15 
B13 Change in equipment used in the antigen manufacturing process  16 
B14 Change in specification for the materials  17 
B15 Change to in -process tests and/or acceptance criteria applied during manufacture 
of the antigen  18 
B16 Change in in -process controls testing site  18 
C Control of the Antigen/Drug Substance   
C17 Change affecting the quality control (QC) (release and stability) testing of the 
antigen  19 
C18 Change in the specification used to release the antigen  20 
D Reference Standards or Materials   
D19 Qualification of a new reference standard against a new primary international 
standard  21 
D20 Change in the reference standard from in -house (no relationship with 
international standard) to pharmacopoeial or international standard  21 
D21 Qualification of a new lot of reference standard against the approved reference 
standard (including qualification of a new lot of a secondary reference standard 
against the approved primary standard)  21 
D22 Change to reference standard qualification protocol  21 
D23 Extension of reference standard shelf -life 21 
E Container Closure System   
E24 Change in the primary container closure system(s) for the storage and shipment of 
the antigen  21 Philippine Variation Guideline f or Biological  Products  
 
 
4 E25 Change in the specification of the primary container closure system for the 
antigen  22 
F Stability   
F26 Change in the shelf -life/hold -time for the antigen or for a stored intermediate of 
the antigen  23 
F27 Change in the post -approval stability protocol of the antigen  23 
F28 Change in the storage conditions for the antigen  24 
II. CHANGES TO THE FINAL PRODUCT  
G Description and Composition of the Final Product   
G29 Change in the description or composition of the final product  25 
H Description and Composition of the Final Product: Change to an Adjuvant   
H30 Change involving an approved chemical/synthetic adjuvant  27 
H31 Change involving a biological adjuvant  27 
I Description and Composition of the Final Product: Change to a Diluent   
I32 Change to the diluent  28 
J Manufacture   
J33 Change involving a final product manufacturer/manufacturing facility  29 
J34 Change in the final product manufacturing process  31 
J35 Change in the controls (in -process tests and/or acceptance criteria) applied during 
the manufacturing process or on intermediates  32 
J36 Change in in -process controls testing site  32 
J37 Change in the specification used to release the excipient  33 
J38 Change in the source of an excipient from a vegetable or synthetic source to a 
human or animal source that may pose a TSE or viral risk  34 
J39 Change in the source of an excipient from a TSE risk (for example, animal) 
source to a vegetable or synthetic source  34 
J40 Replacement in the source of an excipient from a TSE risk source to a different 
TSE risk source  34 
J41 Change in manufacture of a biological excipient  34 
J42 Change in supplier for a plasma -derived excipient  (for example, human serum 
albumin)  34 
J43 Change in supplier for an excipient of non -biological origin or of biological 
origin (excluding plasma -derived excipient)  34 
J44 Change in excipient testing site  34 
K Control of the Final Product   
K45 Change affecting the QC testing of the final product (release and stability)  35 
K46 Change in the specification used to release the final product  36 
L Reference Standards or Materials   
L47 Qualification of a reference standard against a new primary international standard  37 
L48 Change of the reference standard from in -house (no relationship with  
international standard) to pharmacopoeial or international standard  37 
L49 Qualification of a new lot of reference standard against the approved reference 
standard (including qualification of a new lot of a secondary reference standard 
against the approve d primary standard)  37 
L50 Change to the reference standard qualification protocol  37 
L51 Extension of the shelf -life of the reference standard  37 
M Container Closure System   
M52  Modification of a container closure system  38 
M53  Change from a reusable container to a disposable container with no changes in 
product contact material (for example, change from reusable pen to disposable 
pen) 38 Philippine Variation Guideline f or Biological  Products  
 
 
5 M54  Deletion of a container closure system  38 
M55  Change in the supplier for a primary container closure component  39 
M56  Change in the specification used to release a primary container closure 
component or functional secondary container closure component  40 
N Stability   
N57 Change in the shelf -life of the final product  40 
N58 Change in the post -approval stability protocol of the final product  41 
N59 Change in the labelled storage conditions for the final product or the diluted or 
reconstituted vaccine  42 
SECTION 2: CHANGES TO APPROVED 
BIOTHERAPEUTIC PRODUCTS  
III. CHANGES TO THE DRUG SUBSTANCE  
O Manufacture   
O60 Change to a drug substance manufacturing facility  44 
O61 Change to the cell banks  45 
O62 Change in the cell bank manufacturing site  45 
O63 Change in the cell bank testing/storage site  45 
O64 Change in the cell bank qualification protocol  45 
O65 Change to the fermentation or cell culture process  46 
O66 Change to the purification process  47 
O67 Change in scale of the manufacturing process  47 
O68 Introduction of reprocessing steps  47 
O69 Addition of a new holding step or change in  the parameters of an approved 
holding step  47 
O70 Change in equipment used in the drug substance manufacturing process  49 
O71 Change in specification for the materials  50 
O72 Change in supplier of raw materials of biological origin (for example, fetal calf 
serum, insulin, trypsin)  50 
O73 Change in source of raw materials of biological origin (for example, bovine 
trypsin to porcine trypsin)  51 
O74 Change to in -process tests and/or acceptance criteria applied during manufacture 
of the drug substance  52 
O75 Change in the in -process controls testing site  52 
O76 Change in the approved design space  53 
P Control of t he Drug Substance   
P77 Change affecting the quality control (release and stability) testing of the drug 
substance  53 
P78 Change in the standard/monograph (that is, specifications and/or test procedures) 
claimed for the drug substance  54 
P79 Change in the specifications and/or test procedures for the drug substance in order 
to comply with an updated pharmacopoeial standard/monograph  54 
P80 Changes in the control strategy of the drug substance  54 
P81 Change in the specification/analytical procedure used to release the drug 
substance  55 
Q Reference Standards or Materials   
Q82 Replacement of a primary reference standard  56 
Q83 Change of the reference standard from pharmacopoeial  or international standard 
to in-house (no relationship with international standard)  56 
Q84 Change of the reference standard from in -house (no relationship with 
international standard) to pharmacopoeial or international standard  56 Philippine Variation Guideline f or Biological  Products  
 
 
6 R85 Qualification of a new batch of reference standard against the approved reference 
standard (including qualifica tion of a new batch of a secondary reference standard 
against the approved primary standard)  56 
R86 Change to reference standard qualification protocol  56 
R87 Extension of the reference standard shelf -life or re -test period  56 
R Drug Substance Container Closure System   
R88 Change in the primary  container closure system(s)  for the storage and shipment  of 
the drug substance  56 
R89 Change in the supplier for a primary container closure  57 
R90 Change in the specification/analytical procedure of the primary container  closure 
system for the drug substance  58 
S Stability   
S91 Change in the shelf -life of the drug substance or for a stored  intermediate of the 
drug substance  58 
S92 Change in the post-approval stability protocol of the  drug substance  59 
S93 Change in the storage conditions for the drug  substance  60 
IV. CHANGES TO THE FINAL PRODUCT  
T Description and Composition of t he Drug Product   
V94 Change in the description or composition of the  drug product  60 
U Description and composition of the drug product: change to a diluent   
V95 Change to the diluent  62 
V Manufacture   
V96 Change in the approved design space  63 
V97 Change involving a drug product manufacturer/manufacturing facility  63 
V98 Change in the drug product manufacturing process  65 
V99 Change in the controls (in -process tests and/or acceptance criteria) applied  during 
the manufacturing process or on intermediates  66 
V100  Change in in-process  controls testing site  67 
V101  Change in the specification/analytical procedure used to  release the excipient  67 
V102  Change in the standard/monograph (that is, specifications and/or test procedures) 
claimed for  the excipient  68 
V103  Change in the source of an  excipient from a vegetable or  synthetic source to a 
human  or animal source that may  pose a TSE or viral risk  69 
V104  Change in the source of an  excipient from a TSE risk (for  example, animal) 
source  to a vegetable or synthetic  source  69 
V105  Replacement in the source  of an excipient from a TSE  risk source to a different 
TSE risk source (for example,  different animal source,  different country of origin)  69 
V106  Change in manufacture of a  biological excipient  69 
V107 Change in supplier for a  plasma -derived excipient  (for example, human serum  
albumin)  69 
V108 Change in supplier for an  excipient of non -biological  origin or of biological 
origin  (excluding plasma -derived  excipient)  69 
V109 Change in excipient testing site  69 
W Control of the drug product   
V110  Change affecting the QC testing of the drug  product (release and stability)  70 
V111  Change in the standard/monograph (that is, specifications and/or test procedures)  
claimed for the drug product  71 
W112 Change in the specifications  and/or test procedures  for the drug product to  
comply with an updated  pharmacopoeial standard/monograph  71 
W113 Changes in the control strategy of the drug  product  71 
W114 Change in the specification/analytical procedure used to  release the drug product  72 Philippine Variation Guideline f or Biological  Products  
 
 
7 X Reference standards   
X115  Replacement of a primary  reference standard  73 
X116  Change of the reference  standards from a pharmacopoeial or  international 
standard to  in-house (no relationship  with international standard)  73 
X117  Change of the reference  standard from in -house  (no relationship with  
international standard)  to a pharmacopoeial or  international standard  73 
X118 Qualification of a new batch  of reference standard against  the approved reference  
standard (including  qualification of a new batch  of a secondary reference  standard 
against the  approved primary standard)  73 
X119 Change to the reference  standard qualification  protocol  73 
X120 Extension of the reference  standard shelf -life or re -test period  73 
Y Drug product container closure system   
Y121  Modification of a  container closure system   74 
Y122  Change from a reusable  container to a disposable container with no changes  in 
product contact material  (for example, change  from reusable pen to  disposable 
pen) 74 
Y123 Deletion of a container  closure system  74 
Y124 Change in the supplier for a primary container closure  component  75 
Y125 Change in the specification used to release a primary container  closure 
component or functional secondary container closure  component  75 
Z Stability   
Z126  Change in the shelf -life of the drug product  76 
Z127  Change in the post -approval stability protocol of the  drug product  76 
Z128  Change in the labelled storage conditions for the drug product or the  diluted or 
reconstituted biotherapeutic products  77 
SECTION 3: PHILIPPINE -SPECIFIC POST -
APPROVAL CHANGES  
 Administrative Changes   
129 Change in brand name  80 
130 Change in Marketing Authorization Holder (MAH)  80 
131 Change/inclusion/deletion of drug distributor  81 
132 Administrative changes affecting entities other than the MAH  81 
133 Subsequent changes to the CLIDP following the approved variation/s of the 
PCPR  82 
 Quality Changes   
134 Change in the European Pharmacopoeial Certificate of Suitability (CEP)  82 
135 Change in the overage that is used for the drug substance  83 
136 Change of pack size for a drug product  83 
 Safety and Efficacy Changes   
137 Change in the labelling of the drug product  84 
138 Change in the route of administration  85 
 Other Changes   
139 Other changes not covered by the country -specific regulations  85 
   
   
VII FEES FOR POST -APPROVAL CHANGE APPLICATION  87 
 
  Philippine Variation Guideline f or Biological  Products  
 
 
8  
 
PHILIPPINE VARIATION GUIDELINE FOR BIOLOGICAL  PRODUCTS  
                                             
I INTRODUCTION  
Throughout the life cycle  of a biological  product,  the marketing authorization holder (MAH) is 
responsible for the product that is placed in the market and is also required to take into account 
technical and scientific progress, and to make any amendments that may be required to enable the 
products to be manufactured and checked by means of generally accepted scientific methods. Such 
amendments have to be approved by the Food and Drug Administration (FDA) Philippines.  
This Philippine Variation Guideline  for Biological Products (PVGB)  is based on the WHO 
Technical Report Series (TRS) incorporating country -specific requirements  in accordance with the 
existing Philippine regulations . It is intended to provide supportive information on the 
requirements for s ubmission of a variation application to implement a change to a biological  
product. Variation applications are categorized into major variation, minor variation (prior 
approval) and minor variation (notification) . Updating of this guideline will be done whenever the 
related guidelines and regulations have been revised  as deemed necessary . 
 
II SCOPE OF THIS GUIDELINE  
This Philippine Variation Guideline for Biological Products  concerns the variation applications 
submitted by marketing authorization holders (MAH) for  biological  products .  
 
III DEFINITION  
III.a  Major Variation  (BMaV)  
Post-Approval Change to a registered biological product  that may affect significantly and/or 
directly the aspects of quality, safety and efficacy and it does not fall within the definition of minor 
variation and new registration.  
 
III.b  Minor Variation  (BMiV -PA) 
Post-Approval Change to a registered biological product  in terms of changes with no or minimal 
impact on the a spects of quality, safety, and efficacy.  
 
III.c Minor Variation  (BMiV -N) 
Post-Approval Change to a registered biological product  in terms of administrative data and/or 
changes with minimal/no significant impact on the aspects of quality, safety, and efficacy.  
 
 
IV PROCEDURE  
Variation applications may be submitted any time within the validity of the Certificate of Product 
Registration (CPR) issued by FDA. Refer to FDA Circular No. 2023-___ Application Process and 
Requirements for Post - Approval Changes of Biological Products Adopting the World Health 
Organization Guidelines for Changes to Approved Vaccines and Biotherapeutic Products  for a 
comprehensive guidance on the application process.  
Once the variation app lication is considered approved or acknowledged, FDA  shall issue the 
appropriate proof of authorization.  
Type of Variation  Proof of Approval or Acknowledgement  Philippine Variation Guideline f or Biological  Products  
 
 
9 Major Variation  and Minor Variation – Prior 
Approval  Variation Certificate indicating the approved  
change/s   
Minor Variation  – Notification  Approval/acknowledgment through  
Document Tracking System (DTS)  
Changes leading to new product registration  New CPR with new validity  
 
  
V CHANGES LEADING TO A NEW PRODUCT REGISTRATION  
The following changes shall lead to a new product registration leading to issuance of a new CPR:  
a. Change/addition of new cell substrate/viral or bacterial seeds that are unrelated to the 
licensed master cell bank (MCB)/master seed lot (MSL) or pre -MCB/MSL  material  
b. Changes to the Active Pharmaceutical Ingredient (API)  
i. Change of an API to a different API including change in salt or isomer  
ii. Inclusion of an additional API to a single component or multicomponent 
product  
iii. Removal of an API from a multicomponent product  
iv. Change in the strength of  one or more APIs  
v. Increase in overage  
c. Changes in the dosage form  
d. Changes in the route of administration (exception for parenteral route)  
e. Change of drug product formulation which involves addition and/or removal of 
excipient  
f. Changes to the adjuvant  
i. Change in adjuvant  
ii. Change in type/structure of a chemical adjuvant  
iii. Change in the type/component of a biological adjuvant  
g. Addition  of alternative drug product manufacturing site (e.g., bulk manufacturer, 
primary packager, secondary packager and batch release site) to the currently approved 
site for the same manufacturing activity  
h. Addition of a new Container Closure System/presentation for a registered drug product, 
including its attached device or delivery system  
 
 
VI OTHERS  
ABBREVIATIONS/ACRONYMS  
   
BMaV  = Major Variation  for Biological Products  
BMiV -PA = Minor Variation – Prior Approval for Biological Products  
BMiV -N = Minor  Variation  – Notification for Biological Products  
B-OTH  = Other changes  not covered by the country -specific regulations  
 
 
 
 
 
 
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
10  
 
 
 
 
SECTION 1:  
CHANGES TO APPROVED 
VACCINES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
11  
 
I. CHANGES TO ANTIGEN/DRUG SUBSTANCE  
 
 
A. General Information  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
1. Change in the name of the antigen  
Note: This change generally applies only to 
influenza vaccines.  Refer to FDA Circular No. 
2020 -002  MaV -SC  
 
 
B. Manufacture  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
2.   Change to an antigen  manufacturing facility : 
a. Replacement or addition of the manufacturing 
facility for the antigen bulk, or any 
intermediate of the antigen  7–10 1–4, 6–8 BMaV -1 
1–4, 7–10  2, 4–8 BMaV -2 
b. Deletion of a manufacturing facility or 
manufacturer of an antigen intermediate, or 
antigen bulk  5, 6 9 BMiV -N1 
c. Change of the name and/or address (for 
example: postal code, street name) of a 
manufacturer of the antigen/drug substance  11 1, 2 BMiV -N2 
Conditions  
1. The new manufacturing facility/suite is an approved antigen manufacturing site.  
2. Any changes to the manufacturing process and/o r controls are considered minor.  
3. The new facility/suite is under the same quality assurance/quality control (QA/QC)  oversight.  
4. The proposed change does not involve additional containment requirements.  
5. There should remain at least one site/manufacturer, as previously authorized,  performing the 
same function as the one(s) to be deleted.  
6. The deletion should not be due to critical deficiencies in manufacturing (such  as recurrent 
deviations, recurrent out -of-specification events, environmental  monitoring failures and so on).  
7. Specifications of the antigen remain unchanged. If there are changes to the specification o f the 
antigen, the applicant shall  file for the applicable change/s . See changes 18  and 27.    
8. If there is a change in the manufacturing site of the final product, the applicant shall file for the 
applicable change/s . See change 33 . 
9. If there are changes to the manufacturing process  of the antigen , the applicant shall file for the 
applicable change/s . See changes 3  and 4. 
10. If there is a change in scale  of the antigen,  the applicant shall file for the applicable change/s . 
See change 5 . 
11. The manufacturing site of the antigen  remains unchanged.  
Supporting data  
1. Evidence that the facility is GMP compliant.  For C hange of the name and/or address of a 
manufacturer of the antigen  (BMiV -N2), a valid GMP Certificate reflecting the proposed name 
and/or address of the manufacturer.  Philippine Variation Guideline f or Biological  Products  
 
 
12 2. Updated information including name, address and responsibility of the manufacturer of the 
antigen (i.e., Section S2 of the ACTD/ ICH CTD).  
3. Process validation study reports.  
4. Comparability of the pre - and post-change antigen with respect to physicochemical properties, 
biological activity, purity, impurities and contaminants, as appropriate. Nonclinical and/or 
clinical bridging studies may occasionally be required when quality data are insufficient to 
establ ish comparability. The extent and nature of nonclinical and/or clinical studies should be 
determined on a case -by-case basis, taking into consideration the quality -comparability 
findings, the nature and level  of knowledge of the vaccine, existing relevant nonclinical and 
clinical data, and  aspects of vaccine use.  
5. Justification for the classification of any manufacturing process and/or control  changes as  
minor.  
6. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for at least three (3) consecutive commercial -scale 
batches of the pre - and post -change antigen. Comparative pre -change test results do not need to 
be generated concurrently; relevant historical testing results are acc eptable. Matrixing, 
bracketing, the use of smaller -scale  batches, and/or the use of fewer than 3 batches may be 
acceptable where justified.  
7. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attribut es for at least three (3) commercial -scale antigen batches produced 
with the proposed changes under real -time/real -temperature testing conditions. Comparative 
pre-change test results do not need to be generated concurrently; relevant historical results for  
lots on the stability programme are acceptable. The data should cover a minimum of 3 months 
of testing unless otherwise justified. Additionally, the manufacturer should commit to 
undertake real -time stability studies to support the full shelf -life/hold -time of the antigen under 
its normal storage conditions and to report any failures in these ongoing long -term stability 
studies. Matrixing, bracketing, the use of smaller -scale batches, the use of fewer than 3 batches 
and/or use of forced degradation or  accelerated temperature conditions for stability testing may 
be acceptable where  justified.  
8. Updated post -approval stability protocol.  
9. Reason for withdrawal/deletion.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
3.   Change to the antigen fermentation, viral propagation or cellular propagation process : 
a. A critical change (a change with high potential 
to have an impact on the quality of the antigen 
or final product) (for example,  incorporation of 
disposable  bioreactor technology)  15, 16  1−7, 9, 11 , 
15 BMaV -3 
b. A change with moderate  potential to have an 
impact on the quality of the antigen or final 
product (for example, extension of the in vitro 
cell age beyond validated parameters)  2, 4, 15, 16  1−6, 8, 10 , 
15 BMaV -4 
c. A noncritical change with minimal potential to 
have an impact on the quality of the antigen or 
final product (for example, a change in 
harvesting and/or pooling procedures which 
does not affect the method of manufacture, 
recovery, intermediate storage condi tions, 
sensitivity of detection of adventitious agents 1−6, 9−11 , 
15, 16  1−4, 15 BMiV -PA1 Philippine Variation Guideline f or Biological  Products  
 
 
13 or production scale; or duplication of  a 
fermentation train)  
4.   Change to the antigen purification process involving:  
a. A critical change (a change with high potential 
to have an impact on the quality of the antigen 
or final product) (for example, a change that 
could potentially have an impact on the viral 
clearance  capacity of the process or the  
impurity profile of the anti gen) 15, 16  1, 2, 5−7, 9,  
11, 12 , 15 BMaV -5 
b. A change with moderate pot ential to have an 
impact on the quality of the antigen or final 
product (for  example, a change in the chemical  
separation method, such as from  ion-exchange 
HPLC to reverse -phase  HPLC)  2, 4, 15, 16  1, 2, 5−7,  
10, 11 , 15 BMaV -6 
c. A noncritical change with minimal potential to 
have an impact on the quality of the antigen or 
final product (for example, addition of  an in -
line filtration step equivalent  to the approved  
filtration step)  1−5, 15, 16  1, 2, 15 BMiV -PA2 
5. Change in scale of the manufacturing process:  
a. At the fermentation, viral  propagation or 
cellular  propagation stage  3–6, 11−13 , 
15, 16  2, 3, 5−7,  
9, 11  BMaV -7 
b. At the purification stage  1, 3, 5, 7 , 15, 
16 2, 5−7, 9, 
11 BMaV -8 
6. Change in supplier of raw materials of 
biological origin (for example, fetal calf 
serum, human serum albumin, trypsin)  17 4, 8, 12, 13  BMaV -9 
8, 17 4, 8 BMiV -PA3 
7. Change in source of raw materials of 
biological origin  17 4, 7, 12, 13 , 
16 BMaV -10 
8, 17 4, 7, 16 BMiV -PA4 
8. Introduction of reprocessing steps  14, 15 8, 10, 11, 
14–15 BMaV -11 
Conditions  
1. No change in the principle of the sterilization procedures of the antigen.   
2. The change does not have an impact on the viral clearance data or the chemical  nature of an 
inactivating agent.  
3. No change in the antigen specification outside the approved limits . If there are changes to the 
specification of the antigen, the applicant shall file for the applicable change/s . See changes 18  
and 27.   
4. No change in the impurity profile of the antigen outside the approved limits.  
5. The change is not necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
6. The change does not affect the purification process.  
7. The change in scale is linear with respect to the proportionality of production  parameters and 
materials.  
8. The change is for compendial raw materials of biological origin (excluding human  plasma -
derived materials).  
9. The new fermentation train is identical to the approved fermentation train(s).  
10. No change in the approved in vitro cell age.  
11. The change is not expected to have an impact on the quality, safety or efficacy of  the final 
product.  
12. No change in the proportionality of the raw materials (that is, the change in scale  is linear).  Philippine Variation Guideline f or Biological  Products  
 
 
14 13. The change in scale involves the use of the same bioreactor (that is, it does not  involve the use 
of a larger bioreactor).  
14. The need for reprocessing is not due to recurrent deviations from the validated  process and the 
root cause triggering repro cessing is identified.  
15. If there are changes to the specification of the antigen, the applicant shall file for the applicable 
change/s . See changes 18  and 27.   
16. If there are changes to the in -process controls applied during the manufacture of antige n, the 
applicant shall file for the applicable change/s . See change 15 . 
17. If there are changes to the specification of the raw material, the applicant shall file for the 
applicable change/s . See change 14 . 
Supporting data  
1. Justification for the classification of the change(s) as critical, moderate or noncritical  as this 
relates to the impact on the quality of the antigen.  
2. Flow diagram (including process and in -process controls) of the proposed  manufacturing 
process(es) and a brief narrative description of the proposed  manufacturing process(es).  
3. If the change results in an increase in the number of population doublings or subcultivations, 
information on the characterization and testing of the  post-production c ell bank for 
recombinant product, or of the antigen for non -recombinant  product.  
4. For antigens obtained from, or manufactured with, reagents obtained from sources that are at 
risk of transmitting bovine spongiform encephalopathy/transmissible spongiform 
encephalopathy (BSE/TSE) agents (for example, ruminant origin), information and evidence 
that the material does not pose a potential BSE/TSE risk (for example, name of manufacturer, 
species and tissues from which the material  is a derivative, country of origi n of the source 
animals, and use and previous  acceptance of the material) . 
5. Process validation study reports.  
6. Comparability of the pre - and post -change antigen with respect to physicochemical properties, 
biological activity, purity, impurities and contaminants, as appropriate. Nonclinical and/or 
clinical bridging studies may occasionally be required when quality data are insufficient to 
establish comparability. The extent and nature of nonclinical and/or clinical studies should be 
determined on a ca se-by-case basis, taking into consideration the quality -comparability 
findings, the nature and level  of knowledge of the vaccine, existing relevant nonclinical and 
clinical data, and  aspects of vaccine use.  
7. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for at least three (3) consecutive commercial -scale 
batches of the pre - and post -change antigen. Comparative pre -change test results do not need to 
be generated concurre ntly; relevant historical testing results are acceptable. Matrixing, 
bracketing, the use of  smaller -scale batches, and/or the use of fewer than 3 batches may be 
acceptable  where justified.  
8. Description of the batches and summary of in -process and release te sting results as quantitative 
data, in a comparative tabular format, for one (1) commercial -scale batch of the pre - and post -
change antigen. Comparative pre -change test results do not need to be generated concurrently; 
relevant historical testing results a re acceptable. Batch data on the next two full -production 
batches should be made available on request and should be reported if outside the  specification 
(with proposed action). The use of a smaller -scale batch may be  acceptable where justified . 
9. Comparativ e pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale antigen batches produced 
with the proposed changes under real -time/real -temperature testing conditions. Com parative 
pre-change test results do not need to be generated concurrently; relevant historical results for 
lots on the stability programme are acceptable. The data should cover a minimum of 3 months 
of testing unless otherwise justified. Additionally, the manufacturer should commit to 
undertake real -time stability studies to support the full shelf -life/hold -time of the antigen under 
its normal storage conditions and to report any failures in these ongoing long -term stability 
studies. Matrixing, bracketing, the use of smaller -scale batches, the use of fewer than 3 batches Philippine Variation Guideline f or Biological  Products  
 
 
15 and/or use of forced  degradation or accelerated temperature conditions for stability testing may 
be acceptable where justified.  
10. Comparative pre - and post -change test results for the manufact urer’s characterized key 
stability -indicating attributes for at least one (1) commercial -scale antigen batch produced with 
the proposed changes under real -time/real -temperature testing conditions. Comparative pre -
change test results do not need to be gener ated concurrently; relevant historical results for lots 
on the stability programme are acceptable. The data should cover a minimum of 3 months of 
testing unless otherwise justified. Additionally, the manufacturer should commit to undertake 
real-time stabil ity studies to support the full shelf -life/hold -time of the antigen under its normal 
storage conditions and to report any failures in these ongoing long -term stability studies. 
Matrixing, bracketing, the use of smaller -scale  batches, and/or use of forced d egradation or 
accelerated temperature conditions  for stability testing may be acceptable where justified . 
11. Updated post -approval stability protocol and stability commitment to place the  first 
commercial -scale batch of the final product manufactured using th e post -change  antigen into 
the stability programme.  
12. Information assessing the risk with respect to potential contamination with  adventitious agents 
(for example, impact on viral clearance studies and BSE/TSE  risk). 
13. Information demonstrating comparability of the raw materials/reagents of  both sources.  
14. Data describing the root cause triggering the reprocessing, as well as validation  data (for 
example, extended hold -times and resistance to additional mechanical  stress) to help prevent 
the reproc essing from having an impact on the antigen.  
15. Comparative tabulated format of the description of the current and proposed manufacturing 
process es, including in -process controls, with changes highlighted.  
16. Comparative tabulated format of the  information on th e current and proposed sources of the 
raw material  (for example , animal species, country of origin).  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
9. Change to the cell banks:  
Note: New cell substrates that are unrelated to the licensed master cell bank (MCB) or pre ‑MCB 
material generally require a new application for MA or license  application.  
a. Generation of a new MCB  1 1, 2, 5, 7−9  BMaV -12 
b. Generation of a new working cell bank (WCB)  None  1, 2 BMaV -13 
2−4 1, 2 BMiV -PA5 
c. Change in cell bank storage site  7 10 BMiV -N3 
10. Change to the seed lots:  
Note: New viral or bacterial seeds that are unrelated to the master seed lot (MSL) or pre ‑MSL 
material generally require a new application for MA or license  application.  
a. Generation of a new MSL  1 1, 5−9, 11  BMaV -14 
b. Generation of a new working seed lot (WSL)  2, 3 5−9, 11  BMaV -15 
2−4 5-6 BMiV -PA6 
c. Generation of a new WSL by extending the 
passage level of an existing WSL beyond an 
approved level  None  5−7, 11  BMaV -16 
d. Change in seed lot storage site  7 10 BMiV -N4 
11. Change in cell bank/seed lot testing/storage 
site 5, 7 10 BMiV -N5 
12. Change in cell bank/seed lot qualification 
protocol  None  3, 4 BMaV -17 
6 4 BMiV -PA7 
Conditions  Philippine Variation Guideline f or Biological  Products  
 
 
16 1. The new MCB is generated from a pre -approved MCB or WCB or the new MSL is generated 
from a pre -approved MSL or WSL.  
2. The new cell bank/seed lot is generated from a pre -approved MCB/MSL.  
3. The new cell bank/seed lot is at the pre -approved passage level.  
4. The new cell bank/seed lot is released according to a pre -approved protocol/process or as 
described in the original license . 
5. No changes have been made to the tests/acceptance criteria used for the release of the cell 
bank/se ed lot.  
6. The protocol is considered more stringent (that is, addition of new tests or narrowing of 
acceptance criteria).  
7. No changes have been made to the storage conditions used for the cell bank/seed lot and the 
transport conditions of the cell bank/seed lot has been validated.  
Supporting data  
1. Qualification of the cell bank or seed lot according to guidelines considered acceptable . 
2. Information on the characterization and testing of the MCB/WCB, and cells from the end-of-
production passage or post -production passage.  
3. Justification of the change to the cell bank/seed lot qualification protocol.  
4. Updated cell bank/seed lot qualification protocol.  
5. Comparability of the pre - and post -change antigen with respect to physico chemical properties, 
biological activity, purity, impurities and contaminants, as appropriate. Nonclinical and/or 
clinical bridging studies may occasionally be required when quality data are insufficient to 
establish comparability. The extent and nature of  nonclinical and/or clinical studies should be 
determined on a case -by-case basis, taking into consideration the quality -comparability 
findings, the nature and level of knowledge of the vaccine, existing relevant nonclinical and 
clinical data, and aspects of vaccine use.  
6. Quality control test results as quantitative data in tabular format for the new seed lot.  
7. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for at least t hree (3) consecutive commercial -scale 
batches of the antigen derived from the new cell bank/seed lot. Matrixing, bracketing, the use 
of smaller -scale batches, and/or the use of fewer than 3 batches may be acceptable where 
justified and.  
8. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale antigen batches produced 
with the proposed changes under real -time/real -temperature testing conditions. Comparative 
pre-change test results do not need to be generated concurrently; relevant historical results for 
lots on the stability programme are acceptable. The data should cover a minimum of 3 months 
testing unless otherwise justified. Additionally, the manufacturer  should commit to undertake 
real-time stability studies to support the full shelf -life/hold -time of the antigen under its normal 
storage conditions and to report any failures in these ongoing long -term stability studies. 
Matrixing, bracketing, the use of s maller -scale batches, the use of fewer than 3 batches and/or 
use of forced degradation or accelerated temperature conditions for stability testing may be 
acceptable where justified . 
9. Updated post -approval stability protocol.  
10. Evidence that the new company/fa cility is GMP compliant.  
11. Revised information on the quality and controls of critical starting materials (for example, 
specific pathogen -free eggs and chickens) used in the generation of the new WSL, where 
applicable.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
13. Change in equipment used in the antigen manufacturing process, such as:  Philippine Variation Guideline f or Biological  Products  
 
 
17 a. Introduction of new equipment with different 
operating principles  and different product 
contact  material  1, 2 1−6 BMaV -18 
b. Introduction of new equipment with the same 
operating principles  but different product 
contact  material  1, 2 1, 3−6  BMaV -19 
c. Introduction of new equipment with different 
operating principles  but the same product 
contact  material  1, 2 1−3, 5, 6  BMaV -20 
d. Replacement of equipment with  equivalent 
equipment (including  filter)  1, 2 1, 5−7  BMiV -PA8 
Conditions  
1. If there are changes to the specification of the antigen, the applicant shall file for the applicable 
change/s . See changes 18  and 27.   
2. If there are changes to the in -process controls applied during the manufacture of antigen, the 
applicant shall file for the applicable change/s . See change 15 . 
Supporting data  
1. Information on the in -process control testing.  
2. Process validation study reports.  
3. Description of the batches and summary of results as quantitative data, in a comparative tabular 
format, for one (1) commercial -scale batch of the antigen produced with the approved and 
proposed product contact equipment/material. Batch data on th e next two full -production 
batches should be made  available on request and reported if outside specification (with  
proposed action).  
4. Information on leachables and extractables.  
5. Information on the new equipment and comparison of similarities and differences  regarding 
operating principles and specifications between the new and the  replaced equipment.  
6. Information demonstrating requalification of the equipment or requalification of  the change.  
7. Rationale for regarding the equipment as similar/comparable, as appl icable.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
14. Change in specification for the materials, involving:  
a. Raw materials/intermediates:  
Widening of the approved specification limi ts 
or deletion of test parameter and limits for 
starting materials/intermediates, which may 
have a significant effect on the overall quality 
of the antigen and/or final product and are not 
changes to the cell banks or seed lots  None  1, 3−6, 8, 
11, 13 BMaV -21 
b. Raw materials/intermediates:  
Narrowing of the approved specification limits  
or addition of test parameter and limits  for 
starting materials/intermediates  1−4 1, 3−7 , 13 BMiV -PA9 
c. Raw materials/intermediates:  
Change of a test procedure for starting 
materials/intermediates  4, 7 1, 3−7, 13 BMiV -PA10 
d. Raw materials /intermediates : 
Change of specifications and/or test procedure 
following the updates in the compendium  13 1, 3, 13, 15 BMiV -N6 Philippine Variation Guideline f or Biological  Products  
 
 
18 15. Change to in -process tests and/or acceptance criteria applied during manufacture of the 
antigen, involving:  
a. Narrowing of in -process limits  3, 5, 8, 9 , 12 2, 6, 14 BMiV -PA11 
b. Addition of new in -process test  and limits  4, 5, 10, 11 , 
12 2−6, 8, 10 , 
14 BMiV -PA12 
c. Deletion of a non -significant  in‑process test  4−6, 12 2, 6, 9 , 14 BMiV -PA13 
d. Widening of the approved  in‑process limits  12 2−6, 8, 10, 
11, 14 BMaV -22 
3−5, 12 2, 6, 8, 10, 
11, 14 BMiV -PA14 
e. Deletion of an in -process test which may have 
a significant  effect on the overall quality of  the 
antigen  12 2, 6, 8, 10 , 
14 BMaV-23 
f. Addition or replacement of an  in‑process test 
as a result of a  safety or quality issue  12 2−6, 8, 10 , 
14 BMaV-24 
16. Change in in -process controls testing site  3−5, 7, 8  12 BMiV -N7 
Conditions  
1. The change in specification for the materials is within the approved limits.   
2. The grade of the materials is the same or is of higher quality, where appropriate.  
3. No change in the antigen specification outside the approved limits.  the applicant shall file for 
the applicable change/s . See changes 18  and 27.   
4. No change in the impurity profile of the antigen outside the approved limits.  
5. The change is not necessitated by recurring events arising during manufacture or because of 
stability concerns.  
6. The test does not concern a critical attribute (for example, content, impurity, any critical 
physical characteristics or microbial purity).  
7. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and 
sensitivity, if applicable.  
8. No change in the in -process cont rols outside the approved limits . If there are changes to the in -
process controls applied during the manufacture of antigen, the applicant shall file for the 
applicable change/s . See change 15 . 
9. The test procedure remains the same, or changes in the test procedure are minor.  
10. Any new test method does not concern a novel non -standard technique or a standard technique 
used in a novel way.  
11. The new test method is not a biological/immunological/immunochemical or physicochemical 
method or a method using a bi ological reagent (does not include standard pharmacopoeial 
microbiological methods).  
12. Release and shelf -life specifications of the antigen remain unchanged. If there are changes to 
the specification of the antigen, the applicant shall file for the applicabl e change/s . See change s 
18 and 27.   
13. Applicable to compendial specifications and/or test procedure s only. Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Revised information on the quality and controls of the materials (for example,  raw materials, 
starting materials, solvents, reagents and catalysts) used in the  manufacture of the post -change 
antigen.  
2. Revised information on the controls performed at critical steps of the  manufacturing process 
and on intermediates of the proposed antigen.  
3. Updated antigen specification, if changed.  
4. Copies or summaries of analytical procedures, if new analytical procedures  are used.  
5. Validation study reports, if new analytical procedures are used.  Philippine Variation Guideline f or Biological  Products  
 
 
19 6. Comparative table or description, where applicable, of pre - and post -change  in‑process 
tests/l imits.  
7. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for one (1) commercial -scale batch of the pre - and post -
change antigen. Comparative pre -change test results do no t need to be generated concurrently; 
relevant historical testing results are acceptable. Batch data on the next two full -production 
batches should be made available on request and reported if outside  specification (with  
proposed action). The use of a small er-scale batch may be acceptable where  justified . 
8. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for at least three (3) consecutive commercial -scale 
batches of the pre - and post -change antigen. Comparative pre -change test results do not need to 
be generated concurrently; relevant historical testing results are acceptable. Matrixing, 
bracketing, the use of  smaller -scale batches and/or the use of fewer than 3 batches may be 
acceptable  where justified . 
9. Justification/risk assessment showing that the attribute is non -significant.  
10. Justification for the new in -process test and limits.  
11. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stabili ty-indicating attributes for at least three (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; rel evant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support th e full shelf -life/hold -time of the 
final product under its normal storage conditions and to report any failures in these ongoing 
long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches and/or us e of forced degradation or accelerated temperature conditions for 
stability  testing may be acceptable where justified.  
12. Evidence that the new company/facility is GMP compliant.  
13. Comparative tabulated format of the current and revised specifications and/or te st procedure s 
of the raw material/intermediate with changes highlighted.  
14. Comparative tabulated format of description of the current and proposed test procedures/in -
process controls with changes highlighted.  
15. Copy of the official monograph of the updated compendium.  
 
 
C. Control of the Antigen/Drug Substance  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
17. Change affecting the quality control (QC) (release and stability) testing of the antigen, 
involving:  
a. Transfer of the QC testing activities for a non -
pharmacopoeial assay to  a new company not 
approved in  the current MA or licence  1−3 1−2 BMiV -PA15 
b. Transfer of the QC testing activities for a 
pharmacopoeial assay to a  new company not 
approved in the  current MA or licence  1 1−2 BMiV -PA16 
Conditions  
1. The transferred QC test is not a potency assay (for example, the test may be a  bioassay such as 
an endotoxin assay or sterility assay).  
2. No changes to the test method.  
3. Transfer within a site approved in the current MA for the performance of other tests.  Philippine Variation Guideline f or Biological  Products  
 
 
20 Supporting data  
1. Information demonstrating technology transfer qualification.  
2. Evidence that the new company/facility is GMP compliant.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
18. Change in the specification used to release the antigen, involving:  
a. Deletion of a test  None  1, 5, 8 , 9 BMaV -25 
b. Addition of a test  1−3 1−3, 5 , 9 BMiV -PA17 
c. Replacement of an analytical procedure  None  1−5, 9  BMaV -26 
d. Change in animal species/strains for a test (for 
example, new species/strains, animals of 
different age, new supplier where genotype of 
the animal cannot be confirmed)  None  6, 7, 9 BMaV -27 
e. Minor changes to an approved analytical 
procedure  4−7 1, 4, 5, 9 BMiV -PA18 
f. Change from an in -house analytical procedure 
to a recognized compendial/pharmacopoeial 
analytical procedure  4, 7 1−3, 9  BMiV -PA19 
g. Widening of an acceptance criterion  None  1, 5, 8, 9  BMaV -28 
h. Narrowing of an acceptance criterion  1, 8, 9  1, 9 BMiV -PA20 
i. Change of specifications and/or test procedure  
following the updates in the compendium  10 1, 9, 10  BMiV -N8 
Conditions  
1. The change does not result from unexpected events arising during manufacture (for example, 
new unqualified impurity or change in total impurity limits).  
2. No change in the limits/acceptance criteria outside the approved limits for the approved assays.  
3. The addition of the test is not intended to monitor new impurity species.  
4. No change in t he acceptance criteria outside the approved limits.  
5. The method of analysis is the same and is based on the same analytical technique or principle 
(for example, a change in column length or temperature, but not a different type of column or 
method) and no n ew impurities are detected.  
6. The modified analytical procedure maintains or tightens precision, accuracy, specificity and 
sensitivity.  
7. The change does not concern potency testing.  
8. Acceptance criteria for residuals are within recognized or approved acceptance limits (for 
example, within ICH limits for a Class 3 residual solvent, or pharmacopoeial requirements).  
9. The analytical procedure remains the same, or changes to the analytical p rocedure are minor.  
10. Applicable to compendial specifications and/or test procedure s only.  Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Updated antigen specification.  
2. Copies or summaries of analytical procedures, if new analytical procedures are used.  
3. Validation reports, if new analytical procedures are used.  
4. Comparative results demonstrating that the approved and proposed analytical procedures are 
equivalent.  
5. Justification for d eletion of the test or for the proposed antigen specification (for example, 
tests, acceptance criteria or analytical procedures).  
6. Data demonstrating that the change in animals/strains give results comparable to those 
obtained using the approved animals/str ains. 
7. Copies of relevant certificate of fitness for use (for example, veterinary certificate).  Philippine Variation Guideline f or Biological  Products  
 
 
21 8. Declaration/evidence that consistency of quality and of the production process is maintained.  
9. Comparative tabulated format of the currently approved and proposed  specifications  and/or test 
procedures  of the antigen  with changes highlighted.  
10. Copy of the official monograph of the updated compendium.  
 
 
D. Reference Standards or Materials  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
19. Qualification of a new reference standard 
against a new primary international 
standard  None  1, 2 BMiV -PA21 
20. Change in the reference standard from in -
house (no relationship with international 
standard) to pharmacopoeial or 
international standard  None  1, 2 BMiV -PA22 
21. Qualification of a new lot of reference 
standard against the approved reference 
standard (including qualification of a new 
lot of a secondary reference standard against 
the approved primary standard)  1 1, 2 BMiV -PA23 
22. Change to reference standard qualification 
protocol  None  3, 4 BMiV -PA24 
23. Extension of reference standard shelf -life 2 5 BMiV -PA25 
Conditions  
1. Qualification of the new reference standard is according to an approved protocol.  
2. The extension of the shelf -life is according to an approved protocol.  
Supporting data  
1. Justification for the change in reference standard.  
2. Information demonstrating qualification of the proposed reference standards  or materials (for 
example, source, characterization, certificate of analysis and  comparability data).  
3. Justification of the change to the reference standard qualification protocol.  
4. Updated reference standard qualification protocol.  
5. Summary of stability testing and results to support the extension of reference  standard shelf -
life. 
 
 
E. Container Closure System  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
24. Change in the primary container closure 
system(s) for the storage and shipment of the 
antigen  None  1, 2, 4, 5  BMaV -29 
1 1, 3, 5  BMiV -PA26 
Conditions  
1. The proposed container closure system is at least equivalent to the approved  container closure 
system with respect to its relevant properties.  
Supporting data  
1. Information on the proposed container closure system (for example, description,  composition, 
materials of construction of primary packaging components and  specification).  Philippine Variation Guideline f or Biological  Products  
 
 
22 2. Data demonstrating the suitability of the container closure system (for  example,  
extractable/leachable testing).  
3. Results demonstrating that the proposed container closure system is at least equivalent to the 
approved container closure syste m with respect to  its relevant properties (for example, results 
of transportation or interaction  studies, and extractable/leachable studies).  
4. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attrib utes for at least three (3) commercial -scale antigen batches produced 
with the proposed changes under real -time/real -temperature testing conditions. Comparative 
pre-change test results do  not need to be generated concurrently; relevant historical results f or 
lots on  the stability programme are acceptable. The data should cover a minimum of  3 months 
testing unless otherwise justified. Additionally, the manufacturer  should commit to undertake 
real-time stability studies to support the full shelf -life/hold -time of the antigen under its normal 
storage conditions and to report  any failures in these ongoing long -term stability studies. 
Matrixing,  bracketing, the use of smaller -scale batches, the use of fewer than 3 batches  and/or 
use of forced degradation or accel erated temperature conditions for  stability testing may b e 
acceptable where justified . 
5. Comparative table of pre - and post -change specifications.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
25. Change in the specification of the primary container closure system for the antigen, 
involving:  
a. Deletion of a test  1, 2 1, 2, 4 BMiV -PA27 
b. Addition of a test  3 1−3, 4 BMiV -PA28 
c. Replacement of an analytical  procedure  6, 7 1−3, 4 BMiV -PA29 
d. Minor changes to an analytical  procedure  4−7 1−3, 4 BMiV -PA30 
e. Widening of an acceptance  criterion  None  1, 2, 4 BMiV -PA31 
f. Narrowing of an acceptance  criterion  8 1, 4 BMiV -PA32 
Conditions  
1. The deleted test has been demonstrated to be redundant compared to the  remaining tests or is 
no longer a pharmacopoeial requirement.  
2. The change to the specification does not affect the functional properties of the  container 
closure component nor result in a potential impact on the performance  of the antigen.  
3. The change is not  necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
4. There is no change in the acceptance criteria outside the approved limits.  
5. The new analytical procedure is of the same type.  
6. Results of method validation demonst rate that the new or modified analytical  procedure is at 
least equivalent to the approved analytical procedure.  
7. The new or modified analytical procedure maintains or tightens precision,  accuracy, specificity 
and sensitivity.  
8. The change is within the range of approved acceptance criteria or has been made  to reflect a 
new pharmacopoeial monograph specification for the container  closure component.  
Supporting data  
1. Updated copy of the proposed specification for the primary container closure  system.  
2. Rationale for the change in specification for a primary container closure system.  
3. Description of the analytical procedure and, if applicable, validation data.  
4. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the primary container closure system with changes highlighted.  
 
 Philippine Variation Guideline f or Biological  Products  
 
 
23 F. Stability  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
26. Change in the shelf -life/hold -time for the antigen or for a stored intermediate of the 
antigen, involving:  
a. Extension  None  1−5 BMaV -30 
1−5 1, 2, 5  BMiV -PA33 
b. Reduction  None  1−5 BMaV -31 
6 2−4 BMiV -PA34 
Conditions  
1. No changes to the container closure system in direct contact with the antigen with the potential 
of impact on the antigen, or to the recommended storage conditions of the antigen.  
2. The approved shelf -life is at least 24 months.  
3. Full long -term stability data are available covering the proposed shelf -life and are based on 
stability data generat ed on at least three (3) commercial -scale batches.  
4. Stability data were generated in accordance with the approved stability protocol.  
5. Significant changes were not observed in the stability data.  
6. The reduction in the shelf -life is not necessitated by recurri ng events arising during 
manufacture or because of stability concerns. Note: Problems arising during manufacturing or 
stability concerns should be reported for evaluation.  
Supporting data  
1. Summary of stability testing and results (for example, studies conducted, protocols used and 
results obtained).  
2. Proposed storage conditions and shelf -life, as appropriate.  
3. Updated post -approval stability protocol and stability commitment.  
4. Justification of the change to the post -approval stability protocol or s tability commitment.  
5. Results of stability testing (that is, full real -time/real -temperature stability data covering the 
proposed shelf -life generated on at least three (3) commercial -scale batches). For 
intermediates, data to show that the extension of shelf -life has no negative impact on the 
quality of the antig en. Under special circumstances , interim stability testing results and a 
commitment to notify of any failures in the ongoing long -term stability studies may be 
provided.  
 
 
Descripti on of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
27. Change in the post -approval stability  protocol of the antigen, involving:  
a. Significant change to the post -approval stability 
protocol or stability commitment, such as 
deletion of a test parameter or limit , 
replacement  of an analytical procedure , 
widening of specification limits,  or change  in 
storage temperature  None  1−7 BMaV -32 
1 1, 2, 4− 7 BMiV -PA35 
b. Addition of time point(s) into the  post-approval 
stability protocol  None  4, 6 BMiV -PA36 
c. Addition of test(s) into the post-approval 
stability protocol  or tightening of specification 
limits  2 1, 2, 4, 6 , 7 BMiV -PA37 
d. Deletion of time point(s) from the  post-
approval stability protocol  beyond the approved 
shelf -life None  4, 6 BMiV -PA38 Philippine Variation Guideline f or Biological  Products  
 
 
24 e. Deletion of time point(s) from the post -
approval stability protocol within the approved 
shelf -life 3 4, 6 BMiV -PA39 
f. Change to the post -approval stability protocol, 
such as change in specifications and/or test 
procedures following the updates in the 
compendium  4 4, 7, 8 BMiV -N9 
Conditions  
1. For the replacement of an analytical procedure, the new analytical procedure  maintains or 
tightens precision, accuracy, specificity and sensitivity.  
2. The addition of test(s) is not due to stability concerns or to the identification of  new impurities.  
3. The approved a ntigen shelf -life is at least 24 months.  
4. Applicable to compendial specifications and/or test procedure s only. Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Copies or summaries of analytical procedures, if new analytical procedures are used.  
2. Validation study reports, if new analytical procedures are used.  
3. Proposed storage conditions and/or shelf -life, as appropriate.  
4. Updated post -approval stability protocol and stabilit y commitment.  
5. If applicable, stability testing results to support the change to the post -approval stability 
protocol or stability commitment (for example, data showing greater  reliability of the 
alternative test).  
6. Justification for the change to the post -approval stability protocol.  
7. Comparative tabulated format of the currently approved and proposed stability protocols or 
stability commitments  with changes highlighted.  
8. Copy of the official monograph of the updated compendium.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
28. Change in the storage conditions for the antigen, involving:  
a. Addition or change of storage condition for the 
antigen (for  example, widening or narrowing  of 
a temperature criterion)  None  1−4 BMaV -33 
1, 2 1−3 BMiV -PA40 
Conditions  
1. The change is not necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
2. The change consists in the narrowing of a temperature criterion within the  approved ranges.  
Supporting data  
1. Proposed storage conditions and shelf -life. 
2. Updated post -approval stability protocol and stability commitment.  
3. Justification of the change in the labelled storage conditions/cautionary statement.  
4. Results of stability testing (that is, full real-time/real -temperature stability data  covering the 
proposed shelf -life generated on at least three (3) commercial -scale  batches).  
 
 
II. CHANGES TO THE FINAL PRODUCT  
 
 
G. Description and Composition of t he Final Product  
 Philippine Variation Guideline f or Biological  Products  
 
 
25 Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
29. Change in the description or composition of the final product, involving:  
a. Addition of a dosage form (for example,  
lyophil ised powder to liquid ) New registration application  
b. Change in the formulation (for example, 
addition or removal  of an excipient)  New registration application  
c. Change in the formulation (for example, 
qualitative or quantitative change of excipient, 
or new diluents for lyophilized product)  
Note: Change in formulation does  not include 
changes in antigen(s) or  adjuvants . A change in 
antigen(s) or adjuvant(s) requires the filing of a 
new application for MA or licensure.   1 1−10  BMaV -34 
d. Change in fill volume (that is, same  
concentration, different volume)  1, 2 1, 5, 7, 10  BMaV -35 
e. Change of presentation (for example, from pre -
filled syringe to vial)  1 1, 3, 5, 
7−10  BMaV -36 
f. Addition of a new presentation (for example, 
addition of a new pre -filled syringe where the 
approved  presentation is a vial for a vaccine  in 
a liquid dosage form)  1 1, 3, 5, 
7−11  BMaV -37 
Conditions  
1. Change will need to comply with the finished product specifications, for example release and 
shelf -life specifications of the drug product remain unchanged, except for the update of product 
description with respect to presentation/ appearance/fill volume as  a consequence of the change 
(where applicable). If there are changes to the specification of the final product, the applicant 
shall file for the applicable change/s. See changes 46  and 58.   
2. The packaging material remains unchanged.  Philippine Variation Guideline f or Biological  Products  
 
 
26 Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Characterization data demonstrating that the conformation and immunogenicity of the antigen 
is com parable in the  formulation.  
3. Comparative tabulated format of the currently approved and proposed packaging 
presentations/primary packaging materials/ diluents or product formulations with calculated 
changes highlighted (state changes in the percentage of the  proposed excipient out of the total 
target dosage form weight, where applicable).  
4. Discussion of the components of the final product, as appropriate (for example, choice of 
excipients, compatibility of antigen and excipients, leachates or compatibility wi th new 
container closure system, as appropriate).  
5. Information on the batch formula, manufacturing process and process controls, control of 
critical steps and intermediates, and process validation study reports.  
6. Control of excipients, if new excipients are proposed (for example, specification).  
7. Information on specification, analytical procedures (if new analytical methods are used), 
validation of analytical procedures (if new analytical methods are used), batch analyses 
(certificate of analysis for three (3)  consecutive commercial -scale batches should be provided). 
Bracketing for multiple -strength products, container sizes and/or fills may be acceptable if 
scientifically justified.  
8. Information on the container closure system and leachables and extractables, i f any of the 
components have changed (for example, description, materials of construction and summary of 
specification).  
9. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least thr ee (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product under its normal storage conditions and to report any failures in these ongoing 
long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches and/or use of forced degradation or accelerated te mperature conditions for 
stability testing may be acceptable where justified.  
10. Supporting clinical data or a justification for why such studies are not needed.  
11. Amended relevant ACTD/ ICH CTD section/s.  
 
 
H. Description and Composition of t he Final Product:  
Change to a n Adjuvant  
Note:  
▪ Change in type/structure of a chemical adjuvant, in the type of a biological adjuvant  
or in a component of a biological adjuvant may necessitate the filing of a new  
application for MA or licensure.  
 
▪ For additi onal guidance on the required supporting data for quality changes for  
chemical and biological adjuvants, see recommendations for other changes to the  final 
product, such as changes to facilities, equipment, manufacturing process,  quality 
control, shelf -life, and so on, as applicable.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  Philippine Variation Guideline f or Biological  Products  
 
 
27 30. Change involving an approved chemical/synthetic adjuvant:  
a. Change in supplier of a chemical/synthetic 
adjuvant  None  4, 5, 10, 11  BMiV -PA41 
1−3 5 BMiV -PA42 
b. Change in manufacture of a  chemical/synthetic 
adjuvant  None  3−5, 10, 11 , 
14 BMiV -PA43 
c. Change in specification of a chemical/synthetic 
adjuvant  (including tests and/or the  analytical 
procedures)  None  7−11 , 14 BMiV -PA44 
1, 3 7−9, 14 BMiV -PA45 
31. Change involving a biological adjuvant:  
a. Change in supplier of a biological  adjuvant  None  1−7, 10−1 3 BMaV -38 
b. Change in manufacture of a  biological adjuvant  None  1−7, 10−1 4 BMaV -39 
4 1−7, 10−12 , 
14 BMiV -PA46 
c. Change in specification of a biological adjuvant 
(including  tests and/or the analytical  
procedures)  None  6−10 , 14 BMiV -PA47 
1, 3 7−8, 14 BMiV -PA48 
Conditions  
1. The specification of the adjuvant is equal to or narrower than the approved limits  (that is, 
narrowing of acceptance criterion).  
2. The adjuvant is an aluminium salt.  
3. The change in specification consists of the addition of a new test or of a minor  change to an 
analytical procedure.  
4. There is no change in the manufacturer and/or supplier of the adjuvan t. 
Supporting data  
1. Information assessing the risk with respect to potential contamination with adventitious agents 
(for example, impact on the viral clearance studies, BSE/TSE  risk). 
2. Information on the quality and controls of the materials (for example, raw  materials, starting 
materials) used in the manufacture of the proposed adjuvant.  
3. Flow diagram of the proposed manufacturing process(es), a brief narrative description of the 
proposed manufacturing process(es), and information on  the controls p erformed at critical 
steps of the manufacturing process and on  intermediates of the proposed adjuvant.  
4. Process validation study reports (for example, for manufacture of the adjuvant)  unless 
otherwise justified.  
5. Description of the general properties, includ ing stability, characteristic features  and 
characterization data of the adjuvant, as appropriate.  
6. Comparability of the pre - and post -change adjuvant with respect to physicochemical 
properties, biological activity, purity, impurities and contaminants, as ap propriate. Nonclinical 
and/or clinical bridging studies may occasionally be required when quality data are insufficient 
to establish comparability. The extent and nature of nonclinical and clinical studies should be 
determined on a case -by-case basis, taki ng into consideration the quality -comparability 
findings, the nature and level of knowledge of the adjuvant, existing relevant nonclinical and 
clinical  data, and aspects of vaccine use.  
7. Updated copy of the proposed specification for the adjuvant (and updat ed analytical procedures 
if applicable).  
8. Copies or summaries of analytical procedures, if new analytical procedures are used.  
9. Validation study reports, if new analytical procedures are used.  
10. Description of the batches and summary of results as quantitative  data, in a  comparative tabular 
format, for at least three (3) consecutive commercial -scale  batches of the final product with the 
pre-change (approved) and post -change  (proposed) adjuvant, as applicable. Comparative test 
results for the approved  adjuvant d o not need to be generated concurrently; relevant historical 
testing  results are acceptable.  Philippine Variation Guideline f or Biological  Products  
 
 
28 11. Comparative pre - and post -change test results for the manufacturer’s characterized  key 
stability -indicating attributes for at least three (3) commercial -scale final product  batches 
produced with the proposed changes under real -time/real -temperature  testing conditions. 
Comparative pre -change test results do not need to be generated  concurrently; relevant 
historical results for lots on the stabili ty programme are  acceptable. The data should cover a 
minimum of 3 months testing unless otherwise  justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product  under its  normal storage conditions and to report any failures in these ongoing  
long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches,  the use of 
fewer than 3 batches and/or use of forced degradation or accelerated  temperatu re conditions for 
stability testing may be acceptable where justifie d. 
12. Supporting nonclinical and clinical data, if applicable.  
13. Evidence that the facility is GMP compliant.  
14. Comparative tabulated format of the currently approved and proposed manufacturing 
processes/specifications and/or test procedures of the adjuvant with changes highlighted.  
 
 
I. Description and Composition of t he Final Product: Change 
to a Diluent  
Note: Changes to diluents containing adjuvants and/or antigens are considered final  products 
and as such the corresponding changes to final product (not diluent) should  be applied.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
32. Change to the diluent, involving:  
Note: Inclusion or replacement of the diluent for the drug product, refer to BMaV -34.  
a. Change in manufacturing process  None  1−4, 7 BMiV -PA49 
b. Replacement of the source of a diluent  None  1−6, 9 BMiV -PA50  
c. Addition to the source of a diluent  None  1−6, 8, 9  BMiV -PA51 
d. Change in facility used to manufacture a 
diluent (same company)  1, 2 1, 3, 5 , 6 BMiV -PA52 
d. Addition of a diluent filling line  1−3 1, 3, 5 , 7 BMiV -PA53 
e. Addition of a diluent into an  approved filling 
line 1, 2 1, 3, 5  BMiV -PA54 
f. Deletion of a diluent  None  10 BMiV -N10 
Conditions  
1. The diluent is water for injection or a salt solution (including buffered salt solutions) – that is, 
it does not include an ingredient with a functional activity (such as a  preservative) and there is 
no change to its composition.  
2. After reconstitution, there is no change in the final product specification outside  the approved 
limits.  
3. The addition of the diluent filling line is in an approved filling facility.  
Supporting data  
1. Flow diagram (including process and in-process controls) of the proposed manufacturing 
process(es) and a brief narrative description of the proposed  manufacturing process(es).  
2. Updated copy of the proposed specification for the diluent.  
3. Description of the batches and summary of results as qua ntitative data, in a comparative tabular 
format, for at least three (3) consecutive commercial -scale batches of the approved and 
proposed diluent. Comparative test results for the  approved diluent do not need to be generated 
concurrently; relevant historic al testing results are acceptable.  
4. Updated stability data on the product reconstituted with the new diluent.  Philippine Variation Guideline f or Biological  Products  
 
 
29 5. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately authorized for the product  and/or  activity  concerned.  
6. Comparative tabulated format of information on the currently registered and proposed 
production facilities (such as name, address and responsibilities).  
7. Comparative tabulated format of the description of the current and proposed manufacturing 
processes or lines, including in -process controls, with changes highlighted.  
8. Amended relevant ACTD/ ICH CTD section/s.  
9. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporatin g the proposed change (where applicable).  
10. Reason for withdrawal/deletion.  
 
 
J. Manufacture  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
33. Change involving a final product manufacturer/manufacturing facility, such as:  
a. Replacement of a manufacturing facility for the 
final product (including formulation/filling and 
primary packaging)  None  1−7, 11 BMaV -40 
1−5 1−3, 5−8 , 
11 BMaV -41 
b. Addition of a manufacturing facility for the 
final product (including formulation/filling and 
primary packaging)  None  1−7, 9, 11 BMaV -42 
1−5 1−3, 5−9 , 
11 BMaV -43 
c. Replacement of a secondary packaging facility,  
a labelling/storage facility or a  distribution 
facility  2, 3 1−3, 11 BMiV -PA55 
d. Addition of a secondary packaging facility, a 
labelling/storage facility or a distribution 
facility  2, 3 1−3, 9 , 11 BMiV -PA56 
e. Replacement of the company or party 
responsible for batch release  9 1, 2, 11, 1 2 BMiV -PA57 
f. Addition of the company or party responsible 
for batch release  9 1, 2, 9, 11, 
12 BMiV -PA58 
g. Deletion of a final product manufacturing 
facility/ packager/ batch releaser  6 10, 11  BMiV -N11 
h. Change of the name or address (for example: 
postal code, street name) of the 
manufacturer /packager  of drug product or 
company responsible for batch release  7, 8 2, 11, 1 3 BMiV -N12 
i. Change of product owner  7, 10  11, 14−16 BMiV -N13 
Conditions  
1. The proposed facility is an approved formulation/filling facility (for the same  company/MA 
holder).  
2. If there is/are changes in the composition, manufacturing process , and/or final product 
specification , the applicant shall file for the applicable change/s. See change s 29, 30, 31, 34, 
46, and 58. 
3. If there is/are  change s in the container/closure system and storage conditions , the applicant 
shall file for the applicable change/s. See changes  52, 53, and 59.. 
4. The same validated manufacturing process is used.  
5. The newly introduced product is in the same family of product(s) or therapeutic  classification 
as the products already approved at the site, and also uses the same  filling process/equipment.  Philippine Variation Guideline f or Biological  Products  
 
 
30 6. There should remain at least one site/manufacturer/batch releaser, as previously authorized, 
performing the same function as the one(s) to be deleted.  
7. The manufacturing/ packaging/ batch release site remains unchanged.  
8. Not applicable in case it involves change in ownership of the manufacturer.  
9. Method transfer from the currently approved to the proposed site or test la boratory has been 
successfully completed.  
10. This shall cover imported drug products only. For locally manufactured drug products, refer to 
the conditions and requirements stipulated in BMiV -N41. 
Supporting data  
1. Comparative tabulated format of information on the currently registered and proposed 
production facilities (such as name, address and responsibilities) involved in the manufacture 
of the drug product including bulk, packaging and release.  
2. A valid FDA -issued Good Manufacturing Practice (G MP) Certificate substantiating that the 
proposed site is appropriately authorized for the product  and/or activity concerned. In the case 
of BMiV -N12, a valid FDA -issued GMP Certificate reflecting the proposed name and/or 
address of the manufacturer.  
3. Confir mation that the manufacturing process description of the final product has not changed 
as a result of the submission (other than the change in facility), or  revised description of the 
manufacturing process.  
4. Comparative description of the manufacturing proc ess if different from the  approved process, 
and information on the controls performed at critical steps of  the manufacturing process and on 
the intermediate of the proposed final product.  
5. Process validation study reports. The data should include transport between sites,  if relevant.  
6. Description of the batches and summary of results as quantitative data, in a comparative tabular 
format, for at least three (3) consecutive commercial -scale batches of the pre - and post -change 
final product. Comparativ e pre -change test results do not need to be generated concurrently; 
relevant historical testing results are acceptable. Bracketing for multiple -strength products, 
container sizes and/or  fills may be acceptable if scientifically justified.  
7. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comp arative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manu facturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product under its normal storage conditions and to report any failures in these ongoing 
long-term stability studies. Matrixing, bracketing , the use of smaller -scale batches, the use of 
fewer than 3 batches and/or use of forced degradation or accelerated temperature conditions for 
stability testing may be  acceptable where justified.  
8. Rationale for considering the proposed formulation/filling facility as equivalent.  
9. Amended relevant ACTD/ ICH CTD section/s.  
10. Reason for withdrawal/deletion.  
11. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (w here applicable).  
12. Official letter from product owner authorizing the company/manufacturer to be responsible for 
batch release (where applicable).  
13. Official letter from product owner authorizing the manufacturer with proposed name/address to 
manufacture/rel ease the drug product.  
14. Declaration on the transfer of ownership between the currently approved and the proposed 
product owner.  
15. Official letter from the proposed product owner declaring the change and authorizing the local 
license holder to be responsible f or the product license.  Philippine Variation Guideline f or Biological  Products  
 
 
31 16. If the proposed product owner is not the manufacturer of the drug product, an official letter by 
the proposed product owner authorizing the manufacturer to manufacture the drug product on 
its behalf, and letter of acceptance from t he manufacturer that it will be held responsible for 
manufacturing and ensuring the efficacy, quality and safety aspect of the drug product.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
34. Change in the final product manufacturing process, such as:  
a. Scale-up of the manufacturing  process at the 
formulation/filling  stage  1−4 1−6 BMaV -44 
b. Addition or replacement of equipment (for 
example, formulation tank, filter housing,  
filling line and head, and  lyophilizer)  None  1−8 BMaV -45 
5 2, 7−9  BMiV -PA59 
c. Addition of a new scale bracketed by the 
approved scales or scale -down  of the  
manufacturing  process  1−4 1, 4 BMiV -PA60 
d. Addition of a new step (for  example, filtration)  3 1−6 BMaV -46 
Conditions  
1. The proposed scale uses similar/comparable equipment to the approved equipment. Note: 
Change in equipment size is not considered as using similar/  comparable equipment.  
2. Any changes to the manufacturing process and/or to the in -process controls are only those 
necessitated by the change in batch size (for example, the same formulation, controls and SOPs 
are utilized).   
3. The change should not be a result of recurring events having arisen during  manufacture or 
because of stability concerns.  
4. No change in the principl e of the sterilization procedures of the final product.  
5. Replacement of equipment with equivalent equipment; the change is considered  “like for like” 
(that is, in terms of product contact material, equipment size and  operating principles).  
6. If there are changes to the specification of the final product, the applicant shall file for the 
applicable change/s. See changes 46  and 58.   
7. If there are changes to the in -process controls applied during the manufacture of drug product, 
the applicant sha ll file for the applicable change/s. See change 35 .   
Supporting data  
1. Description of the manufacturing process, if different from the approved process, and 
information on the controls performed at critical steps of the manufacturing  process and on the 
intermediate of the proposed final product.  
2. Information on the in -process control testing, as applicable.  
3. Process validation study reports (for example, media fills), as appropriate.  
4. Description of the batches and summary of results as quantitative data, i n a comparative tabular 
format, for at least three (3) consecutive commercial -scale batches of the pre - and post -change 
final product. Comparative pre -change test results do not need to be generated concurrently; 
relevant historical testing results are acc eptable. Bracketing for multiple -strength products, 
container sizes and/or  fills may be acceptable if scientifically justified.  
5. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at le ast three (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the  
final product under its normal storage conditions and to report any failures in these ongoing Philippine Variation Guideline f or Biological  Products  
 
 
32 long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches  and/or use of forced  degradation or acceler ated temperature conditions for 
stability testing may be   acceptable where justified.  
6. Information on leachables and extractables, as applicable.  
7. Information on the new equipment and comparison of similarities and differences regarding 
operating principles and specifications between the new and the  replaced equipment.  
8. Information demonstrating requalification of the equipment or requalification of  the change.  
9. Rationale for regarding the equipment as similar/comparable, as applicable.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
35. Change in the controls (in -process tests and/or acceptance criteria) applied during the 
manufacturing process or on intermediates, such as:  
a. Narrowing of in-process limits  1–3, 7 1, 5, 11 BMiV -PA61 
b. Addition of new in -process test  and limits  1–3, 8, 9 1−6, 8 , 11 BMiV -PA62 
c. Deletion of a non -significant  in‑process test  1−4 1, 5, 7 , 11 BMiV -PA63 
d. Widening of the approved in ‑process limits  1 1−6, 8, 9 , 
11 BMaV -47 
1−3 1, 5, 6, 8, 9 , 
11 BMiV-PA64 
e. Deletion of an in -process test which may have 
a significant effect  on the overall quality of the 
final product  1 1, 5, 6, 8 , 
11 BMaV -48 
f. Addition or replacement of an  in‑process test 
as a result of a  safety or quality issue  1 1−6, 8 , 11 BMaV -49 
36. Change in in -process controls testing site  1−3, 5, 6   10 BMiV -N14 
Conditions  
1. No change in final product specification outside the approved limits.  If there are changes to the 
specification of the final product, the applicant shall file for the applicable change/s. See 
changes 46  and 58.   
2. No change in the impurity profile of the final product outside the approved limits.  
3. The change is not necessitated by recurring events arising during manufacture or because of 
stability concerns.  
4. The test does not concern a critical attribute (for example, content, impurities, any critical 
physical characteristics or microbial purity).  
5. The replaced analyti cal procedure maintains or tightens precision, accuracy, specificity and 
sensitivity, if applicable.  
6. No change in the in -process control limits outside the approved limits.  
7. The test procedure remains the same, or changes in the test procedure are minor.  
8. Any new test method does not concern a novel non -standard technique or a standard technique 
used in a novel way.  
9. The new test method is not a biological/immunological/immunochemical or physicochemical 
method or a method using a biological reagent (does not  include standard pharmacopoeial 
microbiological methods)  
Supporting data  
1. Revised information on the controls performed at critical steps of the  manufacturing process 
and on intermediates of the proposed antigen.  
2. Updated final product specification if changed.  
3. Copies or summaries of analytical procedures, if new analytical procedures  are used.  
4. Validation study reports, if new analytical procedures are used.  
5. Comparative table or description, where applicable, of current and proposed  in‑process tests.  Philippine Variation Guideline f or Biological  Products  
 
 
33 6. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for at least three (3) consecutive commercial -scale 
batches of the pre - and post -change final  product (certificates of analysis should be provided). 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical testing results  are acceptable.  
7. Justification/risk assessment showing that the attribute is non -signif icant.  
8. Justification for the new in -process test and limits.  
9. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product under its normal storage conditions and to report an y failures in these ongoing 
long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches and/or use of forced degradation or accelerated temperature conditions for 
stability testing may be  acceptable  where justified.  
10. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately authorized for the product  and/or activity  concerned.  
11. Comparative tabulated format of description of the current and proposed test procedures/in -
process controls with changes highlighted.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
37. Change in the specification used to release the excipient, involving:  
Note: This change excludes adjuvants. See adjuvant -specific changes for details ( changes 30  and 
31). 
a. Deletion of a test  5, 8 1, 3, 4 BMiV -PA65 
b. Addition of a test  4 1−4 BMiV -PA66 
c. Replacement of an analytical  procedure  1−3 1, 2, 4 BMiV -PA67 
d. Minor changes to an approved  analytical 
procedure  None  1, 2, 4 BMiV -PA68 
e. Change from an in -house analytical procedure 
to a recognized compendial analytical  
procedure  None  1, 2, 4 BMiV -PA69 
f. Widening of an acceptance  criterion  None  1, 3, 4 BMiV -PA70 
g. Narrowing of an acceptance  criterion  3, 4, 6, 7  1, 4 BMiV -PA71 
h. Change of specific ations and/or test procedure 
following the updates in the  compendium  9 1, 4, 5 BMiV -N15 
Conditions  
1. Results of method validation demonstrate that the proposed analytical procedure is at least 
equivalent to the approved analytical procedure.  
2. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and 
sensitivity.  
3. The change is within the range of approved acceptance criteria or ha s been made to reflect the 
new pharmacopoeial monograph specification for the excipient.  
4. Acceptance criteria for residual solvents are within recognized or approved acceptance limits 
(for example, within ICH limits for a Class 3 residual solvent or pharmac opoeial 
requirements).  Philippine Variation Guideline f or Biological  Products  
 
 
34 5. The deleted test has been demonstrated to be redundant compared to the remaining tests or is 
no longer a pharmacopoeial requirement.  
6. The analytical procedure remains the same, or changes in the test procedure are minor.  
7. The change do es not result from unexpected events arising during manufacture (for example, 
new unqualified impurity or change in total impurity limits).  
8. An alternative test analytical procedure is already authorized for the specification attribute/test 
and this procedu re has not been added through a minor change submission.  
9. Applicable to compendial specifications and/or test procedure s only. Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Updated excipient specification.  
2. Where an in -house analytical procedure is used and a recognized compendial standard is 
claimed, results of an equivalency study between the in -house and compendial methods.  
3. Justification of the proposed excipient specificat ion (for example, demonstration of the 
suitability of the monograph to control the excipient and potential impact on the performance 
of the final product).  
4. Comparative tabulated format of the current and revised specifications and/or test procedure s 
of the  excipient  with changes highlighted.  
5. Copy of the official monograph of the updated compendium.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
38. Change in the source of an excipient from a 
vegetable or synthetic source to a human or 
animal source that may pose a TSE or viral 
risk 7 2−7, 11 BMaV -50 
39. Change in the source of an excipient from a 
TSE risk (for example, animal) source to a 
vegetable or synthetic source  7 1, 3, 5, 6 , 
11 BMiV -PA72 
40. Replacement in the source of an excipient 
from a TSE risk source to a different TSE 
risk source  5−7 2−7, 11 BMiV -PA73 
41. Change in manufacture of a biological 
excipient  
Note: This change excludes biological 
adjuvants; see adjuvant -specific changes above 
for details ( changes 30  and 31). 7 2−7 BMaV -51 
2, 7 2−7 BMiV -PA74 
1, 2, 7 2−7 BMiV -PA75 
42. Change in supplier for a plasma -derived 
excipient (for example, human serum 
albumin)  7 3−8 BMaV -52 
3, 4, 7 5, 6, 9  BMiV -PA76 
43. Change in supplier for an excipient of non -
biological origin or of biological origin 
(excluding plasma -derived excipient)  
Note: This change excludes adjuvants; see 
adjuvant -specific changes above for details 
(changes 30  and 31). 7 2, 3, 5−7  BMiV -PA77 
1, 5−7 3 BMiV -PA78 
44. Change in excipient testing site  1, 7 10 BMiV -N16 
Conditions  
1. No change in the specification of the excipient or final product outside the  approved limits.  
2. The change does not concern a human plasma -derived excipient.  Philippine Variation Guideline f or Biological  Products  
 
 
35 3. The human plasma -derived excipient from the new supplier is an approved medicinal product 
and no manufacturing changes were made by the su pplier of  the new excipient since its last 
approval.  
4. The excipient does not influence the structure/conformation of the active  ingredient.  
5. The TSE risk source is covered by a TSE certificate of suitability and is of the same or  lower 
TSE risk as the previously approved material . 
6. Any new excipient does not require the assessment of viral safety data.  
7. If there are changes to the sp ecification of the excipient, the applicant shall file for the 
applicable change/s. See change 37.  
Supporting data  
1. Declaration from the manufacturer of the excipient that the excipient is entirely of  vegetable or 
synthetic origin.  
2. Details of the source of the excipient (for example, animal species, country of origin)  and the 
steps undertaken during processing to minim ize the risk of TSE exposure . 
3. Information demonstrating comparability in terms of physicochemical properties, and the 
impurity profile of the proposed excipient compared to the  approved excipient.  
4. Information on the manufacturing process  and on the controls performed at critical steps of the 
manufacturing process, and on the intermediate of the  proposed excipient.  
5. Description of the batches and summary of results as quantitative data, in a comparative tabular 
format, for at least three (3 ) commercial -scale batches of the  proposed excipient.  
6. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale final product batches 
produced with the pro posed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum  of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product under its normal storage conditions and to report any failu res in these ongoing 
long-term stability studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches and/or use of forced  degradation or accelerated temperature conditions for 
stability testing may be  acceptable where justified.  
7. Information assessing the risk with respect to potential contamination with adventitious agents 
(for example, impact on the viral clearance studies, or BSE/TSE  risk) including viral safety 
documentation where necessary.  
8. Complete manufacturing an d clinical safety data to support the use of the  proposed human 
plasma -derived excipient.  
9. Letter from the supplier certifying that no changes were made to the plasma -derived excipient 
compared to the currently approved corresponding medicinal  product.  
10. Evid ence that the new company/facility is GMP compliant.  
11. Comparative tabulated format of the information on the current and proposed sources of the 
excipient ( for example , animal species, country of origin).  
 
 
K. Control of t he Final Product  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
45. Change affecting the QC testing of the final product (release and stability), involving:  
a. Transfer of the QC testing activities for a non -
pharmacopoeial  assay (in -house) to a new 
company or  to a different site within the same  
company  2 1−3 BMiV -PA79 Philippine Variation Guideline f or Biological  Products  
 
 
36 b. Transfer of the QC testing activities  for a 
pharmacopoeial assay to a  new company  1, 2 1−3 BMiV -PA80 
c. Addition or replacement of the company or 
party responsible for quality control/stability 
testing (different from the batch release site)  2 1−3  BMiV -N17 
Conditions  
1. The transferred QC test is not a potency assay or a bioassay.  
2. The manufacturer of the final product remains unchanged. If there are changes to the 
manufacturer of the final product, the applicant shall file for the applicable change/s. See 
change 33.  
Supporting data  
1. Information demonstrating technology transfer qualification.  
2. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately authorized for the product and/or activity concerned.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
46. Change in the specification used to release the final product, involving:  
a. For products or components subject to terminal 
sterilization by heat (for example, diluent for 
reconstitution of lyophilized vaccines), 
replacing the sterility  test with process 
parametric  release  None  1, 2, 6, 8, 
10, 12 BMaV -53 
b. Deletion of a test  None  2, 9, 10 , 12 BMaV -54 
c. Addition of a test  1, 2, 9  2−4, 8 , 12 BMiV -PA81 
d. Change in animal species/strains for a test (for 
example, new species/strains, animals of 
different  ages, and/or new supplier where  
genotype of the animal cannot be  confirmed)  None  5, 11 , 12 BMaV -55 
e. Replacement of an analytical procedure  None  2−4, 7, 8 , 
12 BMaV -56 
f. Minor changes to an approved analytical 
procedure  3–6 3, 8, 12 BMiV -PA82 
g. Change from an in -house analytical procedure 
to a recognized compendial analytical 
procedure  3, 6 2−4, 12 BMiV -PA83 
h. Widening of an acceptance criterion  None  2, 8, 10 , 12 BMaV -57 
i. Narrowing of an acceptance criterion  7−10  2, 12 BMiV -PA84 
j. Change of specifications and/or test procedure 
following the updates in the compendium  11 2, 12 –14 BMiV -N18 
Conditions  
1. No change in the limits/acceptance criteria outside the approved limits for the  approved assays.  
2. The additional test is not intended to monitor new impurity species.  
3. No change in the acceptance criteria outside the approved limits.  
4. The method of analysis is the same (for example, a change in column length or  temperature, 
but not a different type of column or method) and no new impurities  are detected.  
5. The modified analytical procedure maintains or tightens precision, accuracy,  specificity and 
sensitivity.  
6. The change does not concern potency testing.  
7. The change i s within the range of approved acceptance criteria.  Philippine Variation Guideline f or Biological  Products  
 
 
37 8. Acceptance criteria for residual solvents are within recognized or approved acceptance limits 
(for example, within ICH limits for a Class 3 residual solvent, or  pharmacopoeial  
requirements).  
9. The change does not result from unexpected events arising during manufacture (for example, 
new unqualified impurity, or impurity content outside of the  approved limits).  
10. The analytical procedure remains the same, or changes to the analytica l procedure  are minor.  
11. Applicable to compendial specifications and/or test procedure s only. Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Process validation study reports on the proposed final product.  
2. Updated copy of the proposed final product specification.  
3. Copies or summaries of analytical procedures, if new analytical procedures are used.  
4. Validation study reports, if new analytical procedures are used.  
5. Data demonstrating that the change in animals gives results comparable to those  obtained using 
the approved animals.  
6. Description of the batches and summary of results as quantitative data for a  sufficient number 
of batches to support the process parametric release.  
7. Description of  the batches and summary of results as quantitative data, in a  comparative tabular 
format, for at least three (3) commercial -scale batches of the  final product.  
8. Justification for the change to the analytical procedure (for example, demonstration  of the 
suitability of the analytical procedure in monitoring the final product,  including the degradation 
products) or for the change to the specification (for  example, demonstration of the suitability of 
the revised acceptance criterion in  controlling the final pro duct).  
9. Justification for the deletion of the test (for example, demonstration of the  suitability of the 
revised specification in controlling the final product).  
10. Declaration/evidence that consistency of quality and of the production process  is maintained.  
11. Copies of relevant certificates of fitness for use (for example, veterinary certificate).  
12. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the drug product  with changes highlighted.  
13. For change in test procedure, appropriate verification data of the proposed test procedure . 
14. Copy of the official monograph of the updated compendium.  
 
 
L. Reference Standards or Materials  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
47. Qualification of a reference standard against 
a new primary international standard  None  1, 2 BMiV -PA85 
48. Change of the reference standard from in -
house (no relationship with international 
standard) to pharmacopoeial or 
international standard  None  1, 2 BMiV -PA86 
49. Qualification of a new lot of reference 
standard against the approved reference 
standard (including qualification of a new 
lot of a secondary reference standard against 
the approved primary standard)  1 2 BMiV -PA87 
50. Change to the reference standard 
qualification protocol  None  3, 4 BMiV -PA88 
51. Extension of the shelf -life of the reference 
standard  2 5 BMiV -PA89 Philippine Variation Guideline f or Biological  Products  
 
 
38 Conditions  
1. The qualification of a new standard is carried out in accordance with an  approved protocol.  
2. The extension of the shelf -life of the reference standard is carried out in  accordance with an 
approved protocol.  
Supporting data  
1. Revised product labelling to reflect the change in reference standard (as applicable).  
2. Qualification data of the proposed reference standards or materials (for example,  source, 
characterization and certificate of analysis).  
3. Justification of the change to the reference standard qualification protocol.  
4. Updated reference standard qualification protocol.  
5. Summary of stability testing and results or retest data to support the extension of  the reference 
standard shelf -life. 
 
 
M. Container Closure System  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
52. Modification of a  container closure system :  
Note:  
▪ The addition of a new container closure system (for example, addition of a pre -filled syringe 
where the currently approved presentation is only a vial) is considered a change in 
presentation; refer to BMaV -37. 
a. Change in primary container closure system 
(for example, new coating, adhesive, stopper or 
type of glass)  None  1−8 BMaV -58 
4 1, 3, 7, 8  BMiV -PA90 
1−3 1, 3, 8  BMiV -PA91 
b. Change in any part of the packaging material 
not directly in contact with the finished product 
formulation such as change in the bossing 
(from direct printing to use of sticker) on the 
labeling materials, inclusion/deletion of an 
aluminum pouch, and inclusion/deletion of 
blister pack enclosing the primary packaging of 
a drug product  5 1, 3, 6, 8  BMiV -PA92 
53. Change from a reusable  container to a 
disposable  container with no changes in  
product contact material (for  example, 
change from reusable  pen to disposable pen)  None  1, 3, 6 , 8 BMaV -59 
54. Deletion of a container closure system  None  1 BMiV -N19 
Conditions  
1. No change in the type of container closure or materials of construction.  
2. No change in the shape or dimensions of the container closure.  
3. The change is made only to improve the quality of the container and does not  modify the 
product contact material (for example, increased thickness of the glass  vial without changing 
interior dimensions).  
4. The modified part is not in contact with the drug product.  
5. For the change in the bossing on the labeling materials, the layout and information on th e 
labels remain unchanged. Otherwise, refer to change 1 37 (whichever is applicable) for the 
change in the labeling of the drug product.  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  Philippine Variation Guideline f or Biological  Products  
 
 
39 2. For sterile products, process validation study reports, or providing equivalency rationale. For a 
secondary functional container closure system, validation  testing report.  
3. Information on the pr oposed container closure system, as appropriate (for  example, 
description, materials of construction of primary/secondary packaging  components, 
performance specification).  
4. Results demonstrating protection against leakage, no leaching of undesirable substan ce and 
compatibility with the product, and results from the toxicity and  biological reactivity tests.  
5. Summary of results as quantitative data, in a comparative tabular format, for at least three (3) 
consecutive commercial -scale batches of the pre - and post -change final product. Comparative 
pre-change test results do not need to be generated concurrently; relevant historical testing 
results are acceptable. Bracketing for multiple -strength products, container sizes and/or fills 
may be acceptable if  scientific ally justified.  
6. Comparative pre - and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three (3) commercial -scale final product batches 
produced with the proposed changes under real -time/real -temperature testing conditions. 
Comparative pre -change test results do not need to be generated concurrently; relevant 
historical results for lots on the stability programme are acceptable. The data should cover a 
minimum of 3 months testing unless otherwise justified. Additionally, the manufacturer should 
commit to undertake real -time stability studies to support the full shelf -life/hold -time of the 
final product under its normal storage conditions and to report any failures in these ongoing 
long-term stabili ty studies. Matrixing, bracketing, the use of smaller -scale batches, the use of 
fewer than 3 batches and/or use of forced degradation or accelerated temperature conditions for 
stability testing may be  acceptable where justified.  
7. Information demonstrating t he suitability of the proposed container/closure system with respect 
to its relevant properties (for example, results from last media fills; results of transportation 
and/or interaction studies demonstrating the preservation  of protein integrity and mainte nance 
of sterility for sterile products; results of  maintenance of sterility in multidose containers and 
results of user testing).  
8. Comparative tabulated format of descriptions and specifications of the current and proposed 
packaging materials, including il lustrations.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
55. Change in the supplier for a primary container closure component, involving:  
a. Replacement or addition of a  supplier  1, 2 1, 2 BMiV -PA93 
b. Deletion of a supplier  None  3 BMiV -N20 
Conditions  
1. No change in the type of container closure, materials of construction, shape and  dimensions, or 
in the sterilization process for a sterile container closure component.  
2. No change in the specification of the container closure component outside the approved limits.  
If there are changes to the specification of the container closure, the applicant shall file for the 
applicable change/s. See change 56 . 
Supporting data  
1. Letter from the MA holder certifying that there are no changes to the container  closure system.  
2. Certificate of analysis for the container provided by the new supplier and  comparison with the 
certificate of analysis for the approved container.  
3. Reason for withdrawal/deletion.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  Philippine Variation Guideline f or Biological  Products  
 
 
40 56. Change in the specification used to release a primary container closure component or 
functional secondary container closure component, involving:  
a. Deletion of a test  1, 2 1, 2, 4 BMiV -PA94 
b. Addition of a test  3 1, 2, 4 BMiV -PA95 
c. Replacement of an analytical  procedure  6, 7 1−3, 4 BMiV -PA96 
d. Minor changes to an analytical  procedure  4−7 1−4 BMiV -PA97 
e. Widening of an acceptance criterion  None  1, 2, 4 BMiV -PA98 
f. Narrowing of an acceptance  criterion  8 1, 4 BMiV -PA99 
Conditions  
1. The deleted test has been demonstrated to be redundant compared to the  remaining tests or is 
no longer a pharmacopoeial requirement.  
2. The change to the specification does not affect the functional properties of the container 
closure component nor result in a potential impact on the performance  of the final product.  
3. The change is not necessitated by recurring events arising during manufacture or  because of  
stability concerns.  
4. There is no change in the acceptance criteria outside the approved limits.  
5. The new analytical procedure is of the same type.  
6. Results of method validation demonstrate that the new or modified analytical  procedure is at 
least equivalent to the approved analytical procedure.  
7. The new or modified analytical procedure maintains or tightens precision,  accuracy, specificity 
and sensitivity.  
8. The change is within the range of approved acceptance criteria or has been  made to reflect new 
pharmacopoeial monograph specifications for the container  closure component.  
Supporting data  
1. Updated copy of the proposed specification for the primary or functional  secondary container 
closure component.  
2. Rationale for the change in specification for a primary container closure component.  
3. Description of the analytical procedure and, if applicable, validation data.  
4. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the container  closure with changes highlighted.  
 
 
N. Stability  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
57. Change in the shelf -life of the final product, involving:  
a. Extension (includes extension of shelf -life of 
the final product as packaged for sale, and 
hold-time after opening and after dilution or  
reconstitution)  None  1−5 BMaV -60 
b. Reduction (includes reduction as packaged for 
sale, after  opening, and after dilution or  
reconstitution)  None  1−5 BMiV -PA100 
Conditions  
None  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Proposed storage conditions and shelf -life, as appropriate.  
3. Updated post -approval stability protocol.  
4. Justification of the change to the post -approval stability protocol or  stability commitment.  Philippine Variation Guideline f or Biological  Products  
 
 
41 5. Results of stability testing under real -time/real -temperature conditions covering  the proposed 
shelf -life generated on at least three (3) comme rcial-scale batches.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
58. Change in the post -approval stability protocol of the final product, involving:  
a. Major change to the post -approval stability 
protocol or stability commitment, such as 
deletion of a test  parameter or limit , 
replacement /deletion  of an analytical 
procedure , widening of specification limits,  or 
change in storage temperature  None  1−6 BMaV -61 
b. Addition of time point(s) into the post-approval 
stability protocol  None  4, 6 BMiV -PA101 
c. Addition of test(s) into the post -approval 
stability protocol  or tightening of specification 
limits  1 4, 6 BMiV -PA102 
d. Deletion of time point(s) from the post -
approval stability protocol beyond the approved 
shelf -life None  4, 6 BMiV -PA103 
e. Deletion of time point(s) from the post -
approval stability protocol within the approved 
shelf -life 2 4, 6 BMiV -PA104 
f. Replacement of the sterility testing by the 
container/closure system integrity testing  None  1, 2, 4, 6  BMaV -62 
3 4, 6 BMiV -PA105 
g. Change to the post -approval stability protocol, 
such as change in specifications and/or test 
procedures following the updates in the 
compendium  4 4, 7−9 BMiV -N21  
Conditions  
1. The addition of the test(s) is not due to stability concerns or to the identification of new 
impurities.  
2. The approved shelf -life of the final product is at least 24 months.  
3. The method used to demonstrate the integrity of the container/closure system has already been 
approved as part of a previous application.  
4. Applicable to compendial specifications and/or test procedures only. Change is made 
exclusively to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Copies or summaries of analytical procedures, if new analytical procedures are used.  
2. Validation study reports, if new analytical procedures are used.  
3. Proposed storage conditions and or shelf -life, as appropriate.  
4. Updated post -approval stability protocol and stability commitment.  
5. If applicable, stability testing results to support the change to the post -approval stability 
protocol or stability commitment (for example, data showing greater reliability of the 
alternative test).  
6. Justification of the change to the post -approval stability protocol or stability commitment.  
7. Comparative tabulated format of the currently approved and proposed stability protocols or 
stability commitments with changes highlighted.  
8. For change in test procedure, appropriate verification data of the proposed test pr ocedure . 
9. Copy of the official monograph of the updated compendium.  
 Philippine Variation Guideline f or Biological  Products  
 
 
42  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
59. Change in the labelled storage conditions for the final product or the diluted or 
reconstituted vaccine, involving:  
a. Addition or change of storage condition(s) for 
the final product, or for diluted or reconstituted 
vaccine (for example, widening or narrowing of 
a temperature criterion, or addition of or 
change  to controlled temperature chain  
conditions)  None  1−4, 6  BMiV -PA106 
b. Addition of a cautionary statement  (for 
example, “Do not freeze”)  None  1, 2, 4, 5  BMiV -PA107 
c. Deletion of a cautionary statement  (for 
example, “Do not freeze”)  None  1, 2, 4, 6  BMiV -PA108 
Conditions  
None  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Proposed storage conditions and shelf -life. 
3. Updated post -approval stability protocol and stability commitment.  
4. Justification of the change in the labelled storage conditions/cautionary statement.  
5. Results of stability testing under appropriate stability conditions covering the proposed shelf -
life, generated on one (1) commercial -scale batch unl ess otherwise justified.  
6. Results of stability testing under appropriate conditions covering the proposed  shelf -life, 
generated on at least three (3) commercial -scale batches unless  otherwise justified.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
43  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION 2 : 
BIOTHERAPEUTIC 
PRODUCTS  
 
 
 
 
 
 
 
 
 
 
 
 
  Philippine Variation Guideline f or Biological  Products  
 
 
44  
 
III. CHANGES TO THE DRUG SUBSTANCE  
 
O. Manufacture  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
60. Change to a drug substance manufacturing facility:  
a. Replacement or addition of a manufacturing 
facility for the bulk drug substance or any 
intermediate  7–10 1–4, 6–8 BMaV -63 
1–3, 7–10 1–8 BMaV -64 
b. Conversion of a drug substance manufacturing 
facility from single -product to multi -product  4 9, 10  BMaV -65 
c. Deletion of a manufacturing facility or 
manufacturer of an intermediate drug 
substance, or bulk  5, 6 11 BMiV -N22 
d. Change of the name and/or address (for 
example: postal code, street name) of a 
manufacturer of the drug substance  11 1, 2 BMiV -N23 
Conditions  
1. The proposed facility is an approved drug substance facility for biotherapeutics . 
2. Any changes to the manufacturing process and/or controls are considered minor (for example, 
duplication of product line).  
3. The new facility/suite is under the same quality assurance/quality control oversight.  
4. The proposed change does not involve additional containment requirements.  
5. There should remain at least one site/manufacturer, as previously authorized, performing the 
same function as the one(s) to be deleted.  
6. The deletion should not be due to critical deficiencies in manufacturing (for example, recurrent 
out-of-specification events, environmental monitoring failures, etc.).  
7. Specifications of the drug substance remain unchanged. If there are changes to the specification 
of the drug substance , the applicant shall file for the applicable change/s. See changes 78, 79, 81 
and 92. 
8. If there is a change in the manufacturing site of the drug product, the applicant shall file for the 
applicable change/s. See change 9 7. 
9. If there are changes to the manufacturing process, the applicant shall file for the applicable 
change/s. See change s 65 and 66. 
10. If there is a  change in scale of the drug substance, the applicant shall file for the applicable 
change/s. See change 67 . 
11. The manufacturing site of the drug substance remains unchanged.  
Supporting data  
1. Evidence of GMP compliance of the facility.  For Change of the name and/or address of a 
manufacturer of the antigen (BMiV -N23), a valid GMP Certificate reflecting the proposed name 
and/or address of the manufacturer.  
2. Updated information including name, address and responsibility of the manufacturer of the drug 
substance (i.e., Section S2 of the ACTD/ICH CTD).  
3. Summary of the process validation studies and results.  
4. Comparability of the pre -change and post -change drug substance with respect to 
physicochemical properties, biological activity, purity, impurities and contaminants, as 
appropriate. Nonclinical and/or clinical bridging studies may be required if quality data alone Philippine Variation Guideline f or Biological  Products  
 
 
45 are insufficient to establish comparability. The extent and nature of nonclinical and/or clinical 
studies should be determined on a case -by-case basis, taking into consideration the quality 
comparability findings, the nature and level of the knowledge of the product, existing relevant 
nonclinical and clinical data, and aspects of their use.  
5. Justification for the classification of any manufacturin g process and/or control changes as minor.  
6. Description of the batches and summary of in -process control and release testing results as 
quantitative data, in a comparative tabular format, for at least three consecutive commercial -
scale batches of the pre -change and post -change drug substance. Comparative pre -change test 
results do not need to be generated concurrently; relevant historical testing results are acceptable. 
Matrixing, bracketing, use of smaller -scale batches, use of fewer than three batches and/ or 
leveraging data from scientifically justified representative batches, or batches not necessarily 
manufactured consecutively, may be acceptable where justified.  
7. Comparative pre -change and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three commercial -scale drug substance batches 
produced with the proposed changes and stored under accelerated and/or stress conditions for a 
minimum of 3 months. Test results that cover a minimum of 6 months in real-time/real -
temperature conditions should also be provided. A possibility of 3 months of real -time data could 
be acceptable if properly justified (for example, it can be proven that the relevant effect, if 
present, can already be observed within 3 month s). Comparative pre -change test results do not 
need to be generated concurrently; relevant historical results for batches on the stability 
programme are acceptable. Additionally, the manufacturer should commit to undertake real -time 
stability studies to co nfirm the full shelf -life/holdtime of the drug substance under its normal 
storage conditions and to report any failures in these ongoing long -term stability studies. 
Matrixing, bracketing, use of smaller -scale batches and/or use of fewer than three batches  of 
drug substance for stability testing may b e acceptable where justified . 
8. Updated post -approval stability protocol.  
9. Information describing the change -over procedures for shared product -contact equipment and 
the segregation procedures, as applicable. If n o revisions, the manufacturer should state that no 
changes were made to the change -over procedures.  
10. Cleaning procedures (including data in a summary validation report and the cleaning protocol 
for the introduction of new products,  as applicable) demonstrating lack of carry -over or cross -
contamination.  
11. Reason for withdrawal/deletion.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
61. Change to the cell banks:  
Note: New cell substrates that are unrelated to the licensed master cell bank (MCB) or pre -MCB 
material may require a new application for marketing authorization or licen se application.  
a. Adaptation of an MCB into a  new culture 
medium  None  1, 2, 5 –8, 
10 BMaV -66 
b. Generation of a new MCB  1 1, 2, 5 –8 BMaV -67 
c. Generation of a new working  cell bank (WCB)   2–4 1, 2 BMiV -PA10 9 
62. Change in the cell bank manufacturing site  None  1, 2, 9  BMaV -68 
63. Change in the cell bank testing/storage site  5, 7 9 BMiV -N24 
64. Change in the cell bank qualification 
protocol  None  3, 4 BMaV -69 
6 4 BMiV -PA110 
Conditions  
1. The new MCB is generated from the original clone or from a pre -approved MCB and is grown 
in the same culture medium.  
2. The new cell bank is generated from a pre -approved MCB.  
3. The new cell bank is at the pre-approved passage level.  Philippine Variation Guideline f or Biological  Products  
 
 
46 4. The new cell bank is released according to a pre -approved protocol/process or as described in 
the original licen se. 
5. No changes have been made to the tests/acceptance criteria used for the release of the cell 
bank.  
6. The protocol i s considered more stringent (that is, addition of new tests or narrowing of 
acceptance criteria).  
7. No changes have been made to the storage conditions used for the cell bank, and the transport 
conditions of the cell bank have been validated.  
Supporting data  
1. Qualification of the cell bank.  
2. Information on the characterization and testing of the MCB/WCB, and cells from the end -of 
production passage or post -production passage.  
3. Justification of the change to the cell bank qualification protocol.  
4. Updated cell bank qualification protocol.  
5. Comparability of the pre -change and post -change drug substance with respect to 
physicochemical properties, biological activity, purity, impurities and contaminants, as 
appropriate. Nonclinical and/or clinical bridgin g studies may occasionally be required when 
quality data are insufficient to establish comparability. The extent and nature of nonclinical 
and/or clinical studies should be determined on a case -by-case basis, taking into consideration 
the quality -comparabi lity findings, the nature and level of knowledge of the product, existing 
relevant nonclinical and clinical data, and aspects of its use.  
6. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparativ e tabular format, for at least three consecutive commercial -scale batches of 
the drug substance derived from the new cell bank. Matrixing, bracketing, use of smaller -scale 
batches, use of fewer than three batches and/or leveraging data from scientifically justified 
representative batches, or batches not necessarily manufactured consecutively, may be 
acceptable where justified.  
7. Comparative pre -change and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three commercial -scale drug substance batches 
produced with the proposed changes and stored under accelerated and/or stress conditions for a 
minimum of 3 months. Test results that cover a minimum of 6 months in real -time/real -
temperature conditions s hould also be provided. A possibility of 3 months of real -time data could 
be acceptable if properly justified (for example, it can be proven that the relevant effect, if 
present, can already be observed within 3 months). Comparative pre -change test results  do not 
need to be generated concurrently; relevant historical results for batches on the stability 
programme are acceptable. Additionally, the manufacturer should commit to undertake real -time 
stability studies to confirm the full shelf -life/hold  time of the drug substance under its normal 
storage conditions and to report any failures in these ongoing long -term stability studies. 
Matrixing, bracketing, the use of smaller -scale batches and/or the use of fewer than three batches 
of drug substance for stabili ty testing may be acceptable where justified.  
8. Updated post -approval stability protocol.  
9. Evidence that the new company/facility is GMP -compliant.  
10. Supporting nonclinical and clinical data or a request for a waiver of in vivo studies with 
justification.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
65. Change to the fermentation or cell culture process:  
a. A critical change (a change with high potential 
to have an impact on the quality of the drug 
substance or drug product; for example, 14, 15  1–7, 9, 11 , 
15 BMaV -70 Philippine Variation Guideline f or Biological  Products  
 
 
47 incorporation of disposable bioreactor 
technology)  
b. A change with moderate  potential to have an 
impact on the quality of the drug substance or 
drug product (for example, extension of the in 
vitro cell age beyond validated parameters)  1, 3, 14, 15  1–6, 8, 10 , 
15 BMaV -71 
c. A noncritical change with  minimal potential to 
have  an impact on the quality of  the drug 
substance or drug product, such as:  
• a change in harvesting and/  or pooling 
procedures which  does not affect the method  of 
manufacture, recovery,  intermediate storage  
conditions, sensitivity of  detection of 
adventitious  agents or production scale;  
• duplication of a fermentation  train; or  
• addition of similar/comparable bioreactors  1–5, 7–10, 
14, 15  1, 2, 4, 8 , 
15 BMiV -PA111 
66. Change to the purification process, involving the following:  
a. A critical change (a change with high potential 
to have an impact on the quality of the drug 
substance or drug product, for example, a 
change that could potentially have an impact on 
the viral clearance capacity of the process or 
the impurity profile of the drug subs tance)  14, 15  1, 2, 5 –7, 9, 
11, 12 , 15 BMaV -72 
b. A change with moderate potential to have an 
impact on the quality of the  drug substance or 
drug product  (for example, a change in the 
chemical separation method, such as ion -
exchange HPLC1 to reversed -phase HPLC)  1, 3, 14, 15  1, 2, 5 –7, 
10–12, 15 BMaV -73 
c. A noncritical change with minimal potential to 
have  an impact on the quality of the drug 
substance or  drug product (for example, 
addition of an in -line filtration step equivalent 
to the approved filtration step)  1–4, 14, 15  1, 2, 15 BMiV -PA11 2 
67. Change in scale of the manufacturing process:  
a. At the cell culture stage  3, 9–11, 14, 
15 2, 3, 5 –7, 9, 
11 BMaV -74 
b. At the purification stage  1, 2, 4, 6 , 14, 
15 2, 5–7, 9, 
11 BMaV -75 
68. Introduction of reprocessing steps  12–14 8, 10, 11, 
13, 15 BMiV -PA11 3 
69. Addition of a new holding step or change in  
the parameters of an approved holding step  14  5, 14 , 15 BMaV -76 
Conditions  
1. The change does not have an impact on the viral clearance data or the chemical nature of an 
inactivating agent.  
2. There is no change in the drug substance specification outside the approved limits.  If there are 
changes to the specification of the drug substance, the applicant shall file for the applicable  
change/s. See changes 78 , 79, 81 and 92. 
3. There is no change in the drug substance impurity profile outside the approved limits.  
4. The change is not necessitated by recurring events arising during manufacture or because of 
stability concerns.  
5. The change does not affect the purification process.  Philippine Variation Guideline f or Biological  Products  
 
 
48 6. The change in scale is linear with respect to the proportionality of production parameters and 
materials.  
7. The new fermentation train is identical to the approved fermentation train(s).  
8. There is no change in the approved in vitro cell age.  
9. The change is not expected to have an impact on the quality, safety or efficacy of the final 
product.  
10. There is no change in the proportionality of the raw materials (that is, the change in scale is 
linear).  
11. The change in sca le involves the use of the same bioreactor (that is, it does not involve the use 
of a larger bioreactor).  
12. The need for reprocessing is not due to recurrent deviations from the validated process, and the 
root cause triggering reprocessing is identified.  
13. The proposed reprocessing steps have been shown to have no impact on product quality.  
14. If there are changes to the specification of the drug substance, the applicant shall file for the 
applicable change/s. See changes 78 , 79, 81 and 92. 
15. If there are changes to the in -process controls applied during the manufacture of drug substance, 
the applicant shall file for the applicable change/s. See change 74.  
Supporting data  
1. Justification for the classification of the change(s) as critical, moderate or noncritical  in terms of 
its impact on the quality of the drug substance.  
2. Flow diagram (including process and in -process controls) of the proposed manufacturing 
process(es) and a  brief narrative description of the proposed manufacturing process(es).  
3. If the change results in an increase in the number of population doublings or subcultivations, 
information on the characterization and testing of the postproduction cell bank for recom binant 
product or of the drug substance for nonrecombinant product.  
4. For drug substance obtained from, or manufactured with, reagents obtained from sources that 
are at risk of transmitting bovine spongiform encephalopathy/ transmissible spongiform 
encephalo pathy (BSE/TSE) agents (for example, ruminant origin), information and evidence that 
the material does not pose a potential BSE/TSE risk (for example, name of manufacturer, species 
and tissues from which the material is a derivative, country of origin of t he source animals, use 
and previous acceptance of the material).  
5. Process validation results.  
6. Comparability of the pre -change and post -change drug substance with respect to 
physicochemical properties, biological activity, purity, impurities and contaminants , as 
appropriate. Nonclinical and/or clinical bridging studies may occasionally be required when 
quality data are insufficient to establish comparability. The extent and nature of nonclinical 
and/or clinical studies should be determined on a case -by-case b asis, taking into consideration 
the quality – comparability findings, the nature and level of knowledge of the product, existing 
relevant nonclinical and clinical data, and aspects of its use.  
7. Description of the batches and summary of in -process and release  testing results as quantitative 
data, in a comparative tabular format, for at least three consecutive commercial -scale batches of 
the pre -change and post -change drug substance. Comparative pre -change test results do not need 
to be generated concurrently; relevant historical testing results are acceptable. Matrixing, 
bracketing, the use of smaller -scale batches, the use of fewer than three batches and/or leveraging 
data from scientifically justified representative batches, or batches not necessarily manufac tured 
consecutively, may be acceptable where justified.  
8. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for one commercial -scale batch of the pre -change and post -
change  drug substance. Comparative prechange test results do not need to be generated 
concurrently; relevant historical testing results are acceptable. Batch data on the next two full -
production batches  should be made available on request and should be reported by the marketing 
authorization holder if outside the specification (with proposed action). The use of a smaller -
scale batch may be acceptable where justified and.  Philippine Variation Guideline f or Biological  Products  
 
 
49 9. Comparative pre -change and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes for at least three commercial -scale drug substance batches 
produced with the proposed changes and stored under accelerated and/or stress conditions for a 
minimum of 3 months. Test results that cover a minimum of 6 months in real-time/real -
temperature conditions should also be provided. A possibility of 3 months and one batch of real -
time data could be acceptable if properly justified (for example, it can be proven that the relevant 
effect, if present, can already be observed within 3 months). Comparative prechange test results 
do not need to be generated concurrently; relevant historical results for batches on the stability 
programme are acceptable. Additionally, the manufacturer should commit to undertake real -time 
stability studies to confirm the full shelf -life/hold -time of the drug substance under its normal 
storage conditions and to report any failures in these ongoing long -term stability studies. 
Matrixing, bracketing, the use of smaller -scale batches and/or the use of fe wer than three batches 
of drug substance for stability testing may be acceptable where justified.  
10. Comparative pre -change and post -change test results for the manufacturer’s characterized key 
stability -indicating attributes with at least one commercial -scale drug substance batch produced 
with the proposed changes under real -time/ real -temperature testing conditions. Comparative 
pre-change test results do not need to be generated concurrently; relevant historical results for 
batches on the stability programme  are acceptable. Test results that cover a minimum of 6 months 
in real -time/real -temperature conditions should also be provided. A possibility of 3 months of 
real-time data could be acceptable if properly justified (for example, it can be proven that the 
relevant effect, if present, can already be observed within 3 months). Additionally, the 
manufacturer should commit to undertake real -time stability studies to confirm the full shelf -
life/hold -time of the drug substance under its normal storage conditions a nd to report any failures 
in these ongoing long -term stability studies. Matrixing, bracketing, the use of smaller -scale 
batches and/or use of forced degradation or accelerated temperature conditions for stability 
testing may be acceptable where justified.  
11. Updated post -approval stability protocol and stability commitment to place the first commercial -
scale batch of the drug product manufactured using the postchange drug substance into the 
stability programme.  
12. Information assessing the risk with respect to po tential contamination with adventitious agents 
(for example, impact on viral clearance studies and BSE/TSE risk).  
13. Data describing the root cause triggering the reprocessing, as well as validation data (for 
example, extended hold -times, resistance to additi onal mechanical stress) to help prevent the 
reprocessing from having an impact on the drug substance.  
14. Demonstration that the new or revised holding step has no negative impact on the quality of the 
drug substance (data from one commercial -scale or scientif ically justified representative drug 
substance batch should be provided).  
15. Comparative tabulated format of the description of the current and proposed manufacturing 
processes, including in -process controls, with changes highlighted.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
70. Change in equipment used in the drug substance manufacturing process, involving the 
following:  
Note: New bioreactor technology (for example, a change from stainless steel bioreactor to 
disposable bioreactor) is excluded from this table and should be filed according to BMaV -70. 
a. Introduction of new equipment with different 
operating principles and di fferent product 
contact material  6, 7  1, 3–5 BMaV -77 
b. Introduction of new equipment with the same  
operating principles but different product 
contact material  3, 4, 6, 7  1, 4, 5  BMiV -PA11 4 Philippine Variation Guideline f or Biological  Products  
 
 
50 c. Introduction of new equipment with different  
operating principles but the same product 
contact material  6, 7 1–3, 5 BMaV -78 
4, 6, 7  1, 2, 5  BMiV -PA11 5 
d. Replacement of product  contact equipment 
with equivalent equipment  6, 7 3 BMiV -PA11 6 
e. Change of product -contact equipment from 
dedicated to shared  1, 2, 6, 7  1, 6 BMiV -PA11 7 
f. Relocation of major equipment to another room 
in the same facility/suite/ premises  2, 4–7 7 BMiV -PA11 8 
Conditions  
1. The site is approved as a multi -product facility.  
2. The change has no impact on the risk of cross -contamination and is supported by validated 
cleaning procedures.  
3. The manufacturing process is not impacted by the change in product -contact equipment.  
4. The change has no impact on product quality.  
5. Re-qualification of the equipment follows the original qualification protocol.  
6. If there are changes to the specification of drug substance, the applicant shall file for the 
applicable change/s. See changes 78 , 79, 81 and 92. 
7. If there are changes to the in -process controls applied during the manufacture of drug substance, 
the applicant shall file for the applicable change/s. See change 74.  
Supporting data  
1. Information on the in -process control testing.  
2. Process validation study reports.  
3. Description of the batches and summary of results as quantitative data, in a comparative tabular 
format, for one commercial -scale batch of the drug substance produced with the approved and 
proposed product contact equipment/materi al. Batch data on the next two full -production batches 
should be made available on request and reported by the marketing authorization holder if 
outside specification (with proposed action).  
4. Information on leachables and extractables.  
5. Information on the ne w equipment and comparison of similarities and differences regarding 
operating principles and specifications between the new and the replaced equipment.  
6. Information describing the change -over procedures for the shared product -contact equipment.  
7. Justificati on for the proposed change.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
71. Change in specification for the materials, involving the following:  
a. Narrowing of the approved specification limits 
or addition of test parameter and limits for 
starting materials/intermediates  1–4 1–3, 5, 11 BMiV -PA11 9 
b. Widening of the approved specification limits 
or deletion of test parameter and limits for 
starting materials/intermediates  None  1–3, 5, 7 , 
11 BMaV -79 
3–7 3–6, 11 BMiV -PA120 
c. Change of a test procedure for starting 
materials/intermediates  4 1–3, 5, 11 BMiV -PA121 
d. Change of specifications and/or test procedure 
of the raw material s/intermediates , following the 
updates in the compendium  9 1, 2, 11, 12   BMiV -N25 
72. Change in supplier of raw materials of 
biological origin (for example, fetal calf 
serum, insulin, trypsin)  None  4, 6, 9, 10  BMaV -80 
8 4, 6 BMiV -PA122 Philippine Variation Guideline f or Biological  Products  
 
 
51 73. Change in source of raw materials of 
biological origin (for example, bovine 
trypsin to porcine trypsin)  None  4, 7, 9, 10 , 
13 BMaV -81 
8 4, 7, 13 BMiV -PA12 3 
Conditions  
1. The change in specification for the materials is within the approved limits.  
2. The grade of the materials is the same or is of higher quality, where appropriate.  
3. There is no change in the drug substance specification outside the approved limits.  If there are 
changes to the specification of the  drug substance, the applicant shall file for the applicable 
change/s. See changes 78 , 79, 81 and 92. 
4. There is no change in the impurity profile of the drug substance outside the approved limits.  
5. The change has no significant effect on the overall quality of the drug substance and/or drug 
product and there are no changes to the cell banks.  
6. The change is not necessitated by recurring events arising during manufacture or because of 
stability concerns.  
7. The test does not concern a critical attribute (fo r example, content, impurity, any  
critical physical characteristics or microbial purity).  
8. The change is for compendial raw materials of biological origin (excluding human  
plasma -derived materials).  
9. Applicable to compendial specifications and/or test procedures only. Change is made exclusively 
to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Revised information on the quality and controls of the materials (for example, raw materials, 
starting materials, solvents, reagents and catalysts) used in the manufacture of the post -change 
drug substance.  
2. Updated drug substance specification, if changed.  
3. Copies or summaries of analytical procedures if new analytical procedures are used.  
4. For drug substance  obtained from, or manufactured with, reagents obtained from sources that 
are at risk of transmitting bovine spongiform encephalopathy/ transmissible spongiform 
encephalopathy (BSE/TSE) agents (for example, ruminant origin), information and evidence that 
the material does not pose a potential BSE/TSE risk (for example, name of manufacturer, species 
and tissues from which the material is a derivative, country of origin of the source animals, use 
and previous acceptance of the material).  
5. Comparative table or description, where applicable, of pre -change and postchange in -process 
tests/limits.  
6. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for one commercial -scale batch of t he pre -change and post -
change drug substance. Comparative prechange test results do not need to be generated 
concurrently; relevant historical testing results are acceptable. Batch data on the next two full -
production batches  should be made available on re quest and reported by the marketing 
authorization holder if outside specification (with proposed action). The use of a smaller -scale 
batch may be acceptable where justified.  
7. Description of the batches and summary of in -process and release testing results a s quantitative 
data, in a comparative tabular format, for three consecutive commercial -scale batches of the pre -
change and post -change drug substance. Comparative pre -change test results do not need to be 
generated concurrently; relevant historical testing  results are acceptable. Matrixing, bracketing, 
the use of smaller -scale batches, the use of fewer than three batches and/or leveraging data from 
scientifically justified representative batches, or batches not necessarily manufactured 
consecutively, may be  acceptable where justified.  
8. Justification/risk assessment showing that the attribute is non -significant.  
9. Information assessing the risk with respect to potential contamination with adventitious agents 
(for example, impact on viral clearance studies and BS E/TSE risk).  
10. Information demonstrating suitability of the auxiliary materials/reagents of both sources through 
the comparability of the drug substance.  Philippine Variation Guideline f or Biological  Products  
 
 
52 11. Comparative tabulated format of the current and revised specifications and/or test procedures of 
the raw  material/intermediate with changes highlighted.  
12. Copy of the official monograph of the updated compendium.  
13. Comparative tabulated format of the information on the current and proposed sources of the raw 
material ( for example , animal species, country of orig in). 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
74. Change to in -process tests and/or acceptance criteria applied during manufacture of the 
drug substance, involving the following:  
a. Narrowing of approved in-process limits  1, 3, 6, 7  1, 4, 10 BMiV -PA12 4 
b. Addition of new in -process test and limits  1–3, 6 1–5, 8, 10 BMiV -PA12 5 
c. Deletion of a non -significant  in-process test  1–4, 6 1, 4, 7 , 10 BMiV -PA12 6 
d. Widening of the approved  in-process limits  None  1–4, 6, 8, 
10 BMaV -82 
1–4 1, 4, 5, 8 , 
10 BMiV -PA12 7 
e. Deletion of an in -process test  which may have 
a significant  effect on the overall quality of  the 
drug substance  None  1, 4, 6, 8 , 
10 BMaV -83 
f. Addition or replacement of  an in -process test as 
a result  of a safety or quality issue  1 1–4, 6, 8 , 
10 BMaV -84 
75. Change in the in -process controls testing site  1–3, 5, 6  9 BMiV -N26 
Conditions  
1. No change in the drug substance specification outside the approved limits.  If there are changes 
to the specification of the drug substance, the applicant shall file for the applicable change/s. See 
changes 78 , 79, 81 and 92. 
2. No change in the impurity profile of the drug substance outside the approved limits.  
3. The change is not necessitated by recurring events arising during manufacture or because of 
stability concerns.  
4. The test does not concern a critical attribute (for example, content, impurity, any critical physical 
characteristics or microbial purity).  
5. The replaced analytica l procedure maintains or tightens precision, accuracy, specificity and 
sensitivity, if applicable.  
6. No change in the approved in -process controls outside the approved limits.  
7. The test procedure remains the same, or changes in the test procedure are minor.  
Supporting data  
1. Revised information on the controls performed at critical steps of the manufacturing process and 
on intermediates of the proposed drug substance.  
2. Updated drug substance specification, if changed.  
3. Copies or summaries of analytical procedures if new analytical procedures are used.  
4. Comparative table or description, where applicable, of pre -change and post -change in -process 
tests/limits.  
5. Description of the batches and summary of in -process and release testing results as quan titative 
data, in a comparative tabular format, for one commercial -scale batch of the pre -change and post -
change drug substance. Comparative pre -change test results do not need to be generated 
concurrently; relevant historical testing results are acceptabl e. Batch data on the next two full -
production batches should be made available on request and reported by the marketing 
authorization holder if outside specification (with proposed action). The use of a smaller -scale 
batch may be acceptable where justified . 
6. Description of the batches and summary of in -process and release testing results as quantitative 
data, in a comparative tabular format, for three consecutive commercial -scale batches of the pre -Philippine Variation Guideline f or Biological  Products  
 
 
53 change and post -change drug substance. Comparative pre -chang e test results do not need to be 
generated concurrently; relevant historical testing results are acceptable. Matrixing, bracketing, 
the use of smaller -scale batches, the use of fewer than three batches and/or leveraging data from 
scientifically justified r epresentative batches, or batches not necessarily manufactured 
consecutively, may be acceptable where justified.  
7. Justification/risk assessment showing that the attribute is non -significant.  
8. Justification for the new in -process test and limits.  
9. Evidence tha t the new company/facility is GMP -compliant.  
10. Comparative tabulated format of description of the current and proposed test procedures/in -
process controls with changes highlighted.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
76. Change in the approved design space, involving the following:  
a. Establishment of a new design space  None  1 BMaV -85 
b. Expansion of the approved design space  None  1 BMaV -86 
c. Reduction in the approved design space (any 
change that reduces or limits the range of 
parameters used to define the design space)  1 1 BMiV -PA12 8 
Conditions  
1. The reduction in design space is not necessitated by recurring problems arising during 
manufacture.  
Supporting data  
1. Manufacturing development data to support the establishment of, or changes to,  the design space.  
 
P. Control of the Drug S ubstance  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
Category  
77. Change affecting the quality control (release and stability) testing of the drug substance, 
involving the following:  
a. Transfer of the quality control testing activities 
for a non -pharmacopoeial assay to a new 
company not approved in the current marketing 
authorization or licence, or to a different site 
within the sa me company  None  1–3 BMaV -87 
1–3 1–3 BMiV -PA12 9 
b. Transfer of the quality control testing activities 
for a pharmacopoeial assay to a new company 
not ap proved in the current marketing 
authorization or licence  None  1–3 BMaV -88 
1 1–3 BMiV -PA130 
Conditions  
1. The transferred quality control test is not a potency assay or bioassay.  
2. No changes are made to the test method.  
3. The transfer is within a facility approved in the current marketing authorization for the 
performance of other tests.  
Supporting data  
1. Information demonstrating technology transfer qualification for the non -pharmacopoeial assay 
or verification for the pharmacopoeial assay.  
2. Evidence that the new company/facility is GMP -compliant.  Philippine Variation Guideline f or Biological  Products  
 
 
54 3. Comparative tabulated format of information on the currently registered and proposed 
production facilities (such as name, address and responsibilities) involved in the manufacture 
of the drug substance.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
78. Change in the standard/monograph (that is, specifications  and/or test procedures ) 
claimed for the drug substance, involving the following:  
a. A change from a  pharmacopoeial 
standard/monograph to an in -house  standard  None  1–6 BMaV -89 
b. A change from an in -house standard to a 
pharmacopoeial standard/monograph or from 
one pharmacopoeial standard/monograph to a 
different pharmacopoeial standard/monograph  1–4 1–3, 6, 7 BMiV -PA131 
79. Change in the specifications  and/or test 
procedures  for the drug substance in order 
to comply with an updated pharmacopoeial 
standard/monograph  1, 2 1, 2, 6, 7 BMIV -N27 
Conditions  
1. The change is made exclusively in order to comply with a pharmacopoeial monograph.  
2. There is no change in drug substance specifications outside the approved ranges . If there are 
other changes to the specification of drug substance, the applicant shall file for the applicable 
change/s. See changes 78,  79, 81 and 92.   
3. There is no deletion of tests or relaxation of acceptance criteria of the approved specifications, 
except to comply with a pharmacopoeial standard/monograph.  
4. There are no deletions or changes to any analytical procedures, except to comply with a 
pharmacopoeial standard/monograph.  
Supporting data  
1. Revised drug product labelling information, as applicable.  
2. Updated copy of the proposed drug substance specifications.  
3. Where an in -house analytical procedure is used and a pharmacopoeial standard/ monograph is 
claimed, results of an equivalency study between the in -house and pharmacopoeial methods.  
4. Copies or summar ies of validation reports if new analytical procedures are used.  
5. Justification of specifications  and/or test procedure  with data.  
6. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the drug substance with changes highlighted.  
7. Copy of the officia l monograph  containing the proposed specification and/or test procedure . 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
80. Changes in the control strategy of the drug substance, involving the following:  
a. Change from end -product testing to upstream  
controls for some test(s) (for example, real -time 
release testing, process analytical technology)  None  1–3, 5 BMaV -90 
b. Addition of a new critical quality attribute in 
the control strategy  None  1–5 BMaV -91 
c. Deletion of a critical quality attribute from the 
control strategy  None  1, 5 BMaV -92 
Conditions  
None  
Supporting data  Philippine Variation Guideline f or Biological  Products  
 
 
55 1. Information on the controls performed at critical steps of the manufacturing process and on 
intermediates of the proposed drug substance.  
2. Updated copy of the proposed drug substance specifications.  
3. Copies or summaries of analytical procedures if new analytical procedures are used.  
4. Copies or summaries of validation rep orts if new analytical procedures are used to monitor the 
new CQA at release.  
5. Justification and supporting data for each proposed change to the control strategy.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
81. Change in the specification/analytical procedure used to release the drug substance, 
involving the following:  
a. Deletion of a test  8  1, 5–7 BMaV -93 
b. Addition of a test  1–3, 8 1–3, 5, 7 BMiV -PA132 
c. Replacement of an analytical procedure  8 1–5, 7 BMaV -94 
5, 6, 8 1, 4, 5 , 7 BMiV -PA133 
d. Changes to an approved  analytical procedure  8 1–5, 7 BMaV -95 
2, 4–6, 8 1, 4, 5 , 7 BMiV -PA13 4 
e. Change from an in -house analytical procedure 
to a recognized compendial/pharmacopoeial  
analytical procedure  None   1–5, 7 BMiV -PA13 5 
2, 6 1–3, 7 BMiV -PA13 6 
f. Widening of an approved acceptance criterion  8 1, 5–7 BMaV -96 
g. Narrowing of an approved acceptance criterion  1, 4, 7 , 8 1, 7 BMiV -PA13 7 
Conditions  
1. The change does not result from unexpected events arising during manufacture (for example, 
new unqualified impurity, change in total impurity limits).  
2. There is no change in the limits/acceptance criteria outside the approved limits for the approved 
assays used at release/ stability.  
3. The addition of the test is not intended to monitor new impurity species.  
4. 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.  
5. The modified analytical procedure maintains or improves performance parameters of the 
method.  
6. The change does not concern potency -testing.  
7. Acceptance criteria for residual solvent are within recognized or approve d acceptance limits (for 
example, within ICH limits for a Class 3 residual solvent, or pharmacopoeial requirements).  
8. For changes in the standard/monograph (specifications and/or test procedures) claimed for the 
drug substance, or change of specifications o f the drug substance following the updates in the 
compendium, see changes 78,  and 79. 
Supporting data  
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.  
5. Justification for the proposed drug substance specification (for example, tests, acceptance criteria 
or analytical procedures).  
6. Documented evidence that consistency of quality is maintained.  
7. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the drug substance with changes highlighted.  
 Philippine Variation Guideline f or Biological  Products  
 
 
56 Q. Reference Standards or M aterials  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
82. Replacement of a primary reference 
standard  None  1, 2 BMaV -97 
83. Change of the reference standard from 
pharmacopoeial or international standard to 
in-house (no relationship with international 
standard)  None  1, 2 BMaV -98 
84. Change of the reference standard from in -
house (no relationship with international 
standard) to pharmacopoeial or 
international standard  3 1, 2 BMiV -PA13 8 
85. Qualification of a new batch of reference 
standard against the approved reference 
standard (including qualification of a new 
batch of a secondary reference standard 
against the approved primary standard)  1 1, 2 BMiV -PA13 9 
86. Change to reference standard qualification 
protocol  None  3, 4 BMiV -PA140 
87. Extension of the reference standard shelf -life 
or re -test period  2 5 BMiV -PA141 
Conditions  
1. Qualification of the new reference standard is in accordance with an approved protocol.  
2. The extension of the shelf -life of the reference standard is in accordance with an approved 
protocol.  
3. The reference standard is used for a physicochemical test.  
Supporting data  
1. Justification for the change in reference standard.  
2. Information demonstrating qualification of the proposed reference standards or materials (for 
example, source, characterization, certificate of analysis, comparability data).  
3. Justification of the change to the reference standard qualification protocol.  
4. Updated reference standard qualification protocol.  
5. Summary of stability testing and results to support the extensi on of reference standard shelf -life. 
 
R. Drug Substance Container Closure System  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
88. Change in the primary  container closure 
system(s)  for the storage and shipment  of the 
drug substance  None  1, 2, 4, 5  BMaV -99 
1 1, 3, 5 BMiV -PA142 
Conditions  
1. The proposed container closure system is at least equivalent to the approved  container closure 
system with respect to its relevant properties (including results  of transportation or 
compatibility studies, if appropriate).  
Supporting data  Philippine Variation Guideline f or Biological  Products  
 
 
57 1. Updated dossier sections describing information on the proposed container  closure system (for 
example, description, composition, materials of construction  of primary packaging components, 
specifications).  
2. Data demonstrating the suitability of the container closure system (for example,  
extractable/leachable testing) and compliance with pharmacopoeial standards, if  applicable.  
3. Results demonstrating that the proposed cont ainer closure system is at least  equivalent to the 
approved container closure system with respect to its relevant  properties (for example, results of 
transportation or compatibility studies, and  extractable/leachable studies).  
4. Comparative pre -change and po st-change test results for the manufacturer’s  characterized key 
stability -indicating parameters with commercial -scale drug  substance material using several 
container batches (for example, three different  batches) produced with the proposed changes and 
stored under accelerated and/  or stress conditions for a minimum of 3 months. Test results that 
cover a minimum  of 6 months in real -time/real -temperature conditions should also be provided. 
A possibility of 3 months of real -time data could be acceptable if properly justified  (for example, 
it can be proven that the relevant effect, if present, can already be  observed within 3 months). 
Comparative pre -change test results do not need to  be generated concurrently; relevant historical 
results for ba tches on the stability  programme are acceptable. Additionally, the manufacturer 
should commit to  undertake real -time stability studies to confirm the full shelf -life/hold -time of 
the drug substance under its normal storage conditions and to report any  failures in these ongoing 
long-term stability studies. Matrixing, bracketing, the use  of smaller -scale batches and/or the use 
of fewer than three container batches for  stability testing may be acceptable where justified.  
5. Comparative table of pre -change and pos t-change specifications of the container  closure system.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
89. Change in the supplier for a primary container closure,  involving the following:  
a. Replacement or addition of a  supplier  None  1–4 BMaV -100 
1, 2 1 BMiV -PA14 3 
b. Deletion of a supplier  None  1, 5 BMiV -PA14 4 
Conditions  
1. There is no change in the type of container closure, the materials of construction  or the 
sterilization process for a sterile container closure component.  
2. There is no change in the specifications of the container closure component  outside the approved 
ranges.  If there are changes to the specification of the container closure, the applicant shall file 
for the applicable change/s. See change 90 . 
Supporting data  
1. Comparative tabulated format of information on the currently registered and proposed supplier  
for a primary container closure .  
2. Data demonstrating the suitability of the container closure system (for example,  
extractable/leachable testing).  
3. Information on the proposed container closure system (for example, description,  materials of 
construction of primary packaging components, specifications).  
4. Test results that cover a minimum of 6 months in real -time/real -temp erature  conditions should 
also be provided. A possibility of 3 months of real -time data could  be acceptable if properly 
justified (for example, it can be proven that the relevant  effect, if present, can already be observed 
within 3 months). Comparative pre change  test results do not need to be generated concurrently; 
relevant historical  results for batches on the stability programme are acceptable. Additionally, 
the manufacturer should commit to undertake real -time stability studies to confirm the  full shelf -
life/hold -time of the drug substance under its normal storage conditions  and to report any failures 
in these ongoing long -term stability studies.  Matrixing, bracketing, the use of smaller -scale 
batches and/or the use of fewer  than three batches of dr ug substance for stability testing may be 
acceptable where  justified.  Philippine Variation Guideline f or Biological  Products  
 
 
58 5. Reason for withdrawal/deletion.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
90. Change in the specification/analytical procedure of the primary container  closure system 
for the drug substance, involving the following:  
a. Deletion of a test  1, 2 1, 2, 4 BMiV -PA14 5 
b. Addition of a test  3 1–4 BMiV -PA14 6 
c. Replacement of an analytical  procedure  6, 7 1–4 BMiV -PA14 7 
d. Minor changes to an  analytical procedure  4–7 1–4 BMiV -PA14 8 
e. Widening of an acceptance  criterion  None  1, 2, 4 BMiV -PA14 9 
f. Narrowing of an acceptance  criterion  8 1, 4 BMiV -PA150 
Conditions  
1. The deleted test has been demonstrated to be redundant compared to the  remaining tests or is no 
longer a pharmacopoeial requirement.  
2. The change to the specification does not affect the functional properties of the  container closure 
component and does not result in a potential impact on the  performance of the drug substance.  
3. The change is not necessitated by unexpected recurring events arising during  manufacture of the 
primary container closure system or because of stability  concerns.  
4. There is no change in the acceptance criteria outside the approved limits.  
5. The new  analytical procedure is of the same type.  
6. Results of method validation demonstrate that the new or modified analytical  procedure is at 
least equivalent to the approved analytical procedure.  
7. The new or modified analytical procedure maintains or tightens precision,  accuracy, specificity 
or sensitivity.  
8. The change is within the range of approved acceptance criteria.  
Supporting data  
1. Updated copy of the proposed specification for the primary container closure  system.  
2. Rationale for the change.  
3. Description of the analytical procedure and, if applicable, validation data.  
4. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the primary container closure system with changes highlighted.  
 
S. Stability  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
91. Change in the shelf -life of the drug substance or for a stored  intermediate of the drug 
substance, involving the following:  
a. Extension  None  1–5 BMaV -101 
1–4 1, 2, 5  BMiV -PA151 
b. Reduction  None  1–5 BMaV -102 
5 2–4 BMiV -PA152 
Conditions  
1. There are no changes to the container closure system in direct contact with the  drug substance 
with the potential of impact on the drug substance, or to the  recommended storage conditions of 
the drug substance.  
2. Full long -term stability data are available covering the proposed shelf -life and are  based on 
stability data generated on at least three commercial -scale batches.  
3. Stability data were generated in accord ance with the approved stability protocol.  Philippine Variation Guideline f or Biological  Products  
 
 
59 4. Significant changes were not observed in the stability data.  
5. The reduction in the shelf -life is not necessitated by recurring events arising  during manufacture 
or because of stability concerns (Note: Problems aris ing during  manufacturing or stability 
concerns should be reported for evaluation).  
Supporting data  
1. Summary of stability testing and results (for example, studies conducted, protocols  used, results 
obtained).  
2. Proposed storage conditions and shelf -life, as appropriate.  
3. Updated post -approval stability protocol and stability commitment.  
4. Justification for the change to the post -approval stability protocol or stability  commitment.  
5. Results of stability testing (that is, full real-time/real -temperature stability data  covering the 
proposed shelf -life generated on stability testing of at least three  commercial -scale batches unless 
otherwise justified). For intermediates, data to  show that the extension of shelf -life has no 
negati ve impact on the quality of the  drug substance. Under special circumstances, interim 
stability -testing results and  a commitment to report  any failures in the ongoing long -term 
stability  studies may be provided. In such cases, the extrapolation of shelf -life should be  made 
in accordance with ICH Q1E guidelines.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
92. Change in the post -approval stability protocol of the  drug substance, involving :  
a. Substantial change to the post-approval stability 
protocol or stability commitment, such as 
deletion of a test  parameter or limit , replacement 
of an analytical procedure , widening of 
specification limits,  or change in storage 
temperature  None  1–6 BMaV -103 
1 1, 2, 4 –6 BMiV -PA15 3 
b. Addition of a test or limit  into the post -approval 
stability protocol  or tightening of specification 
limits  2 1, 2, 4 –6 BMiV -PA15 4 
c. Deletion of time point(s) from  the post -approval 
stability  protocol within the approved  shelf -life 3 4, 5 BMiV -PA15 5 
d. Change to the post -approval stability protocol, 
such as change in specifications and/or test 
procedures following the updates in the 
compendium  4 4, 6, 7  BMiV -N28 
Conditions  
1. In the case of replacement of an analytical procedure, the new analytical  procedure maintains or 
tightens precision, accuracy, specificity and sensitivity.  
2. The addition of test(s) is not due to stability concerns or to the identification of  new impurities.  
3. Deletion of time point(s) is made in accordance with relevant guidelines . 
4. Applicable to compendial specifications and/or test procedures only. Change is made exclusively 
to comply with an update of the relevant monograph of the same compendium.  
Supporting data  
1. Copies or summaries of analytical procedures if new analytical procedures are used.  
2. Validation results if new analytical procedures are used.  
3. Proposed storage conditions and/or shelf -life, as appropriate.  
4. Updated post -approval stability protocol including justification for the changes,  and stability 
commitment.  
5. If applicable, stability -testing results to support the change to the post -approval  stability protocol 
or stability commitment (for example, data to show greater  reliability of the alternative test).  Philippine Variation Guideline f or Biological  Products  
 
 
60 6. Comparative tabulated format of t he currently approved and proposed stability protocols or 
stability commitments with changes highlighted.  
7. Copy of the official monograph of the updated compendium.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
93. Change in the storage conditions for the drug  substance, involving the following:  
a. Addition or change to storage conditions for the  
drug substance (for example, widening or 
narrowing of a temperature criterion)  None  1–4 BMaV -104 
1, 2 1–3 BMiV -PA15 6 
b. Addition of a cautionary statement  None  1, 3, 4  BMaV -105 
1 1, 3, 4  BMiV -PA15 7 
c. Deletion of a cautionary  statement  None  1, 3, 5  BMiV -PA15 8 
Conditions  
1. The change is not necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
2. The change consists in the narrowing of a temperature criterion within the  approved ranges.  
Supporting data  
1. Proposed storage conditions and shelf -life. 
2. Updated post -approval stability protocol and stability commitment.  
3. Justification of the change in the storage conditions/cautionary statement.  
4. Results of stability testing (that is, full real -time/real -temperature stability data  covering the 
proposed shelf -life generated on one commercial -scale batch).  
5. Results  of stability testing (that is, full real time/real temperature stability data  covering the 
proposed shelf -life generated on at least three commercial -scale  batches).  
 
IV. CHANGES TO THE FINAL PRODUCT  
 
T. Description and Composition of the Drug P roduct  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
Category  
94. Change in the description or composition of the  drug product, involving the following:  
a. Addition of a do sage form (for example, 
lyophil ised powder to liquid)  New registration application  
b. Change in the formulation (for example, 
addition or removal of an excipient)
 
change in the formulation (for example, addition 
or  removal of an excipient)  New registration application  
c. Change in the formulation (for example, 
qualitative or quantitative change of excipient, 
or new diluents for lyophilized product)  1 1–10 BMaV -106 
d. Change in fill volume (same concentration, 
different volume)  1, 2 1, 5, 7, 9, 
10 BMaV -107 
e. Change in the concentration  of the active 
ingredient (for  example, 20 units/ml versus  10 
units/ml)  New registration application  Philippine Variation Guideline f or Biological  Products  
 
 
61 f. Change of presentation (for example, from pre -
filled syringe to vial)  change of presentation (for 
example, from prefilled syringe to vial) 1 1, 5, 7 –10 BMaV -108 
g. Addition of a new  presentation (for example,  
addition of a new pre -filled  syringe where the 
approved  presentation is a vial for a  
biotherapeutic in a liquid  dosage form)  1 1, 5, 7 –11 BMaV -109 
Conditions  
1. Change will need to comply with the finished product specifications, for example release and 
shelf -life specifications of the drug product remain unchanged, except for the update of product 
description with respect to presentation/appearance/fill volume as  a consequence of the change 
(where applicable). If there are other changes to the specification of drug product, the applicant 
shall file for the applicable change/s. See changes 111 , 112, 114 and 127.   
2. The packaging material remains unchanged.  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Characterization data demonstrating comparability of the new formulation.  
3. Comparative tabulated format of the currently approved and proposed packaging 
presentations/primary packaging materials/diluents or product formulations with calculated 
changes highlighted (state changes in the percentage of the proposed excip ient out of the total 
target dosage form weight, where applicable).  
4. Discussion of the components of the drug product, as appropriate (for example,  choice of 
excipients, compatibility of drug substance and excipients, leachates,  compatibility with new 
conta iner closure system).  
5. Information on the batch formula, manufacturing process and process controls,  controls of 
critical steps and intermediates, process validation results.  
6. Control of excipients if new excipients are proposed (for example, specification).  
7. Information on specification, analytical procedures (if new analytical methods are  used), 
validation of analytical procedures (if new analytical methods are used),  batch analyses 
(certificate of analysis for three consecutive commercial -scale  batches shou ld be provided). 
Bracketing for multiple -strength products, container  sizes and/or fills may be acceptable if 
scientifically justified.  
8. Information on the container closure system and leachables and extractables,  if any of the 
components have changed (for example, description, materials of  construction and summary of 
specification).  
9. Comparative pre -change and post -change test results for the manufacturer’s  characterized key 
stability -indicating attributes for at least three commercial -scale  drug product bat ches produced 
with the proposed changes and stored under  accelerated and/or stress conditions for a minimum 
of 3 months. Test results that  cover a minimum of 6 months in real -time/real -temperature 
conditions should  also be provided. A possibility of 3 mont hs of real -time data could be 
acceptable if  properly justified (for example, it can be proven that the relevant effect, if present,  
can already be observed within 3 months). Comparative pre -change test results  do not need to 
be generated concurrently; relevant historical results for batches  on the stability programme are 
acceptable. Additionally, the manufacturer should  commit to undertake real -time stability studies 
to confirm the full shelf -life/ hold-time of the drug product under its n ormal storage conditions 
and to report  any failures in these ongoing long -term stability studies. Matrixing,  bracketing, the 
use of smaller -scale batches and/or the use of fewer than three  batches of drug product for 
stability testing may be acceptable whe re justified.  
10. Supporting clinical data or a justification for why such studies are not needed.  
11. Amended relevant ACTD/ ICH CTD section/s . 
 Philippine Variation Guideline f or Biological  Products  
 
 
62  
U. Description and Composition of the D rug Product:  
Change to a D iluent  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
95. Change to the diluent, involving the following:  
Note: Inclusion or replacement of the diluent for the drug product, see BMaV -106. 
a. Change in manufacturing  process  None  1–4, 10 BMiV -PA15 9 
b. Replacement of the source of a diluent  None  1–6, 9 BMiV -PA160 
c. Addition to  the source of a diluent  None  1–7, 9 BMiV -PA16 1 
d. Change in facility used to  manufacture a 
diluent (same  company)  1, 2 1, 3, 5 , 9 BMiV -PA16 2 
e. Addition of a diluent filling  line 1, 2, 4 1, 3, 5 , 10 BMiV -PA16 3 
f. Deletion of a diluent  None  8 BMiV -N29 
Conditions  
1. The diluent is water for injection or a salt solution (including buffered salt  solutions) – that is, 
it does not include an ingredient with a functional activity such  as a preservative, and there is 
no change to its composition.  
2. After reconstitution, there is no change in the drug product specification outside  the approved 
limits.  
3. The addition of the diluent filling line is in an approved filling facility.  
Supporting data  
1. Flow diagram (including process and in -process controls) of the proposed  manufacturing 
process(es) and a brief narrative description of the proposed  manufacturing process(es).  
2. Updated copy of the proposed specification for the diluent.  
3. Desc ription of the batches and summary of results as quantitative data, in a  comparative tabular 
format, for at least three consecutive commercial -scale  batches of the approved and proposed 
diluent. Comparative test results for the  approved diluent do not need  to be generated 
concurrently; relevant historical  testing results are acceptable.  
4. Updated stability data on the product reconstituted with the new diluent.  
5. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately author ized for the product  and/or activity concerned.  
6. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
7. Amended rele vant ACTD/ ICH CTD section/s.  
8. Reason for withdrawal/deletion.  
9. Comparative tabulated format of information on the currently registered and proposed 
production facilities (such as name, address and responsibilities).  
10. Comparative tabulated format of the descri ption of the current and proposed manufacturing 
processes or lines, including in -process controls, with changes highlighted.  
 
 
V. Manufacture  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
96. Change in the approved design space, involving the following:  Philippine Variation Guideline f or Biological  Products  
 
 
63 a. Establishment of a new  design space  None  1 BMaV -110 
b. Expansion of the approved  design space  None  1 BMaV -111 
c. Reduction in the approved  design space (any 
change  that reduces or limits the  range of 
parameters used to  define the design space)  1 1 BMiV -PA16 4 
Conditions  
1. The reduction in design space is not necessitated by recurring problems that have  arisen during 
manufacture.  
Supporting data  
1. Pharmaceutical development data to support the establishment or changes to  the design space.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
97. Change involving a drug product manufacturer/manufacturing facility, involving the 
following:  
a. Replacement of  a manufacturing facility for  the 
drug product (including  formulation/filling and  
primary packaging)  None  1–7 BMaV -112 
1–5 1–3, 5–8 BMaV -113 
b. Addition of  a manufacturing facility for  the 
drug product (including  formulation/filling and  
primary packaging)  None  1–7, 11 BMaV -114 
1–5 1–3, 5–8, 
11 BMaV -115 
c. Conversion of a drug product  manufacturing 
facility from  single -product to multiproduct  
facility  None  9, 10  BMaV -116 
d. Replacement of a secondary packaging  facility, 
including secondary  functional packaging (that 
is, assembly) facility  2, 3 1–3 BMiV -PA16 5 
e. Addition  of a secondary packaging  facility, 
including secondary  functional packaging (that 
is, assembly) facility  2, 3 1–3, 11 BMiV -PA16 6 
f. Replacement of the company or party 
responsible for batch release  10 1, 2, 13, 14  BMiV -PA167 
g. Addition of the company or party responsible 
for batch release  10 1, 2, 11, 13, 
14 BMiV -PA168 
h. Deletion of a drug product  manufacturing 
facility/ packaging site /batch releaser  6, 7 12, 13 BMiV -N30 
i. Change of the name or address (for example: 
postal code, street name) of the 
manufacturer/packager of drug product or 
company responsible for batch release  8, 9 2, 13, 15  BMiV -N31 
j. Change of product owner  8, 11  13, 16 –18 BMiV -N32 
Conditions  
1. The proposed facility is an approved formulation/filling facility (for the same  
company/marketing authorization holder).  
2. If there is/are changes in the composition, manufacturing process , and/or final product 
specification , the applicant shall file for the applicable change/s. See changes  94, 95, 98, 111, 
112, 114, and 127. 
3. If there is/are  change s in the container/closure system and storage conditions.  the applicant 
shall file for the applicable change/s. See changes  121, 122, and 128. Philippine Variation Guideline f or Biological  Products  
 
 
64 4. The same validated manufacturing process at critical steps (that is, compounding  and filling) is 
used.  
5. The newly introduced product is in the same family of product(s), or in the same  therapeutic 
classification, as the products already approved at the site, and also  uses the same filling 
process/equipment.  
6. There should remain at least one site/manufacturer, as previously authorized,  performing the 
same functio n as the one(s) to be deleted.  
7. The deletion should not be due to critical deficiencies in manufacturing (for example,  recurrent 
out-of-specification events, environmental monitoring failures, etc.).  
8. The manufacturing/packaging/batch release site remains unchanged.  
9. Not applicable in case it involves change in ownership of the manufacturer.  
10. Method transfer from the currently approved to the proposed site or test laboratory has been 
successfully completed.  
11. This shall cover imported drug products only. For locally manufactured drug products, see 
conditions and requirements stipulated in BMiV -N41. 
Supporting data  
1. Comparative tabulated format of information on the currently registered and proposed 
production facilities (such as name, address and responsibilities) involved in the manufacture 
of the drug product including bulk, packaging and release.  
2. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site  is appropriately authorized for the product  and/or activity  concerned. In the case 
of BMiV -N31, a valid FDA -issued GMP Certificate reflecting the proposed name and/or 
address of the manufacturer.  
3. Confirmation that the description of the manufacturing proc ess of the drug  product has not 
changed (other than the change in facility), or submission of  supporting data on the revised 
description of the manufacturing process if the  process has changed.  
4. Comparative description of the manufacturing process, if different from the  approved process, 
and information on the controls performed at critical steps of  the manufacturing process and on 
the intermediate of the proposed final product.  
5. Summary of the process validation studies and results.  
6. Description of the b atches and summary of in -process control and release testing  results as 
quantitative data, in a comparative tabular format, for at least three  consecutive commercial -
scale batches of the pre -change and post -change drug  product. Comparative pre-change test 
results do not need to be generated  concurrently; relevant historical testing results are acceptable. 
Bracketing for  multiple -strength products, container sizes and/or fills may be acceptable if  
scientifically justified.  
7. Comparative pre -change and post -change test results for the manufacturer’s  characterized key 
stability -indicating attributes for at least three commercial -scale  drug product batches produced 
with the proposed changes and stored under  accelerated and/or stress conditions for a minimum 
of 3 months. Test results that  cover a minimum of 6 months in real -time/real -temperature 
conditions should  also be provided. A possibility of 3 months of real -time data could be 
acceptable if  properly justified (for example, it can be proven that  the relevant effect, if present,  
can already be observed within 3 months). Comparative pre -change test results  do not need to 
be generated concurrently; relevant historical results for batches  on the stability programme are 
acceptable. Additionally, the m anufacturer should  commit to undertake real -time stability studies 
to confirm the full shelf -life/ hold-time of the drug product under its normal storage conditions 
and to report  any failures in these ongoing long -term stability studies. Matrixing,  bracket ing, the 
use of smaller -scale batches and/or the use of fewer than three  batches of drug product for 
stability testing may be acceptable where justified.  
8. Rationale for considering the proposed formulation/filling facility as equivalent.  Philippine Variation Guideline f or Biological  Products  
 
 
65 9. Information describ ing the change -over procedures for shared product -contact  equipment and 
the segregation procedures, as applicable. If there are no revisions,  the manufacturer should state 
that no changes were made to the change -over procedures.  
10. Cleaning procedures (includ ing data in a summary validation report and the  cleaning protocol 
for the introduction of new products, as applicable)  demonstrating lack of carry -over or cross -
contamination.  
11. Amended relevant ACTD/ ICH CTD section/s.  
12. Reason for withdrawal/deletion.  
13. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
14. Official letter from product owner authorizing the company/manufacturer to be responsible for 
batch release (where applicable).  
15. Official letter from product owner authorizing the manufacturer with proposed name/address to 
manufacture/release the drug product.  
16. Declaration on the transfer of ownership betwee n the currently approved and the proposed 
product owner.  
17. Official letter from the proposed product owner declaring the change and authorizing the local 
license holder to be responsible for the product license.  
18. If the proposed product owner is not the manuf acturer of the drug product, an official letter by 
the proposed product owner authorizing the manufacturer to manufacture the drug product on 
its behalf, and letter of acceptance from the manufacturer that it will be held responsible for 
manufacturing and ensuring the efficacy, quality and safety aspect of the drug product.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
98. Change in the drug product manufacturing process,  involving the following:  
a. Scale -up of the  manufacturing process at the  
formulation/filling stage  9, 10  1–6, 10 BMaV -117 
b. Addition or replacement of  equipment (for 
example,  formulation tank, filter  housing, 
filling line and head,  lyophilizer)  9, 10  1–7 BMaV -118 
5, 9, 10  2, 7, 8  BMiV -PA16 9 
c. Addition of a new scale bracketed by the 
approved scales or scale -down of the 
manufacturing process  9, 10  1, 3–5, 10 BMaV -119 
1–4, 8, 9 1, 4, 10 BMiV -PA170 
d. Addition of a new step (for  example, filtration)  3, 9, 10  1–6, 10 BMaV -120 
e. Product -contact equipment  change from 
dedicated  to shared (for example,  formulation 
tank, filter  housing, filling line and head,  
lyophilizer)  6, 7, 9, 10  2, 9 BMiV -PA17 1 
Conditions  
1. The proposed scale uses similar/comparable equipment to the approved  equipment. Note: 
Change in equipment size is not considered as using similar/comparable equipment.  
2. Any changes to the manufacturing process and/or to the in -process controls  are only those 
necessitated by the change in batch size (for example, the  same  formulation, controls and 
standard operating procedures are utilized) . If there are changes to the in -process controls applied 
during the manufacture of drug product, the applicant shall file for the applicable change/s. See 
change 99.  
3. The change should not be a result of recurring events that have arisen during  manufacture or 
because of stability concerns.  Philippine Variation Guideline f or Biological  Products  
 
 
66 4. There is no change in the principle of the sterilization procedures of the drug  product.  
5. Replacement of equipment with equivalent equipm ent; the change is considered  “like for like” 
(that is, in terms of product contact material, equipment size and  operating principles).  
6. The site is approved as a multi -product facility.  
7. The change has no impact on the risk of cross -contamination and is sup ported by  validated 
cleaning procedures.  
8. The change does not affect the lyophilization step.  
9. If there are changes to the specification of drug product, the applicant shall file for the applicable 
change/s. See changes 111 , 112, 114 and 127.   
10. If there are changes to the in -process controls applied during the manufacture of drug product, 
the applicant shall file for the applicable change/s. See change 99.  
Supporting data  
1. Description of the manufacturing process, if different from the approved process,  and 
information on the controls performed at critical steps of the manufacturing  process and on the 
intermediate of the proposed drug product.  
2. Information on the in -process control testing, as applicable.  
3. Process validation results (for example, media fills), as appropriate.  
4. Description of the batches and summary of in -process control and release testing  results as 
quantitative data, in a comparative tabular format, for at least three  consecutive commercial -
scale batches of the pre -change and post -change drug  product. Comparative pre -change test 
results do not need to be generated  concurrently; relevant historical testing results are acceptable. 
Bracketing for  multiple -strength products, container sizes and/or fills may be acceptable if 
scientifically justified.  
5. Comparative pre -change and post -change test results for the manufacturer’s  characterized key 
stability -indicating attributes for at least three commercial -scale  drug product batches produced 
with the proposed changes and stored  under  accelerated and/or stress conditions for a minimum 
of 3 months. Test results that  cover a minimum of 6 months in real -time/real -temperature 
conditions should  also be provided. A possibility of 3 months of real -time data could be 
acceptable if  proper ly justified (for example, it can be proven that the relevant effect, if present,  
can already be observed within 3 months). Comparative pre -change test results  do not need to 
be generated concurrently; relevant historical results for batches  on the stabili ty programme are 
acceptable. Additionally, the manufacturer should  commit to undertake real -time stability studies 
to confirm the full shelf -life/ hold-time of the drug product under its normal storage conditions 
and to report  any failures in these ongoing  long-term stability studies. Matrixing,  bracketing, the 
use of smaller -scale batches and/or the use of fewer than three  batches of drug product for 
stability testing may be acceptable where justified.  
6. Information on leachables and extractables, as applica ble. 
7. Information on the new equipment and comparison of similarities and differences  regarding 
operating principles and specifications between the new and the  replaced equipment.  
8. The rationale for regarding the equipment as similar/comparable, as applicabl e. 
9. Information describing the change -over procedures for the shared product -contact  equipment.  
10. Comparative tabulated format of the description of the current and proposed manufacturing 
processes, including in -process controls, with changes highlighted  (where applicable) . 
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
99. Change in the controls (in -process tests and/or acceptance criteria) applied  during the 
manufacturing process or on intermediates, involving the following:  
a. Narrowing of approved in -process  limits  1–3, 7 1, 4, 10 BMiV -PA17 2 
b. Addition of new in -process  test and limits  1–3, 6 1–5, 8, 10 BMiV -PA17 3 Philippine Variation Guideline f or Biological  Products  
 
 
67 c. Deletion of a non -significant  in-process test  1–4 1, 4, 7 , 10 BMiV -PA17 4 
d. Widening of the approved  in-process limits  1 1–4, 6, 8 , 
10 BMaV -121 
1–3 1, 4, 5, 8 , 
10 BMiV -PA17 5 
e. Deletion of an in -process test  which may have 
a significant  effect on the overall quality of  the 
drug product  1 1, 4, 6,  8, 
10 BMaV -122 
f. Addition or replacement of  an in -process test as 
a result  of a safety or quality issue  1 1–4, 6, 8 , 
10 BMaV -123 
100. Change in in -process  controls testing site  1–3, 5, 6  9 BMiV -N33 
Conditions  
1. Drug product specification s remain unchanged . If there are changes to the specification of the 
drug product , the applicant shall file for the applicable change/s. See changes 111 , 112, 114 
and 127.   
2. There is no change in the impurity profile of the drug product outside the  approved limits.  
3. The change is not necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
4. The test does not concern a critical attribute (for example, content, impurities, any  critical 
physical characteristics or microbial purity).  
5. The replaced analytical procedure maintains or improves precision, accuracy,  specificity and 
sensitivity, if applicable.  
6. There is no change in the in -process control limits outside the approved limits.  
7. The test procedure remains the same, or chang es in the test procedure are minor.  
Supporting data  
1. Revised information on the controls performed at critical steps of the  manufacturing process and 
on intermediates of the proposed drug substance.  
2. Updated drug product specification if changed.  
3. Copies or summaries of analytical procedures if new analytical procedures are used.  
4. Comparative table or description, where applicable, of current and proposed  in-process tests.  
5. Description of the batches and summary of in -process control and release testi ng results as 
quantitative data, in a comparative tabular format, for one commercial  scale  batch of the pre -
change and post -change drug product (certificates of  analysis should be provided). Comparative 
pre-change test results do not need to  be generated c oncurrently; relevant historical testing results 
are acceptable. Batch  data on the next two full -production batches should be made available on 
request  and reported by the marketing authorization holder if outside specification (with  
proposed action). The use of a smaller -scale batch may be acceptable where justified.  
6. Description of the batches and summary of in -process control and release testing  results as 
quantitative data, in a comparative tabular format, for at least three  consecutive commercial -
scale batches of the pre -change and post -change drug  product (certificates of analysis should be 
provided). Comparative pre -change test  results do not need to be generated concurrently; 
relevant historical testing results  are acceptable.  
7. Justification/risk asses sment showing that the attribute is non -significant.  
8. Justification for the new in -process test and limits.  
9. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately authorized for the product and/or activity concerned.  
10. Comparative tabulated format of description of the current and proposed test procedures/in -
process controls with changes highlighted.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
101. Change in the specification/analytical procedure used to  release the excipient, involving:  Philippine Variation Guideline f or Biological  Products  
 
 
68 a. Deletion of a test  5, 8 1, 3, 4 BMiV -PA17 6 
b. Addition of a test  4 1–3, 4 BMiV -PA17 7 
c. Replacement of an analytical  procedure  1–3 1, 2, 4 BMiV -PA17 8 
d. Minor changes to an  approved analytical  
procedure  None  1, 2, 4 BMiV -PA17 9 
e. Change from an in -house  analytical procedure 
to a recognized compendial  analytical 
procedure  None  1, 2, 4 BMiV -PA180 
f. Widening of an approved  acceptance criterion  None  1, 3, 4 BMiV -PA18 1 
g. Narrowing of an approved  acceptance criterion  3, 4, 6, 7  1, 4 BMiV -PA18 2 
Conditions  
1. Results of method validation demonstrate that the proposed analytical procedure  is at least 
equivalent to the approved analytical procedure.  
2. The replaced analytical procedure maintains or improves precision, accuracy,  specificity and 
sensitivity.  
3. The change is within the range of approved acceptance criteria or has been made  to reflect the 
new pharmacopoeial monograph specification for the excipien t. 
4. Acceptance criteria for residual solvents are within recognized or approved  acceptance limits 
(for example, within ICH limits for a Class 3 residual solvent or  pharmacopoeial requirements).  
5. The deleted test has been demonstrated to be redundant compared  to the  remaining tests or is no 
longer a pharmacopoeial requirement.  
6. The analytical procedure remains the same, or changes in the test procedure are  minor.  
7. The change does not result from unexpected events arising during manufacture  (for example, 
new unqu alified impurity, change in total impurity limits).  
8. An alternative test analytical procedure is already authorized for the specification  attribute/test 
and this procedure has not been added through a minor change  submission.  
Supporting data  
1. Updated excipient specification.  
2. Where an in -house analytical procedure is used and a recognized compendial  standard is 
claimed, results of an equivalency study between the in -house and  compendial methods.  
3. Justification of the proposed excipient specification (for  example, demonstration  of the 
suitability of the monograph to control the excipient and potential impact  on the performance 
of the drug product).  
4. Comparative tabulated format of the current and revised specifications and/or test procedures 
of the excipien t with changes highlighted.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
102. Change in the standard/monograph (that 
is, specifications  and/or test procedures) 
claimed for  the excipient  None  1–6 BMiV -N34 
1–5 1–6 BMiV -N35 
Conditions  
1. The change is from a House standard to a pharmacopoeial standard/monograph.  
2. The change is made exclusively to comply with a pharmacopoeial standard/monograph.  
3. There is no change to the specifications for the functional properties of the  excipient outside 
the approved ranges, and no change that results in a potential  impact on the performance of the 
drug product.  
4. There is no deletion of tests or relaxation of acceptance criteria of the approved  specifications, 
except to c omply with a pharmacopoeial standard/monograph.  
5. There is no deletion or change to any analytical procedures, except to comply with  a 
pharmacopoeial standard/monograph . Philippine Variation Guideline f or Biological  Products  
 
 
69 Supporting data  
1. Updated excipient specifications.  
2. Where a House analytical procedure is used and a pharmacopoeial/compendial  
standard/monograph is claimed, results of an equivalency study between the  House and 
compendial methods.  
3. Justification of the proposed excipient specifications (for example, demonst ration  of the 
suitability of the monograph to control the excipient and potential impact  on the performance 
of the drug product).  
4. A declaration that consistency of quality and of the production process of the  excipient is 
maintained.  
5. Comparative tabulated format of the current and revised specifications and/or test procedures 
of the excipient with changes highlighted.  
6. Copy of the official monograph containing the proposed specification and/or test procedure.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
103. Change in the source of an  excipient from a  
vegetable or  synthetic source to a human  or 
animal source that may  pose a TSE or viral 
risk 1 2–7, 11 BMaV -124 
104. Change in the source of an  excipient from a 
TSE risk (for  example, animal) source  to a 
vegetable or synthetic  source  1 1, 3, 5, 6 , 
11 BMiV -PA18 3 
105. Replacement in the source  of an excipient 
from a TSE  risk source to a different TSE  
risk source (for example,  different animal 
source,  different country of origin)  1, 5, 6  2–7, 11 BMiV -PA18 4 
106. Change in manufacture of a  biological 
excipient  None  2–7 BMaV-125 
2 2–7 BMiV-PA18 5 
1, 2 2–7 BMiV-PA18 6 
107. Change in supplier for a  plasma -derived 
excipient  (for example, human serum  
albumin)  None  3–8 BMaV-126 
1, 3, 4 5, 6, 9  BMiV-PA18 7 
108. Change in supplier for an  excipient of non -
biological  origin or of biological origin  
(excluding plasma -derived  excipient)  1 2, 3, 5 –7 BMiV-PA18 8 
1, 5, 6 3 BMiV-PA189 
109. Change in excipient testing site  1 10 BMiV-N36 
Conditions  
1. There is no change to the specification of the excipient or drug product outside  the approved 
limits.  If there are other changes to the specification of the excipient or drug product, the 
applicant shall file for the applicable change/s. See changes 10 1, 102, 111, 112 and 114.   
2. The change does not concern a human plasma -derived excipient.  
3. The human plasma -derived excipient from the new supplier is an approved  medicinal product 
and no manufacturing changes were made by the supplier of  the new excipient since its last 
approval.  
4. The excipient does not influence the structure/conformation of the active  ingredient.  
5. The TSE risk source is covered by a TSE certificate of suitability and is of the same  or lower 
TSE risk as the previously approved material.  
6. Any new excipient does not require the assessment of viral safety data.  
Supporting data  Philippine Variation Guideline f or Biological  Products  
 
 
70 1. Declaration from the manufacturer of the excipient that the excipient is entirely of  vegetable or 
synthetic origin.  
2. Details of the source of the excipient (for example, animal species, country of  origin) and the 
steps undertaken during processing to minimize the risk of TSE  exposure.  
3. Information demonstrating comparability in terms of physicochemical properties,  and the 
impurity profile of the proposed excipient compared to the approved  excipient.  
4. Information on the manufacturing process and on the controls performed at  critical steps of the 
manuf acturing process, and on the intermediate of the  proposed excipient.  
5. Description of the batches and summary of results as quantitative data, in a  comparative tabular 
format, for at least three commercial -scale batches of the  proposed excipient.  
6. Comparative  pre-change and post -change test results for the manufacturer’s  characterized key 
stability -indicating attributes for at least three commercial -scale  drug product batches produced 
with the proposed changes and stored under  accelerated and/or stress conditions for a minimum 
of 3 months. Test results that  cover a minimum of 6 months in real -time/real -temperature 
conditions should  also be provided. A possibility of 3 months of real -time data could be 
acceptable if  properly justified (for example, it can  be proven that the relevant effect, if 
present,  can already be observed within 3 months). Comparative pre -change test results  do not 
need to be generated concurrently; relevant historical results for batches  on the stability 
programme are acceptable. Addi tionally, the manufacturer should  commit to undertake real -
time stability studies to confirm the full shelf -life/ hold-time of the drug product under its 
normal storage conditions and to report  any failures in these ongoing long -term stability 
studies. Mat rixing,  bracketing, the use of smaller -scale batches and/or the use of fewer than 
three  batches of drug product for stability testing may be acceptable where justified  
7. Information assessing the risk with respect to potential contamination with  adventitious  agents 
(for example, impact on the viral clearance studies, or BSE/TSE  risk), including viral safety 
documentation where necessary.  
8. Complete manufacturing and clinical safety data to support the use of the  proposed human 
plasma -derived excipient.  
9. A letter  from the supplier certifying that no changes were made to the plasma -derived  excipient 
compared to the currently approved corresponding medicinal  product.  
10. Evidence that the new company/facility is GMP -compliant.  
11. Comparative tabulated format of the informa tion on the current and proposed sources of the 
excipient ( for example , animal species, country of origin).  
 
W. Control of the drug product  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
110. Change affecting the QC testing of the drug  product (release and stability), involving : 
a. Transfer of the quality  control testing activities 
for a non -pharmacopoeial assay  (in-house) to a 
new company  not approved in the current  
marketing authorization or  licence or to a 
different site  within the same company  1 1–3 BMiV -PA19 0 
b. Transfer of the quality  control testing activities 
for a pharmacopoeial assay to a  new company 
not approved  in the current marketing  
authorization or licence  1 1–3 BMiV-PA19 1 
c. Addition or replacement of the company or party 
responsible for quality control/stability testing 
(different from the batch release site)  1 1–3 BMiV -PA192  Philippine Variation Guideline f or Biological  Products  
 
 
71 Conditions  
1. The manufacturer of the drug product remains unchanged. If there are changes to the 
manufacturer of the drug product, the applicant shall file for the applicable change/s. See 
change 97 . 
Supporting data  
1. Information demonstrating technology transfer qualification for the non -pharmacopoeial  assays 
or verification for the pharmacopoeial assays.  
2. A valid FDA -issued Good Manufacturing Practice (GMP) Certificate substantiating that the 
proposed site is appropriately authorized for the p roduct  and/or activity concerned.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
111. Change in the standard/monograph (that is, specifications  and/or test procedures ) 
claimed for the drug product, involving the following:  
a. A change from a  pharmacopoeial standard/  
monograph to an in -house  standard  None 1–6 BMaV -127 
b. A change from an in -house  standard to a 
pharmacopoeial  standard/monograph or  from 
one pharmacopoeial  standard/ monograph to a  
different pharmacopoeial  standard/monograph  1–4 1–3, 6, 7  BMiV -PA19 3 
112. Change in the specifications  and/or test 
procedures  for the drug product to  comply 
with an updated  pharmacopoeial 
standard/monograph  1, 2 1–3, 6, 7  BMiV -N37 
Conditions  
1. The change is made exclusively to comply with a pharmacopoeial monograph.  
2. There is no change in drug product specifications outside the approved ranges.  If there are 
other changes to the specification of drug product, the applicant shall file for the applicable 
change/s. See changes 111 , 112, 114 and 127.   
3. There is no deletion of tests or relaxation of acceptance criteria of the approved  specifications, 
except to comply with a pharmacopoeial standard/monograph.  
4. There is no deletion or change to any analytical procedures, except to comply with  a 
pharmacopoeial standard/monograph.  If there are changes to the specification of drug 
substance, the applicant shall apply for the applicable change/s. See changes 78, 79, 81 and 92. 
Supporting data  
1. Revised drug product labelling information, as applicable.  
2. An updated copy of the proposed drug product specifications.  
3. Where an in -house analytical procedure is used and a pharmacopoeial standard/  monograph is 
claimed, results of an equivalency study between the in -house and  pharmacopoeial methods.  
4. Copies or summaries of validation rep orts if new analytical procedures are used.  
5. Justification of specifications with data.  
6. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the drug product with changes highlighted.  
7. Copy of the official monograph containing the proposed specification and/or test procedure.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
113. Changes in the control strategy of the drug  product, involving the following:  Philippine Variation Guideline f or Biological  Products  
 
 
72 a. Change from end -product  testing to upstream  
controls for some test(s) (for  example, real -time 
release  testing, process analytical  technology)  None  1–3, 5 BMaV -128 
b. Addition of a new critical  quality attribute to 
the control strategy  None  1–5 BMaV -129 
c. Deletion of a critical quality  attribute from the 
control  strategy  None  1, 5 BMaV -130 
Conditions  
None  
Supporting data  
1. Information on the controls performed at critical steps of the manufacturing  process and on 
intermediates of the proposed product.  
2. An updated copy of the proposed drug product specifications.  
3. Copies or summaries of analytical procedures if new analytical procedures are used.  
4. Copies or summaries of validation reports if new analytical procedures are used to  monitor the 
new cri tical quality attribute at release.  
5. Justification and supporting data for each proposed change to the control strategy.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
114. Change in the specification/analytical procedure used to  release the drug product, 
involving the following:  
a. Deletion of a test analytical  procedure and/or an  
acceptance criterion  8 1, 6–8 BMaV -131 
b. Addition of a test  1, 2, 7 , 8 1–3, 5, 8 BMiV -PA19 4 
c. Replacement of an analytical procedure  8 1–5, 8 BMaV -132 
4, 5, 8  1, 4, 5 , 8 BMiV -PA19 5 
d. Changes to an approved  analytical procedure  8 1–5, 8 BMaV -133 
1, 3–5, 8 2, 4, 5 , 8 BMiV -PA19 6 
e. Change from an in -house  analytical procedure to 
a recognized compendial  analytical procedure  None  1–5, 8 BMiV -PA19 7 
1, 5 1–3, 8 BMiV -PA198 
f. Widening of an approved  acceptance criterion  8 1, 5, 7 , 8 BMaV -134 
g. Narrowing of an approved  acceptance criterion  1, 3, 6, 7 , 8 1, 8 BMiV -PA199 
Conditions  
1. There is no change to the limits/acceptance criteria outside the approved limits  for the approved 
assays used at release/ stability.  
2. The additional test is not intended to monitor new impurity species.  
3. The method of analysis is the same (for exa mple, a change in column length or  temperature, but 
not a different type of column or method) and no new impurities  are detected.  
4. The modified analytical procedure maintains or improves the performance  parameters of the 
method.  
5. The change does not concern potency -testing.  
6. Acceptance criteria for residual solvents are within recognized or approved  acceptance limits 
(for example, within ICH limits for a Class 3 residual solvent, or  pharmacopoeial requirements).  
7. The change does not result from unexpected event s arising during manufacture  (for example, 
new unqualified impurity, or impurity content outside the approved  limits).  
8. Applicable to non -compendial spec ifications and/or test procedures. For changes in the 
standard/monograph  (specifications and/or test pro cedures)  claimed for the drug product, or 
change of specifications  of the drug product  following the updates in the compendium, see 
changes 111 , and 112 respectively . 
Supporting data  Philippine Variation Guideline f or Biological  Products  
 
 
73 1. An updated copy of the proposed drug product specification.  
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  procedure s are 
equivalent.  
5. Justification for the change to the analytical procedure (for example,  demonstration of the 
suitability of the analytical procedure in monitoring the drug  product, including the degradation 
products) or for the change to the specification  (for example, demonstration of the suitability of 
the revised acceptance criterion to  control the drug product).  
6. Justification for the deletion of the test (for example, demonstration of the  suitability of the 
revised specification in control ling the final product).  
7. Documented evidence that consistency of quality and of the production process is  maintained.  
8. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the drug product with changes highlighted.  
 
X. Reference standards  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
115. Replacement of a primary  reference 
standard  None  1, 2 BMaV -135 
116. Change of the reference  standards from a  
pharmacopoeial or  international standard to  
in-house (no relationship  with international 
standard)  None  1, 2 BMaV -136 
117. Change of the reference  standard from in -
house  (no relationship with  international 
standard)  to a pharmacopoeial or  
international standard  3 1, 2 BMiV -PA20 0 
118. Qualification of a new batch  of reference 
standard against  the approved reference  
standard (including  qualification of a new 
batch  of a secondary reference  standard 
against the  approved primary standard)  1 2 BMiV -PA20 1 
119. Change to the reference  standard 
qualification  protocol  None  3, 4 BMiV -PA20 2 
120. Extension of the reference  standard shelf -
life or re -test period  2 5 BMiV -PA20 3 
Conditions  
1. The qualification of a new standard is carried out in accordance with an approved  protocol.  
2. The extension of the shelf -life of the reference standard is carried out in  accordance with an 
approved protocol.  
3. The reference standard is used for a physicochemical test.  
Supporting data  
1. Revised product labelling to reflect the change in reference standard, as applicable.  
2. Qualification data of the proposed reference standards or materials (for example,  source, 
characterization, certificate of analysis).  
3. Justification of the change to the reference standard qualification protocol.  
4. Updated reference standard qualification protocol.  
5. Summary of stability testing and results or retest data to support the extension of  the reference 
standard shelf -life. Philippine Variation Guideline f or Biological  Products  
 
 
74  
Y. Drug product container closure system  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
121. Modification of a  container closure system   
Note:  
▪ The addition of a new  container closure system (for  example, addition of a pre -filled  syringe 
where the currently  approved presentation is only a  vial) is considered a change in  
presentation (see BMaV -109). 
a. Change in primary container closure system 
(for example, new coating, adhesive, stopper or 
type of glass)  None  1–8 BMaV -137 
4 1, 3, 7, 8 BMiV -PA20 4 
1–3 1, 3, 8 BMiV -PA20 5 
b. Change in any part of the packaging material 
not directly in contact with the finished product 
formulation such as change in the bossing 
(from direct printing to use of sticker) on the 
labeling materials, inclusion/deletion of an 
aluminum pouch, and inclusion/deletion of 
bliste r pack enclosing the primary packaging of 
a drug product  5 1, 3, 6, 8  BMiV -PA206  
122. Change from a reusable  container to a 
disposable container with no changes  in 
product contact material  (for example, 
change  from reusable pen to  disposable pen)  None  1, 3, 6 , 8 BMaV -138 
123. Deletion of a container  closure system  None  1 BMiV -N38 
Conditions  
1. There is no change in the type of container closure or materials of construction.  
2. There is no change in the shape or dimensions of the container closure.  
3. The change is made only to improve the quality of the container and does not  modify the 
product contact material (for example, increased thickness of the glass  vial without changing 
interior dimensions).  
4. The modified part is not in contact with the drug product.  
5. For the  change in the bossing on the labeling materials, the layout and information on the 
labels remain unchanged. If there are changes to labeling material, the applicant shall file for 
the applicable change/s. See change  137. 
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. For sterilized products, process validation results, unless otherwise justified.  
3. Update dossier co ntaining information on the proposed container closure system,  as appropriate 
(for example, description, materials of construction of primary  packaging components).  
4. Results demonstrating protection against leakage, no leaching of undesirable  substance, 
compatibility with the product, and results from the toxicity and  biological reactivity tests.  
5. Summary of release testing results as quantitative data, in a comparative tabular  format, for at 
least three consecutive commercial -scale batches of the pre -change  and post -change drug 
product. Comparative pre -change test results do not need  to be generated concurrently; relevant 
historical testing results are acceptable.  Bracketing for multiple -strength products, container 
sizes and/or fills may be  acceptable if sci entifically justified.  
6. Comparative pre -change and post -change test results for the manufacturer’s  characterized key 
stability -indicating attributes for at least three commercial -scale  drug product batches produced Philippine Variation Guideline f or Biological  Products  
 
 
75 (unless otherwise justified) with the proposed  changes and stored under accelerated and/or stress 
conditions for a minimum  of 3 months. Test results that cover a minimum of 6 months in real -
time/real  temperature  conditions should also be provided. A possibility of 3 months of real -time 
data co uld be acceptable if properly justified (for example, it can be proven  that the relevant 
effect, if present, can already be observed within 3 months).  Comparative pre -change test results 
do not need to be generated concurrently;  relevant historical results  for batches on the stability 
programme are acceptable.  Additionally, the manufacturer should commit to undertake real -time 
stability  studies to confirm the full shelf -life/hold -time of the drug product under its  normal 
storage conditions and to report any  failures in these ongoing  long-term stability studies. 
Matrixing, bracketing, the use of smaller -scale batches  and/or the use of fewer than three batches 
of drug product for stability testing  may be acceptable where justified.  
7. Information demonstrating th e suitability of the proposed container/closure  system with respect 
to its relevant properties (for example, results from last media  fills; results of interaction studies 
demonstrating preservation of protein integrity  and maintenance of sterility for ster ile products; 
maintenance of sterility in  multidose containers; user testing).  
8. Comparative tabulated format of descriptions and specifications of the current and proposed 
packaging materials, including illustrations.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
124.  Change in the supplier for a primary container closure  component, involving :  
a. Replacement or addition of a  supplier  1, 2 1, 2 BMiV -PA20 7 
b. Deletion of a supplier  None  3 BMiV -N39 
Conditions  
1. There is no change in the type of container closure, materials of construction,  shape and 
dimensions, or in the sterilization process for a sterile container closure  component.  
2. There is no change in the specification of the container closure component  outside the approved 
acceptance criteria.  If there are changes to the specification of the container closure, the applicant 
shall file for the applicable change/s. See change 125 . 
Supporting data  
1. Letter from the marketing authorization holder certifying that there are no  changes t o the 
container closure system.  
2. Certificate of analysis, or equivalent, for the container provided by the new  supplier and 
comparison with the certificate of analysis, or equivalent, for the  approv ed container.  
3. Reason for withdrawal/deletion.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
125. Change in the specification used to release a primary container  closure component or 
functional secondary container closure  component, involving the following:  
a. Deletion of a test  1, 2 1, 2, 4 BMiV -PA20 8 
b. Addition of a test  3 1, 2, 4 BMiV -PA209 
c. Replacement of an analytical  procedure  6, 7 1–4 BMiV -PA21 0 
d. Minor changes to an  analytical procedure  4–7 1–4 BMiV -PA21 1 
e. Widening of an acceptance  criterion  None  1, 2, 4 BMiV -PA21 2 
f. Narrowing of an acceptance  criterion  8 1, 4 BMiV -PA21 3 
Conditions  
1. The deleted test has been demonstrated to be redundant compared to the  remaining tests or is 
no longer a pharmacopoeial requirement.  Philippine Variation Guideline f or Biological  Products  
 
 
76 2. The change to the specification does not affect the functional properties of  the container 
closure component and does not have a potential impact on the  performance of the drug 
product.  
3. The chan ge is not necessitated by recurring events arising during manufacture or  because of 
stability concerns.  
4. There is no change to the acceptance criteria outside the approved limits.  
5. The new analytical procedure is of the same type.  
6. Results of method validatio n demonstrate that the new or modified analytical  procedure is at 
least equivalent to the approved analytical procedure.  
7. The new or modified analytical procedure maintains or improves precision,  accuracy, 
specificity and sensitivity.  
8. The change is within the range of approved acceptance criteria.  
Supporting data  
1. An updated copy of the proposed specification for the primary or functional  secondary container 
closure component.  
2. Rationale for the change in specification for a primary container closure component.  
3. Description of the analytical procedure and, if applicable, validation data.  
4. Comparative tabulated format of the currently approved and proposed specifications and/or test 
procedures of the container closure with changes highlighted.  
 
Z. Stability  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
126.  Change in the shelf -life of the drug product,  involving the following:  
a. Extension (includes extension  of shelf -life of the 
drug product as packaged for  sale, and hold -time 
after opening and after dilution or  
reconstitution)  None  1–5 BMaV -139 
b. Reduction (includes  reduction as packaged for  
sale, after opening, and after  dilution or 
reconstitution)  None  1–5 BMiV -PA21 4 
Conditions  
None  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Proposed storage conditions and shelf -life, as appropriate.  
3. Updated post -approval stability protoco l. 
4. Justification of the change to the post -approval stability protocol or stability  commitment.  
5. Results of stability testing under real -time/real -temperature conditions covering  the proposed 
shelf -life generated on at least three commercial -scale batches  unless otherwise justified.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
127.  Change in the post -approval stability protocol of the  drug product, involving :  
a. Substantial change to the post -approval  stability 
protocol or  stability commitment, such as  
deletion of a test  parameter or limit , None  1–6 BMaV -140 Philippine Variation Guideline f or Biological  Products  
 
 
77 replacement /deletion  of an analytical procedure, 
or change in storage temperature  
b. Addition of test(s) into the  post-approval 
stability protocol  or tightening of specification 
limits  1 1, 2, 4 –6 BMiV -PA21 5 
c. Deletion of time point(s) from  the post -approval 
stability  protocol within the approved  shelf -life 2 4, 6 BMiV -PA21 6 
d. Replacement of sterility  testing by the 
container/closure system integrity  testing  None  1, 2, 4 –6 BMaV -141 
3 4–6 BMiV -PA21 7 
e. Change to the post -approval stability protocol, 
such as change in specifications and/or test 
procedures following the updates in the 
compendium  4 4, 6−8 BMiV -N40 
Conditions  
1. The addition of the test(s) is not due to stability concerns or to the identification of  new 
impurities.  
2. Deletion of time point(s) is done according to relevant guidelines . 
3. The method used to demonstrate the integrity of the container/closure system  has already been 
approved as part of a previous application related to the drug  product.  
4. Applicable to compendial specifications and/or test procedures only. Change is made exclusively 
to comply with an update of the relevant monog raph of the same compendium.  
Supporting data  
1. Copies or summaries of analytical procedures if new analytical procedures are used.  
2. Validation results if new analytical procedures are used.  
3. Proposed storage conditions and or shelf -life, as appropriate.  
4. Updated post -approval stability protocol, including justification for the change,  and stability 
commitment.  
5. Comparative results demonstrating that the approved and proposed analytical  procedures are 
equivalent  if new analytical procedures are used . 
6. Comparative tabulated format of the currently approved and proposed stability protocols or 
stability commitments with changes highlighted.  
7. For change in test procedure, appropriate verification data of the proposed test procedure.  
8. Copy  of the official monograph of the updated compendium.  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
128.  Change in the labelled storage conditions for the drug product or the  diluted or 
reconstituted biotherapeutic products, involving the following:  
a. Addition or change of  storage condition(s) for 
the drug product, diluted or  reconstituted drug 
product  (for example, widening or  narrowing of 
a temperature  criterion, addition of or change  to 
controlled temperature  chain conditions)  None  1–4, 6 BMiV -PA21 8 
b. Addition of a cautionary  statement (for example,  
“Do not freeze”)  None  1, 2, 4, 5  BMiV -PA219 
c. Deletion of a cautionary  statement (for example,  
“Do not freeze”)  None  1, 2, 4, 6  BMiV -PA220 
Conditions  
None  
Supporting data  Philippine Variation Guideline f or Biological  Products  
 
 
78 1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Proposed storage conditions and shelf -life. 
3. Updated post -approval stability protocol and stability commitment.  
4. Justification of the change in the labelled storage conditions/cautionary statement.  
5. Results of stability testing under appropriate stability conditions covering the  proposed shelf -
life, ge nerated on one commercial -scale batch unless otherwise  justified.  
6. Results of stability testing under appropriate conditions covering the proposed  shelf -life, 
generated on at least three commercial -scale batches unless otherwise  justified.  
 
  Philippine Variation Guideline f or Biological  Products  
 
 
79  
 
 
 
 
 
SECTION 3 : PHILIPPINE -
SPECIFIC POST -
APPROVAL CHANGES  
  Philippine Variation Guideline f or Biological  Products  
 
 
80  
Administrative Changes  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
129. Change in brand name, involving:  
a. Change or inclusion of drug proprietary product 
name/product brand name  1–5 1–5 BMiV -PA221  
b. Deletion of drug proprietary product 
name/product brand name  1 2, 3   BMiV -PA222 
Conditions  
1. There is no change to the product (formulation, release and shelf -life specifications, 
manufacturing source and process) except for the product name. Otherwise, the applicant shall 
apply for the corresponding variation/s together with this variation under a single DTN.  
2. No confusion with another drug product either when spoken or written.  
3. The proposed name does not ( i) suggest greater safety or efficacy than supported by clinical data 
(ii) imply a therapeutic use (iii) imply superiority over another similar product and (iv) imply the 
presence of substance(s) not present in the product.  
4. Names that are identical to thos e already registered with the FDA in the same product 
classification shall not be allowed.  
5. Names that are offensive, obscene, scandalous or otherwise contrary to public morals and policy 
shall not be allowed.  
Supporting data  
1. Official letter from product owner or marketing authorization holder authorizing the change of 
product name and committing to inform users of the relevant changes (where applicable).  
2. A declaration from the marketing authorization holder that there is no other changes to the 
product/label except for t he drug product name change.  
3. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change.  
4. Updated Certificate of Pharmaceutical Product (CPP) (where applic able).  
5. Notarized affidavit of undertaking (a) to change the brand name so submitted should the proper 
authority decides with finality that he/she/it has no right to appropriate and utilize the brand 
name; and (b) to acknowledge and to agree to indemnify an d/or hold FDA free and harmless 
against any and all third -party claims arising from the acceptance of such brand name of the 
product for registration with FDA. (As per A.O. No. 2005 -0016). Alternatively, trademark 
certificate issued by Intellectual Propert y Office of the Philippines (IPOPHL) may also be 
provided (where applicable).  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
130. Change in Marketing Authorization Holder (MAH):  
a. Change of Marketing Authorization Holder 
(MAH)  1–3  1–4   BMiV -N41 
b. Change in name and/or address (for example: 
postal code, street name) of the Marketing 
Authorization Holder (MAH)  1–5  1, 4, 5   BMiV -N42 
Conditions  
1. The source of the pharmaceutical product (foreign manufacturer/exporter, local manufacturer) 
remains unchanged.  
2. Administrative change referring only to change of local trader/importer/distributor.  Philippine Variation Guideline f or Biological  Products  
 
 
81 3. The MAH of a certain drug product shall be assigned as follows:  
a. For locally manufactured drug products:  
i. PCPR or Regular CPR – The drug trader is primarily considered as the MAH. If 
no drug trader, then the drug manufacturer shall be the MAH.  
ii. CLIDP – The corresponding drug distributor shall be considered as the MAH.  
b. For imported drug products:  
i. PCPR or Regular CPR – The drug importer shall be considered as the MAH.  
ii. CLIDP – The corresponding drug distributor shall be considered as the MAH.  
4. The name change refers to the renamin g of a company or organization.  
5. The change does not include transfer of marketing authorization to another company.  
Supporting data  
1. Copy of valid License to Operate.  
2. Termination of Contract/Deed of Assignment.  
3. Agreement between the manufacturer and the proposed trader/importer/distributor, or agreement 
between the trader/exporter/importer and the proposed distributor, whichever is applicable.  
4. Currently approved and revised drafts (clean and annotated version) of the package insert an d 
labeling incorporating the proposed change.  
5. Letter by the product owner authorizing the proposed name of MAH to hold the product license 
(where applicable).  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
131. Change/inclusion/deletion of drug 
distributor  1–3  1–4   BMiV -N43 
Conditions  
1. The MAH remains unchanged. Otherwise, BMiV -N41 shall be applied together with this 
variation.  
2. For the change in the distributor of products with a CLIDP, please refer to BMiV -N41. 
3. This change is applicable for products with a valid CPR or those that have been converted to a 
Principal Certificate of Product Registration (PCPR) following A.O. 2005 -0031 and Bureau 
Circular No. 11 s. 2006.  
Supporting data  
1. Termination of Contract/Deed of Assignment.  
2. Letter of Authorization (LOA) or Agreement between MAH and proposed distributor (where 
applicable).  
3. Valid LTO of proposed distributor.  
4. Currently approved and revised drafts (clean and annotated version) of the pa ckage insert and 
labeling incorporating the proposed change.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
132. Administrative changes affecting entities 
other than the MAH  1, 2 1–5   BMiV -N44 
Conditions  
1. The manufacturer and the MAH of the drug product remain unchanged.  
2. The quality attributes – including but not limited to the formulation, manufacture and 
specifications/controls – of the drug product, drug substance and/or excipients remain 
unchanged.  
Supporting data  
1. Valid LTO reflecting the proposed change/s (where applicable).  Philippine Variation Guideline f or Biological  Products  
 
 
82 2. Manufacturing License or any official document from relevant authority of the proposed 
companies/establishments.  
3. Termination of agreement with the previous supplier (where appli cable).  
4. Agreement between the MAH/product owner and the proposed establishment.  
5. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
133.   Subsequent changes to the CLIDP 
following the approved variation/s of the PCPR  1–3  1–4  BMiV -N45 
Conditions  
1. Same variation fees as the PCPR shall be applied.  
2. The applicant may request for reconstruction of CPR reflecting the changes 
approved/acknowledged in the PCPR, with a corresponding fee.  
3. This change does not include variations equivalent to initial registration as per Section V.C.1.c 
of FDA Circul ar No. 202 3-_____  unless updated accordingly . 
Supporting data  
1. Certificate of approval/acknowledgment of notification of the variation/s applied for the PCPR.  
2. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change/s (where applicable) . 
 
 
Quality Changes  
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
134.      Change in the European Pharmacopoeial  Certificate of Suitability (CEP) , involving:  
a. Revision of European Pharmacopoeial 
Certificate of Suitability (CEP) of drug 
substance and/or excipient and/or raw material  None  1–6  BMiV -N46 
b. Renewal of European Pharmacopoeial  
Certificate of Suitability (CEP)  1 1 BMiV -N47 
Conditions  
1. Only applicable if the renewal of CEP does not involve any variation.  
Supporting data  
1. A valid European Pharmacopoeial  Certificate of Suitability (CEP) for the drug 
substance/excipient/raw material, latest version, with all annexes issued by EDQM.  
2. Specifications of drug substance/excipient/raw material (where applicable).  
3. Certificate of analysis and/or batch analysis data (in a comparative tabulated format) from the 
drug substance manufacturer* demonstrating compliance with the Ph. Eur monograph and 
including additional tests/limits listed  on the CEP (where applicable).  
4. Certificate of analysis and/or batch analysis data (in a comparative tabulated format) from the 
raw material/excipient manufacturer demonstrating compliance with the Ph. Eur monograph 
and including additional test/limits listed on the CEP (where applicable).  
5. Additional data to address any relevant parameter(s) not addressed in the CEP such as stability 
data (S7), if a re -test period is not stated on the CEP and physicochemical characteristics (e.g. 
particle size, polymorphism etc.), if applicable.  
6. If this chan ge is due to drug substance specification, a declaration from the applicant that the 
relevant stability studies of the drug product in accordance with ICH Q5C (Stability Testing of Philippine Variation Guideline f or Biological  Products  
 
 
83 Biotechnological/Biological Products) have been started and that the releva nt stability studies 
will be finalized; data should be provided only if outside specification (with proposed action).  
 
*If the drug substance manufacturer is CEP certified and the drug product manufacturer claims 
otherwise (USP, JP, In -house, etc.), data covering S4.1 to S4.5 from the drug product 
manufacturer should be submitted.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
135.       Change in the overage that is used for the drug substance, involving:  
a. Introduction or increase in the overage  New registration application  
b. Reduction or removal of overage  1 1–4  BMiV -PA223  
Conditions  
1. Changes of approved manufacturing overages of drug substance only.  
2. Release and shelf -life specifications of drug product remain unchanged. If there are changes in 
the specification of drug product, the applicant shall apply for  changes 46,  58, 111, 112, 114, 
and 127 (whichever is applicable) together with this variation under a single DTN.  
Supporting data  
1. Justification for the change with supporting scientific evidences.  
2. Comparative tabulated format of currently approved and proposed batch manufacturing 
formulae.  
3. Certificate of analysis and/or batch analysis data (in a comparative tabulated format) for three 
batches of the finished product.  
4. Stability data as per ICH Q5C (Stability Testing of Biotechnological/Biological Products), and 
report if any results  fall outside shelf -life specifications (with proposed action).  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
136.      Change of pack size  for a drug product : 
a. Change or addition of outer carton pack sizes for 
a drug product  1–3 1–3 BMiV -N48 
b. Deletion of pack size for a product  3 1, 2 BMiV -N49 
Conditions  
1. Primary packaging materials remain unchanged.  
2. No other changes except for the change of outer carton pack sizes for a drug product. For the 
change of the pack size and content in the primary packaging of a drug product, refer to changes 
29, 52, 94, and 121. 
3. The remaining pack sizes are adequate to accommodate the dosing regimen as per the approved 
product labeling.  
Supporting data  
1. Currently approved and revised drafts (clean and annotated version) of the package insert and 
labeling incorporating the proposed change (where applicable).  
2. Reason for the change/ addition /deletion of pack size.  
3. Notice of Award, or any equivalent document issued by the Department of Health, Local 
Government Unit or any related government agency (where applicable).  
 
Safety and Efficacy Changes  
 Philippine Variation Guideline f or Biological  Products  
 
 
84 Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
137.       Change in the labelling of  the dru g product , involving the following:  
a. Change and/or addition of indication/dosing 
regimen/patient population and/or inclusion of 
clinical information extending the usage of the 
product  1 1–9   BMaV -142 
b. Change of content of product labeling  1–2  1–5   BMaV -143 
c. Change of product labeling (in accordance with 
country specific labeling requirements), 
including:  
i. Addition/strengthening of warnings, 
precautions, contraindications and/or 
adverse events/effects to the approved 
product labeling.  
ii. Tightening of product’s target population.  
iii. Deletion of indication.  3 1–3, 5 BMiV -PA224  
d. Change of product labelling, including:  
i. Change/s in labeling design.  
ii. Change/s in layout (positioning of graphic 
designs).  
iii. Printing of product information inside the 
carton without change in text.  
iv. Addition or replacement of Global Product 
Identification Number (GPIN).  
i. Change in dimension of box, sticker label 
and/or package insert without change in 
pack size.  
ii. Change of text limited to administrative 
information without altering the content and 
meaning of the labeling, i.e. unapproved 
indica tion, warnings, precautions, 
contraindications, and/or adverse 
events/effects.  3–4  1–3  BMiV -N50  
Conditions  
1. As a subsequent change due to revision of Summary of Product Characteristics (SmPC) or 
equivalent document (USPI).  
2. The change is not a minor variation and not within the scope of BMaV -142. 
3. The change is not considered major  and does not contain promotional information.  
4. The change does not alter the content and meaning on the product information.  
Supporting data  
1. Currently approved product labeling.  
2. Proposed product labeling, a clean and annotated version highlighting the changes made.  
3. Summary of changes (in a comparative tabulated format) of the current and proposed product 
information.  
4. Approved PI/SmPC/PIL from an approved reference regulatory agency or the country of origin 
containing the proposed changes.  
5. Technical justification for the proposed change with supporting scientific evidences  (where 
applicable) . 
6. Clinical documents as per ACTD Part IV/ICH CTD Module 5 (where applicable).  Philippine Variation Guideline f or Biological  Products  
 
 
85 7. For registered Similar Biotherapeutic Products , documents to support the extrapolation of 
clinical data for the additional  indications  relative to the Reference Biotherapeutic Product  
(where applicable) . 
8. Risk Management Plan relative  to the proposed change . 
9. Periodic Safety Update Report (PSUR) or Periodic Benefit Risk Evaluation Report (PBRE R) 
relative  to the proposed change.  
 
 
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
138.        Change in the route of administration , involving the following:  
a. Addition of a new route of administration  1–3 1–6 BMaV -144 
None  New registration application  
b. Deletion of a route of administration  4 1, 2, 7   BMiV -PA22 5 
Conditions  
1. A newly proposed route of administration in addition to the existing approved route.  
2. Product formulation remains unchanged as compared to the currently approved formulation.  
3. Drug product is administered via parenteral administration.  
4. An alternative route  is registered . 
Supporting data  
1. Currently approved product labeling.  
2. Proposed product labeling, a clean and annotated version highlighting the changes made.  
3. Justifi cation for the proposed change  with supporting scientific evidences.  
4. Approved PI/SmPC/PIL from a reference regulatory agency or the country of origin containing 
the proposed changes (where applicable).  
5. Clinical documents as per ACTD Part IV or ICH CTD Module 5.  
6. Reason for deletion.  
 
 
Other Changes  
Description of change  Conditions 
to be fulfilled  Supporting 
data  Reporting  
category  
139.   Other changes not covered by the country -
specific regulations  1–2   1–3 B-OTH  
Conditions  
1. This only covers variations not specified in the Philippine Variation Guidelines for Biological 
Products . 
2. Proposed variation/s should affect the drug substance, excipients, raw materials and/or drug 
product, with respect to its quality (e.g. formulation, manufacture, specifications and container 
closure), safety and effi cacy (e.g. product information).  
Supporting data  
1. Reference variation classification/code with justification on why the change is considered to 
be unclassified in the variation guidelines.  
2. Summary of changes (in a comparative tabulated format).  
3. Supporting documents for the change, including amendment of the relevant sections of the 
dossier following the requirements for registration based on ACTD/ ICH CTD.  
 
 
 
 Philippine Variation Guideline f or Biological  Products  
 
 
86  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Philippine Variation Guideline f or Biological  Products  
 
 
87  
 
7 FEES FOR POST -APPROVAL CHANGE APPLICATION  
 
Variation  Fee (Php)  
(excluding LRF1) 
Major Variation  
BMaV -1 500 
BMaV -2 500 
BMaV -3 500 
BMaV -4 500 
BMaV -5 500 
BMaV -6 500 
BMaV -7 500 
BMaV -8 500 
BMaV -9 500 
BMaV -10 500 
BMaV -11 500 
BMaV -12 500 
BMaV -13 500 
BMaV -14 500 
BMaV -15 500 
BMaV -16 500 
BMaV -17 500 
BMaV -18 500 
BMaV -19 500 
BMaV -20 500 
BMaV -21 500 
BMaV -22 500 
BMaV -23 500 
BMaV -24 500 
BMaV -25 500 
BMaV -26 500 
BMaV -27 500 
BMaV -28 500 
BMaV -29 500 
BMaV -30 500 
BMaV -31 500 
BMaV -32 500 
BMaV -33 500 
BMaV -34 Initial fee2 
BMaV -35 Initial fee2 
BMaV -36 Initial fee2 
BMaV -37 Initial fee2 
BMaV -38 500 
BMaV -39 500 
BMaV -40 Initial fee2 
BMaV -41 Initial fee2 
BMaV -42 Initial fee2 
BMaV -43 Initial fee2 
BMaV -44 500 
BMaV -45 500 
BMaV -46 500 
BMaV -47 500 
BMaV -48 500 
BMaV -49 500 
BMaV -50 500 
BMaV -51 500 
BMaV -52 500 
BMaV -53 500 BMaV -54 500 
BMaV -55 500 
BMaV -56 500 
BMaV -57 500 
BMaV -58 Initial fee2 
BMaV -59 Initial fee2 
BMaV -60 1,000  
BMaV -61 500 
BMaV -62 500 
BMaV -63 500 
BMaV -64 500 
BMaV -65 500 
BMaV -66 500 
BMaV -67 500 
BMaV -68 500 
BMaV -69 500 
BMaV -70 500 
BMaV -71 500 
BMaV -72 500 
BMaV -73 500 
BMaV -74 500 
BMaV -75 500 
BMaV -76 500 
BMaV -77 500 
BMaV -78 500 
BMaV -79 500 
BMaV -80 500 
BMaV -81 500 
BMaV -82 500 
BMaV -83 500 
BMaV -84 500 
BMaV -85 500 
BMaV -86 500 
BMaV -87 500 
BMaV -88 500 
BMaV -89 500 
BMaV -90 500 
BMaV -91 500 
BMaV -92 500 
BMaV -93 500 
BMaV -94 500 
BMaV -95 500 
BMaV -96 500 
BMaV -97 500 
BMaV -98 500 
BMaV -99 500 
BMaV -100 500 
BMaV -101 500 
BMaV -102 500 
BMaV -103 500 
BMaV -104 500 
BMaV -105 500 
BMaV -106 500 
BMaV -107 500 
BMaV -108 500 
BMaV -109 500 Philippine Variation Guideline f or Biological  Products  
 
 
2 BMaV -110 500 
BMaV -111 500 
BMaV -112 Initial fee2 
BMaV -113 Initial fee2 
BMaV -114 Initial fee2 
BMaV -115 Initial fee2 
BMaV -116 500 
BMaV -117 500 
BMaV -118 Initial fee2 
BMaV -119 500 
BMaV -120 500 
BMaV -121 500 
BMaV -122 500 
BMaV -123 500 
BMaV -124 500 
BMaV -125 500 
BMaV -126 500 
BMaV -127 500 
BMaV -128 500 
BMaV -129 500 
BMaV -130 500 
BMaV -131 500 
BMaV -132 500 
BMaV -133 500 
BMaV -134 500 
BMaV -135 500 
BMaV -136 500 
BMaV -137 Initial fee2 
BMaV -138 Initial fee2 
BMaV -139 500 
BMaV -140 500 
BMaV -141 500 
BMaV -142 Initial fee23 
BMaV -143 500 
BMaV -144 Initial fee23 
Minor Variation – Prior Approval  
BMiV -PA1 500 
BMiV -PA2 500 
BMiV -PA3 500 
BMiV -PA4 500 
BMiV -PA5 500 
BMiV -PA6 500 
BMiV -PA7 500 
BMiV -PA8 500 
BMiV -PA9 500 
BMiV -PA10  500 
BMiV -PA11  500 
BMiV -PA12  500 
BMiV -PA13  500 
BMiV -PA14  500 
BMiV -PA15  Initial fee2  
BMiV -PA16  Initial fee2  
BMiV -PA17  Initial fee2  
BMiV -PA18  500 
BMiV -PA19  500 
BMiV -PA20  500 
BMiV -PA21  500 
BMiV -PA22  500 
BMiV -PA23  500 
BMiV -PA24  500 
BMiV -PA25  500 BMiV -PA26  500 
BMiV -PA27  500 
BMiV -PA28  500 
BMiV -PA29  500 
BMiV -PA30  500 
BMiV -PA31  500 
BMiV -PA32  500 
BMiV -PA33  500 
BMiV -PA34  500 
BMiV -PA35  500 
BMiV -PA36  500 
BMiV -PA37  500 
BMiV -PA38  500 
BMiV -PA39  500 
BMiV -PA40  500 
BMiV -PA41  500 
BMiV -PA42  500 
BMiV -PA43  500 
BMiV -PA44  500 
BMiV -PA45  500 
BMiV -PA46  500 
BMiV -PA47  500 
BMiV -PA48  500 
BMiV -PA49  500 
BMiV -PA50  500 
BMiV -PA51  500 
BMiV -PA52  500 
BMiV -PA53  500 
BMiV -PA54  500 
BMiV -PA55  500 
BMiV -PA56 Initial fee2 
BMiV -PA57 500 
BMiV -PA58 Initial fee2 
BMiV -PA59 500 
BMiV -PA60 500 
BMiV -PA61 500 
BMiV -PA62 500 
BMiV -PA63 500 
BMiV -PA64 500 
BMiV -PA65 500 
BMiV -PA66 500 
BMiV -PA67 500 
BMiV -PA68 500 
BMiV -PA69 500 
BMiV -PA70 500 
BMiV -PA71 500 
BMiV -PA72 500 
BMiV -PA73 500 
BMiV -PA74 500 
BMiV -PA75 500 
BMiV -PA76 500 
BMiV -PA77 500 
BMiV -PA78 500 
BMiV -PA79 500 
BMiV -PA80 500 
BMiV -PA81 500 
BMiV -PA82 500 
BMiV -PA83 500 
BMiV -PA84 500 
BMiV -PA85 500 
BMiV -PA86 500 Philippine Variation Guideline f or Biological  Products  
 
 
3 BMiV -PA87 500 
BMiV -PA88 500 
BMiV -PA89 500 
BMiV -PA90 500 
BMiV -PA91 500 
BMiV -PA92 500 
BMiV -PA93 500 
BMiV -PA94 500 
BMiV -PA95 500 
BMiV -PA96 500 
BMiV -PA97 500 
BMiV -PA98 500 
BMiV -PA99 500 
BMiV -PA100 1,000  
BMiV -PA101 500 
BMiV -PA102 500 
BMiV -PA103 500 
BMiV -PA104 500 
BMiV -PA105 500 
BMiV -PA106  500 
BMiV -PA107 500 
BMiV -PA108 500 
BMiV -PA109 500 
BMiV -PA110 500 
BMiV -PA111 500 
BMiV -PA112 500 
BMiV -PA113 500 
BMiV -PA114 500 
BMiV -PA115 500 
BMiV -PA116 500 
BMiV -PA117 500 
BMiV -PA118 500 
BMiV -PA119 500 
BMiV -PA120 500 
BMiV -PA121 500 
BMiV -PA122 500 
BMiV -PA123 500 
BMiV -PA124 500 
BMiV -PA125 500 
BMiV -PA126 500 
BMiV -PA127 500 
BMiV -PA128 500 
BMiV -PA129 500 
BMiV -PA130 500 
BMiV -PA131 500 
BMiV -PA132 500 
BMiV -PA133 500 
BMiV -PA134 500 
BMiV -PA135 500 
BMiV -PA136 500 
BMiV -PA137 500 
BMiV -PA138 500 
BMiV -PA139 500 
BMiV -PA140 500 
BMiV -PA141 500 
BMiV -PA142 500 
BMiV -PA143 500 
BMiV -PA144 500 
BMiV -PA145 500 
BMiV -PA146 500 
BMiV -PA147 500 BMiV -PA148 500 
BMiV -PA149 500 
BMiV -PA150 500 
BMiV -PA151 500 
BMiV -PA152 500 
BMiV -PA153 500 
BMiV -PA154 500 
BMiV -PA155 500 
BMiV -PA156 500 
BMiV -PA157 500 
BMiV -PA158 500 
BMiV -PA159 500 
BMiV -PA160 500 
BMiV -PA161 500 
BMiV -PA162 500 
BMiV -PA163 500 
BMiV -PA164 500 
BMiV -PA165 500 
BMiV -PA166 Initial fee2 
BMiV -PA167 500 
BMiV -PA168 Initial fee2 
BMiV -PA169 500 
BMiV -PA170 500 
BMiV -PA171 500 
BMiV -PA172 500 
BMiV -PA173 500 
BMiV -PA174 500 
BMiV -PA175 500 
BMiV -PA176 500 
BMiV -PA177 500 
BMiV -PA178 500 
BMiV -PA179 500 
BMiV -PA180  500 
BMiV -PA181 500 
BMiV -PA182 500 
BMiV -PA183 500 
BMiV -PA184 500 
BMiV -PA185 500 
BMiV -PA186 500 
BMiV -PA187 500 
BMiV -PA188 500 
BMiV -PA189 500 
BMiV -PA190 500 
BMiV -PA191 500 
BMiV -PA192 500 
BMiV -PA193 500 
BMiV -PA194 500 
BMiV -PA195 500 
BMiV -PA196 500 
BMiV -PA197 500 
BMiV -PA198 500 
BMiV -PA199 500 
BMiV -PA200 500 
BMiV -PA201 500 
BMiV -PA202 500 
BMiV -PA203 500 
BMiV -PA204 500 
BMiV -PA205 500 
BMiV -PA206 500 
BMiV -PA207 500 
BMiV -PA208 500 Philippine Variation Guideline f or Biological  Products  
 
 
4 BMiV -PA209 500 
BMiV -PA210 500 
BMiV -PA211 500 
BMiV -PA212 500 
BMiV -PA213 500 
BMiV -PA214 1,000  
BMiV -PA215 500 
BMiV -PA216 500 
BMiV -PA217 500 
BMiV -PA218  500 
BMiV -PA219 500 
BMiV -PA220 500 
BMiV -PA221 2,500 +  
500 (for each brand name)  
BMiV -PA222 500 
BMiV -PA223 500 
BMiV -PA224 500 
BMiV -PA225 500 
Minor Variation – Notification  
BMiV -N1 500 
BMiV -N2 500 
BMiV -N3 500 
BMiV -N4 500 
BMiV -N5 500 
BMiV -N6 500 
BMiV -N7 500 
BMiV -N8 500 
BMiV -N9 500 
BMiV -N10 500 
BMiV -N11 500 
BMiV -N12 500 
BMiV -N13 500 
BMiV -N14 500 
BMiV -N15 500 
BMiV -N16 500 
BMiV -N17 500 
BMiV -N18 500 
BMiV -N19 500 
BMiV -N20 500 
BMiV -N21 500 
BMiV -N22 500 
BMiV -N23 500 
BMiV -N24 500 
BMiV -N25 500 
BMiV -N26 500 
BMiV -N27 500 
BMiV -N28 500 
BMiV -N29 500 
BMiV -N30 500 
BMiV -N31 500 
BMiV -N32 500 
BMiV -N33 500 
BMiV -N34 500 
BMiV -N35 500 
BMiV -N36 500 
BMiV -N37 500 
BMiV -N38 500 
BMiV -N39 500 
BMiV -N40 500 
BMiV -N41 500 
BMiV -N42 500 BMiV -N43 500 
BMiV -N44 500 
BMiV -N45 PCPR variation fee4 
BMiV -N46 500 
BMiV -N47 500 
BMiV -N48 500 
BMiV -N49 500 
BMiV -N50 500 
Others  
B-OTH  5005  
  
 73  
1Legal Research Fee (LRF) shall be added to the fees for each proposed variation based on FDA Circular Nos. 2011 -003 and 2011 -003-A  
2Amount is according to the previous initial registration fee:  
 - Branded Drug Product: Php 15,000.00  
 - Unbranded Drug Product: Php 10,000.00  
 - Drug Product under Monitored Release (MR): Php 20,000.00 or Php 33,333.00 
3For the inclusion or change in the indication (e.g. MaV -1), additional payment shall be made if review by Clinical Research Section (CRS) is 
necessary.  
4Amount paid for the variation of PCPR + Php500.00 for reconstruction (upon request).  
5 This shall be on a per change basis .