Formulary F-VPP 01 version 7.

PUBLIC HEALTH INSTITUTE OF CHILE

NATIONAL AGENCY OF DRUGS DEPARTMENT
BIOPHARMACY AND BIOEQUIVALENCE SUBDEPARTMENT
SECTION OF PROCESS VALIDATION

FORM F-VPP 01: Solids pharmaceutical forms

PRESENTATION OF RESULTS FOR THE ACCREDITATION OF THE VALIDATION OF
PRODUCTIVE PROCESSES TO ESTABLISH THERAPEUTIC EQUIVALENCE
IMPORTANT: THE COMPLETENESS AND ACCURACY OF ALL THE BACKGROUND TO BE INCLUDED
IN THIS FORM IS THE RESPONSIBILITY OF THE APPLICANT, OTHERWISE APPLY THE PROVISIONS
IN ARTICLE 210 OF THE PENAL CODE.

IT IS OBLIGATORY THE NUMBER OF THE APPROVAL RESOLUTION OF THE FORMULA

MODIFICATION IF THE PRODUCT HAS A REGISTERED FORMULA DIFFERENT THAN THAT IS
INDICATED ON THE MANUFACTURING SCHEDULES, IF IT IS NOT, THE APPLICATION WILL BE
AUTOMATICALLY REFILLED

THE TECHNICAL DIRECTOR MUST SIGN THIS FORM, WILL BE RETURNED IF NOT COMPLY WITH
THAT REQUIREMENT.

Documentation can be presented in both Spanish and English. It will be necessary to attach the
respective translation, if presented in a language other than the above.

The correct entry of the information requested in this form is essential for the evaluation and
condition to respond in the shortest possible time. The indication in the respective boxes "see
CD", or "see Annex" is not appropriate and only obstructs the evaluation. The annexes are
considered only as complementary information.
Aassociated tariff codes:
4150050
4150054
4150051
4150055

GENERAL INFORMATION

Mandatory fields common to all types of validation

Applicant:
 Formulary F-VPP 01 version 7.1

NOTE: The type of modified release of the active ingredient should be according to the "Guide for the
denomination for pharmaceutical products in Chile"

DOCUMENTS THAT MUST BE PRESENTED ALONG THE APPLICATION Page

Proof of payment of the tariff corresponding to the Bioequivalence Studies Revision (BE) to N/A
establish la Therapeutic Equivalence (EQT).

TYPE OF ACCREDITATION
Mark with an X according type of validation to be performed and complete the form only according to
the indicated option.

1. Abbreviated accreditation 2. Extended accreditation

According to resolution:
1.1 Res. Ex N°2274/12 - D. Ex. Nº 634/13
1.2 Res. Ex N°1531/13
1.3 Res. Ex N°2803/09
1. Abbreviated validation Res. 2274/12 - Decree Ex N° 634/13
Attachment forms of the biobatch are requested.

1.1.1. Good Manufacturing Practices Certificate (GMP) or active equivalent. (Must be

issued by any of the regulatory agencies of high sanitary surveillance mentioned in the exempted
resolution N°2274/12 or Decree Ex. N° 634/13. . More than one GMP certificate could be joined).

Regulatory agency (country) that issues the GMP

Name Country
GMP certificate number
Inspected plant address
GMP issue date
Certificate validity

NOTE: If the Biobatch or Bioexemption batch are of an older fabrication and is not covered by the
valid GMP, it will be necessary to also present another GMP certificate that covers that period of
manufacturing.

1.1.2.Valid Pharmaceutic Product Certificate (CPP). ((Must accredit that the product is
commercialized in the regulated country by the agency that authorizes the GMP certificate and that it’s quali-
quantitative formula is the same that the product brought to Chile).

Regulatory agency (country) that issues the CPP

Name Country
CPP Certificate number
Manufacturing plant registered in the CPP

Name Country
CPP issue date
CPP validity
 Formulary F-VPP 01 version 7.1

Indicate
If the answer is NO, you must indicate the number
YES/NO commercialization
of the Approved Resolution of the modification of
country
formula of this institute (read instructions at the
beginning of this form)
¿Is the same Quali-Cuantitative formula ?
(YES/NO)
Reference number of
If the answer is NO, you should apply for change of the Analitycal Date of application
the formulation to ISP. Modification (AM)

1.1.3 If the validity of the CPP does not cover the manufacture of the biolote or batch bioexemption,
you must also attach a production form for a current batch.

Current batch manufacturing worksheet.

Batch code
Manufacturing date
Manufacturing Plant address
1.2 Abbreviatted validation by Res. Ex N°1531/13

Identification of the homologous product

validated
Register number ( if apply )
Proccess reference number
1.3 Abbreviatted validation by Res. Ex N°2803/09
For this type of validation it is requested to attach documentation that shows prequalification of the
drug by WHO.

2. Full / Extended Validation Accreditation manufacturing process

1.1. Critical Support Systems. (Complete the following box with the required information, also the
documents that support this information must be attached. In case of having a GMP certificate issued by
the national sanitary authority ISP dated before the manufacturing of the valid batches, attach said
certificate).

Critical support Code performance Qualification Valid period of Date of last

systems qualification report approval date (PQ) the maintenance
qualification (PQ) prior to the performance prior to the
manufacturing of the qualification manufacturing of
validated batches report (PQ) the validated
batches
HVAC

Purified Water

Sterile Water

Compress Air

Gases (N2)
 Formulary F-VPP 01 version 7.1

1.
2.
2.1.
2.2. Cleanliness validation. (Complete the box with the required information, also the documents that
support this information must be attached)

Document code Document approval date Valid period of the

prior to the manufacturing of document
the validated batches
Cleanliness validation
protocol
Cleanliness validation report

2.3. Analytic Methodology. (Complete the box for each analytic methodology used, also the documents
that support this information must be attached).

Document Document approval Valid period of the

code date prior to the document
manufacturing of the
validated batches
Valuation method of validation report

Dissolution method of validation report

Content uniformity method of

validation report

NOTE: For modified release dosage forms attach the analytical methodology of the dissolution test
performed to verify the type of release.

2.4. Manufacturing equipment. (Complete the following box with the equipment used in the manufacture
of the batches to validate)

Manufacturing Code of operation Date of approval of Valid Date of maintenance

equipment qualification the document prior to period of and/or calibration prior to
document (OQ) the manufacture of de the the manufacturing of the
validated batches document validated batches

2.5. Process control equipment. (Complete the following box with the process control equipment used in
the manufacture of the batches to validate)

Process Operation Rating Date of approval of the Valid Date of maintenance

control Report Code document prior to the period of and/or calibration prior to
equipment (OQ) manufacture of de the the manufacturing of the
validated batches document validated batches
 Formulary F-VPP 01 version 7.1

2.6. Quality control instruments and equipment. (Complete the following box with the instruments used
in the manufacture of the batches to validate)

Quality control Performance Date of approval of the Valid period Date of maintenance
instruments Rating Report Report prior to the of the and/or calibration prior
and equipment Code (PQ) production of the lots document to the manufacturing of
for the validation the validated batches

2.7. Of the process flow diagram. (Indicate if the flow diagram is detailed in the validation protocol and/or in
the validation report. The documents that support this information must be attached).

YES NO Where
Flow diagram is
attached

NOTE: For modified release dosage forms, the process flow chart shall indicate the step (s) in which
the excipient (s) in charge of modifying the release of the active ingredient is included.

2.8. Risk analysis. (In the following bow you must indicate if risk analysis is present in the protocol and/or
report; then according to the risk evaluation, indicate the critical stage and quality attributes corresponding,
to control de critical points. Example: content uniformity, hardness, friability, valuation, dissolution, etc.)

It presents risk analysis (Where?) Protocol Report

Critical Stage according the risk evaluation Involved quality attributes

For modified release dosage forms complete the following table:

Critical stage in the manufacture for the release of the

Attributes of quality involved
active principle, according to risk assessment
 Formulary F-VPP 01 version 7.1

2.9. Sampling plan as in the protocol. (In the following box you must detail the sampling plan to be realized
in the process of manufacture of the batches to validate. Where? How? When?).

Critical stage Sampling location How was realized the Sampling frequency
sampling

2.10.Acceptance criteria. (In the following box you must complete the analysis to be done in each critical stage
with their respective acceptance criteria).

Critical attribute Acceptance criteria

2.11.Data statistical analysis. (Indicate in the table below the results of statistical analysis according to
Technical Note No. 4, using a table for each critical parameter evaluated and attach the
appropriate file format Excel protected against modification).

BATCH 1 BATCH 2 BATCH 3

PARAMETER TO INFORM

Minimum value

Quartile 1

Quartile 2

Quartile 3

Maximum value

Average

Standard deviation (DS)

Variation coefficient (CV)

IC 95%

p-value (Shapiro-Wilk test ) Normality

 Formulary F-VPP 01 version 7.1

Cp
Cpk
p-value for the difference of the mediums
(one way ANOVA test) calculated F and
tabulated F
p-value for the homogeneity of the variances
(Bartlett test)

Note: The interbatch statistical analysis of the results will be evaluated as an informative condition, you
should only demonstrate that the process is capable and it’s under statistical control.

2.12. Process deviation documentation. (Complete the following box only in case that there is process
deviation; in that case attach de corresponding documentation).

Process deviation Documentation

3. Regulatory requirements
3.1. Fórmula cuali-cuantitativa y especificaciones de producto terminado. (For records processed in
the following table only complete the columns for the formula described in the validated batches).

Note: The last approved Q-Q formula resolution should be the same as the formula of the validated
batches. Including the solvents used and eliminated during the process, if they are note declared, you
should request the respective formula modification to this Authority before submitting this form and
attaching the receipt of the request. Failure to comply with this requirement will not be evaluated
background.

Compounds of the quali- Funtion in Quantity Components of the formula Quantity

quantitative formula included formulation (mg, g or Kg) described in validated lots (mg, g or
in the last valid Q-Q formula Kg)
resolution

In Force Resolutions N° Resolution Resolution date

Q-Q formula in force resolution

Finished product specifications in force resolution
3.2. Raw material. Indicate in the following table the list of raw materials for each of the lots used for
validation with their respective batch, certificate of analysis, date of expiration, manufacturer, certificate of
analysis of the manufacturer and qualification of the supplier. Must attach the background and certificates
that support the information issued).
 Formulary F-VPP 01 version 7.1

Raw material Batch N° RM local RM re- RM RM origin Supplier

(RM)(Name, analysis analysis manufacturer analysis qualification
tecnical grade, certificate date certificate code status
and viscosity ) code

NOTE: Indicate the viscosity only in those cases where it is necessary to achieve the correct
determination of the raw material used.

3.3. Stability . (Complete the following table. Must attach the respective documentation )
Note: Only applies when the validated batches have been undergone to stability studies.

YES NO
The validation batches have been submitted to
stability studies.
Authorized effectiveness period

3.4. Validation of product packaging . (Important: Complete the following table only if you have the
validation of primary conditioning.

Document Document code Document approval date

Protocol
Report

COMMITMENT OF THE TECHNICAL DIRECTOR AND Legal Representative:

1.- I declare under oath that the data provided in this form, as well as the accompanying
records, are true and complete.

2.-I am aware of the provisions of article 210 of the penal code, which states that: "whoever
before the authority or his agents perjurare or give false testimony in matters that are not
contentious, will suffer minor prison sentences in their degrees Minimum to medium and fine
of six to ten monthly tax units. "

Firma Director Técnico/ Representante legal

Fecha: ____/____/_____.

CHANGES CONTROL

OF TO DATE CHANGE MADE

Version 3.2 Version 4.1 12-1-14 Change of format. The modifications consist in
the order that the information must be wrote in
 Formulary F-VPP 01 version 7.1

the form.

Modification explanatory note in points 2.1.3.

Version 4.1 Version 4.2 12-5-14
and 2.1.5.

Version 4.2 Version 4.3 01-19-15 Incorporation of Biobatch information.

It’s established that “The Excel archive with the

Version 4.3 Version 4.4 02-18-15 process data must be protected against
modifications”.

The form format is updated and the

Version 4.4 Version 4.5 05-11-15 accreditation process validation by Res. 2274/12
is included.

The format was updated, also the box in 2.11,

also in 3.1, which now includes a formula
Version 4.5 Version 5.0 16-10-15 description box, we added a new 3.5 point, and
a new commitment of responsibility that shall
be signed.

Versión 5.0 Versión 5.1 23-11-15 Including associated tariff codes.

Update format, changing explanatory notes and

information Biolote in 1.3 and 3.5 are included.
Versión 5.1 Versión 6.0 08-04-16
general information of the application is
modified.

Update of format, inclusion of considerations for

Versión 6.0 Versión 7.0 01-03-17
modified release dosage forms.

It is updated membership to Inspection

Subdepartment according to Exempt Resolution
Versión 7.0 Versión 7.1 29-05-17 N ° 1197/17. Updating of content, section 1.1.2
and 3.1 related to the qualitative-quantitative
formula