Guide for the Quality Module 3- Part P- Finished Product

Guide for the Quality Module 3 - Part P

Finished Product

Prepared by the Technical Subcommittee’s experts under the supervision of Dr. Rita Karam,
Head of Quality Assurance of Pharmaceutical Products

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Drug Name dosage form & Strength

Manufacturer:

Applicant:

ICH: Quality Guidelines:

Stability Q1A(R2)-Q1B-Q1C-Q1D-Q1E
AnalyticalValidation : Q2(R1)
Impurities: Q3A(R2)-Q3B(R2)-Q3C(R4)
Pharmacopoeias: Q4B with annexes 1 to 12.
Quality of Biotechnological products Q5A(R1)-Q5B –Q5C-Q5D-Q5E
Specifications : Q6A-Q6B
Good Manufacturing Practice : Q7
Pharmaceutical Development : Q8(R2)
Quality Risk Management : Q9
Pharmaceutical Quality System : Q10
Development and manufacture of drug substances Q11
Lifecycle management Q12

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Module 3 MAQ_R1
Section ICH Product evaluation Comments
Quality Guide for quality submission

3.2.P Drug
Product:
3.2.P.1 Description A description of the drug product and ICH The composition (e.g., components of the
and its composition should be provided. Q6A capsule shell, components of ink used on the
Composition The information provided should drug product) should also be included.
ICH If the diluent is co-packaged with the drug
of the Drug include: Q6B
product, the information on the diluent should
Product.  Description of the dosage form; be placed in a separate Drug Product section.
 Composition, The use of an over-fill should be indicated.
 Function of the components, and a
reference to their quality standards
 Type of container and closure used
for the dosage form

3.2.P.2 Pharmaceutic The Pharmaceutical Development Q6A

and
al section should contain information on
Q6B
development the development studies conducted to And
establish that the dosage form, the Q8(R2)
formulation, manufacturing process,
container closure system,
microbiological attributes and usage
instructions are appropriate for the
purpose specified in the application.
The studies described here are
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distinguished from routine control tests

conducted according to specifications.
In addition , this section should
identify and describe the formulation
and process attributes (critical
parameters ) that can influence batch
reproducibility , product performance
and drug product quality . Supportive
data and results from specific studies
or published literature can be included
within or attached to the
Pharmaceutical Development section.
Additional supportive data can be
referenced to the relevant nonclinical
or clinical sections of the application.

3.2.P.2.1 Components
of the Drug
Product

3.2.P.2.1.1 Drug The compatibility of the drug

Substance. substance with excipients listed in
3.2.P.1 should be discussed.
Additionally, key physicochemical
characteristics (e.g., water content,
solubility, and particle size
distribution, polymorphic or solid state
form) of the drug substance that can
influence the performance of the drug
product should be discussed.

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For combination products, the

compatibility of drug substances with
each other should be discussed.
3.2.P.2.1.2 Excipients The choice of excipients listed in A compatibility studies must be performed.
3.2.P.1, their concentration, their
characteristics that can influence the
drug product performance should be
discussed relative to their respective
functions.
3.2.P.2.2 Drug Product
3.2.P.2.2.1 Formulation A brief summary describing the Q8(R2) This section describes how the final formulation
Development. development of the drug product was arrived at. Some slides from DrSawaya to illustrate:
should be provided, taking into It should give a brief history of the development
including the failures along the way.
consideration the proposed route of
We must try to establish that there is a logical
administration and usage. The and scientific basis for choosing the proposed
differences between clinical formulation from pre formulation to formulation
formulations and the formulation (i.e. to pilot to production.
composition) described in 3.2.P.1 Comparative dissolution test between test
should be discussed. Results from product and reference product(on 3 pHs)
comparative in vitro studies (e.g., Comparative dissolution test among strengths
(on 3 pHs).
dissolution) or comparative in vivo
• At least 12 units should be used for each
studies (e.g., bioequivalence) should profile determination.
be discussed when appropriate. • The dissolution measurements of the test and
reference batches should be made under exactly
the same conditions. The dissolution
time points for both the profiles should be the
same (e.g., for IR products 15, 30, 45, 60
minutes; for ER products 1,2,3,5,and 8 hours).
• For products which are rapidly dissolving, i.e.,
more than 85% in 15 minutes or less, a profile
comparison is not necessary.
Difference Factor f1
is a measure of relative error between the two
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curves of dissolution
Similarity Factor f2
Using an average difference of 10% between
two dissolution profiles at all sampling time
points: f2 is about 50
A test batch dissolution is therefore considered
similar to that of the reference batch if the f2
value of the two true profiles is not less than 50.

• Ideally for curves to be similar:

– f1 should be close to 0, and
– f2 should be close to 100
• Practical considerations:
– f1 between 0 to 15 and
– f2 between 50 to 100

Or
A summary
of dissolution development can be included in
3.2.P.2.2.3, with cross-reference to studies in
Module 5, as considered appropriate.

3.2.P.2.2.2 Overages. Any overages in the formulation(s) Only in two cases :

described in 3.2.P.1 should be justified
-To compensate losses

-For vitamin preparations.

3.2.P.2.2.3 Physiochemic Parameters relevant to the performance A summary of dissolution development should
al & of the drug product, such as pH, ionic be included in 3.2.P.2.2.3, with cross-reference
biological strength, dissolution, re dispersion, to studies in Module 5, as considered
appropriate.
properties. reconstitution, particle size
distribution, particle size of the

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lend/granules flow , properties which

might affect capsule filling or tableting
, aggregation, polymorphism,
rheological properties, biological
activity or potency, and/or
immunological activity, should be
addressed
3.2.P.2.3 Manufacturing The selection and optimization of the
process manufacturing process described in The progress from pre formulation to
development. 3.2.P.3.3, in particular its critical formulation to pilot to production scale batches
should be shown to be logical, reasoned and
aspects, should be explained. Identify
continuous.
critical steps. Identify key validation
parameters in term of mixing times ,
drying times and temperature Where
relevant, the method of sterilization
should be explained and justified.
Differences between the
manufacturing process (es) used to
produce pivotal clinical batches and
the process described in 3.2.P.3.3 that
can influence the performance of the
product should be discussed.
3.2.P.2.4 Container The suitability of the container closure Connections with stability 3.2.P.8
closure system (described in 3.2.P.7) used for
system. the storage, transportation (shipping)
and use of the drug product should be
discussed. This discussion should
consider, e.g., choice of materials,
protection from moisture and light,
compatibility of the materials of
construction with the dosage form

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(including sorption to container and

leaching) safety of materials of
construction, and performance (such as
reproducibility of the dose delivery
from the device when presented as part
of the drug product).
3.2.P.2.5 Microbiologic Where appropriate, the microbiological Q4B Connections with stability 3.2.P.8
al attributes. attributes of the dosage form should be ANNEX
4A(R1)
discussed, including, for example, the Q4B
rationale for not performing microbial ANNEX
limits testing for non-sterile products 4B(R1)
and the selection and effectiveness of Q4B
ANNEX
preservative systems in products
4C(R1)
containing antimicrobial preservatives.
For sterile products, the integrity of the
container closure system to prevent
microbial contamination should be
addressed.
3.2.P.2.6 Compatibility. The compatibility of the drug product There should be a separate Drug Product
with reconstitution diluent(s) or dosage (diluent) section for co-packaged diluents.
devices (e.g., precipitation of drug Choice and development of co-packaged
diluents should be included.
substance in solution, sorption on
injection vessels, stability) should be
addressed to provide appropriate and
supportive information for the
labeling.

3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer( The name, address, and responsibility
s) . of each manufacturer, including
contractors, and each proposed

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production site or facility involved in

manufacturing and testing should be
provided.
3.2.P.3.2 Batch A batch formula should be provided Q8(R2)
Formula. that includes a list of all components of
the dosage form to be used in the
manufacturing process, their amounts
on a per batch basis, including
overages, and a reference to their
quality standards.
3.2.P.3.3 Description of A flow diagram should be presented Q6B
Manufacturing giving the steps of the process and Q8(R2)

Process and showing where materials enter the

Process process. The critical steps and points at
Controls which process controls, intermediate
tests or final product controls are
conducted should be identified.
A narrative description of the
manufacturing process, including
packaging that represents the sequence
of steps undertaken and the scale of
production should also be provided.
Novel processes or technologies and
packaging operations that directly
affect product quality should be
described with a greater level of detail.
Equipment should, at least, be
identified by type (e.g., tumble
blender, in-line homogeniser) and
working capacity, where relevant.
Steps in the process should have the

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appropriate process parameters

identified, such as time, temperature,
or pH. Associated numeric values can
be presented as an expected range.
Numeric ranges for critical steps
should be justified in Section 3.2.P.3.4.
In certain cases, environmental
conditions (e.g., low humidity for an
effervescent product) should be stated.
Proposals for the reprocessing of
materials should be justified. Any data
to support this justification should be
either referenced or filed in this section
(3.2.P.3.3).
Additionally for Biotech see 3.2.A.1
for facilities , if appropriate .

3.2.P.3.4 Control of Critical Steps: Tests and acceptance Q2A

Critical criteria should be provided (with Q2B
Q6A
steps& justification, including experimental Q6B
intermediates. data) performed at the critical steps
identified in 3.2.P.3.3 of the
manufacturing process, to ensure that
the process is controlled.
Intermediates: Information on the
quality and control of intermediates
isolated during the process should be
provided.
3.2.P.3.5 Process Description, documentation, and Q6B Content of process validation protocol:
validation results of the validation and/or -Short description of the process with a
evaluation studies should be provided summary of the critical processing steps.
-Drug product specifications (at release).
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for critical steps or critical assays used -Details of the analytical methods.
in the manufacturing process (e.g., -Acceptance criteria
validation of the sterilisation process -sampling plan (where, when and how samples
are taken).
or aseptic processing or filling). Viral
-details of the methods of recording and
safety evaluation should be provided in evaluation results.
3.2.A.2, if necessary. -proposed time frame.
-batch analytical data.
-certificate of analysis.
-batch production record
-report on unusual findings , modifications or
changes found necessary with appropriate
rational
-conclusion

3.2.P.4 Control of
Excipients
3.2.P.4.1 Specifications. The specifications for excipients Q6A Certificates of analysis(COA)s from quality
should be provided. and control lab(applicant) and from
Q6B suppliers(vendors) must be provided.
3.2.P.4.2 Analytical The analytical procedures used for Q2A
and
Procedures. testing the excipients should be
Q6B
provided, where appropriate.
3.2.P.4.3 Validation of Analytical validation information, Q2A,
Analytical including experimental data, for the Q2B,
and
Procedures analytical procedures used for testing Q6B
the excipients should be provided,
where appropriate.
3.2.P.4.4 Justification Justification for the proposed excipient Q3C
and
of specifications should be provided,
Q6B
specifications. where appropriate.

3.2.P.4.5 Excipients of For excipients of human or animal Q5A, Certificate of TSE/BSE, presence or absence
Human or origin, information should be provided Q5D, should be provided from suppliers.
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Animal regarding adventitious agents (e.g., and

Q6B
Origin. sources, specifications; description of
the testing performed; viral safety
data). (Details in 3.2.A.2).
3.2.P.4.6 Novel For excipient(s) used for the first time
Excipients. in a drug product or by a new route of .
administration, full details of
manufacture, characterization, and
controls, with cross references to
supporting safety data (nonclinical
and/or clinical) should be provided
according to the drug substance
format. (Details in 3.2.A.3).
3.2.P.5 Control of
Drug Product
3.2.P.5.1 Specification( The specification(s) for the drug Q3B, Are the specifications coherent with the dosage
s) product should be provided. Q6A form proposed?
and Is there any differentiation between release
Q6B specifications and shelf-life ones , specially
related to "assay" and related substances
content" parameters?

3.2.P.5.2 Analytical The analytical procedures used for Q2A

Procedures. testing the drug product should be and
Q6B
provided.
3.2.P.5.3 Validation of Analytical validation information, Q2A,
Analytical including experimental data, for the Q2B Validation protocols and reports, with
Procedures. analytical procedures used for testing
and acceptance and rejection criteria and
Q6B specifications and experimental data, for all
the drug product, should be provided.
analytical chemistry methods developed
and used for the characterization of a drug
substance and proposed drug product are to be
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included within the designated sections. These

methods may
include, but are not limited to
(i) identity assays for a drug substance,
intermediates,
and excipients;
(ii) content assays for a drug substance,
intermediates,
and excipients;
(iii) impurity profiling and quantification
assays for a drug substance and proposed drug
product;
(iv) dissolution assays for a proposed drug
product or drug products if more than one is
included in the marketing application;
and
(v) stability-indicating assays for a drug
substance and proposed drug product
The report, data sheets and typical
chromatograms should be provided.
3.2.P.5.4 Batch A description of batches and results of Q3B, Signed COAs for the submission batches should
Analyses batch analyses should be provided. Q3C, be provided. Typical spectrums (IR/UV) and
Q6A, chromatograms for the relevant tests (HPLC)
and are required.
Q6B

3.2.P.5.5 Characterizati Information on the characterization of Q3B,

on of impurities should be provided, if not Q5C,
Q6A,
Impurities. previously provided in "3.2.S.3.2 and
Impurities". Q6B
3.2.P.5.6 Justification Justification for the proposed drug Q3B,
of product specification(s) should be Q6A,

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Specification. provided. and

Q6B
3.2.P.6 Reference Information on the reference standards Q6A
and
standards or or reference materials used for testing
Q6B
materials. of the drug product should be
provided, if not previously provided in
"3.2.S.5 Reference Standards or
Materials".
3.2.P.7 Container A description of the container closure Certificates of analysis from quality control
Closure systems should be provided, including lab (in-house) and from suppliers(vendors)
System. the identity of materials of must be provided.
construction of each primary
packaging component and its
specification. The specifications
should include description and
identification (and critical dimensions,
with drawings where appropriate).
Non-compendia methods (with
validation) should be included where
appropriate.
For non-functional secondary
packaging components (e.g., those that
neither provide additional protection
nor serve to deliver the product), only
a brief description should be provided.
For functional secondary packaging
components, additional information
should be provided.
Suitability information should be
located in 3.2.P.2.
3.2.P.8 Stability : Some slides from Dr. Sawaya to illustrate:

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Look for more details in 3.2.P.8.3

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3.2.P.8.1 Stability The types of studies conducted, Q1A, IF

Summary and protocols used, and the results of the Q1D, • Long‐term and accelerated data showing little
Q1B, or no change over time and little or no
Conclusion studies should be summarized. The Q3B,
summary should include, for example, variability
and
Than
conclusions with respect to storage Q5C,
• Extrapolation of re‐test period or shelf life
conditions and shelf-life, and, if Q6A
beyond the period covered by long‐term data
applicable, in-use storage conditions can be proposed.
and shelf-life. • The proposed re- test period or shelf life can
be UP to TWICE, but should not be more than
12 months beyond the period covered by
long‐term data (X).
( Max: X + 12 months).

3.2.P.8.2 Post-approval The post-approval stability protocol Q1A IF

Stability and stability commitment should be and • At the time of submission:
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Protocol and provided. Q5C At least 2 pilot scale batches + 1 “lab scale“
Stability Accelerated studies up to 6 months
Commitments. Long term up to 12 months
Than

Stability Commitment:
. to continue the stability studies post approval
to place the first 3 production batches on
stability studies.

• After a new product is approved:

First 3 production batches:
1. Accelerated studies
2. Long term studies through the proposed shelf
life.
Thereafter, one batch per year.
Unless otherwise justified, at least one batch per
year of product manufactured in every strength
and every primary packaging type, if relevant,
should be included in the stability program.

3.2.P.8.3 Stability Data Results of the stability studies should Q1A, Stability testing of FP may involve
Q1B,
be presented in an appropriate format monitoring:
(e.g. tabular, graphical, and narrative).
Q1C, • appearance Example of stability data sheet:
Q1D, • loss of API
Information on the analytical Q2A,
• formation of degradation products (ICH Q3B),
procedures used to generate the data Q2B
• changes in drug disintegration and dissolution,
and validation of these procedures Q3B
• loss of package integrity,
and
should be included. • Microbial contamination.
Q5C

• Some specifications parameters depend on

pharmaceutical form
– Tablets: dissolution (or disintegration if
justified), water content, hardness, friability…

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-Hard gelatin capsules: brittleness, dissolution

(or disintegration if justified), water content and
microbial bio burden.

-softgelatin capsules: dissolution(or

disintegration if justified), microbial bioburden,
pH , leakage , and pellicle formation.

-Emulsions:phase separation , pH , viscosity ,

microbial bioburden, mean size and distribution
of dispersed globules.

– Oral solutions and suspensions: formation of a

precipitate, clarity for solutions, pH, viscosity,
microbial bio burden, extractable , leachable,
polymorphic conversion when applicable.
Additional tests for suspensions include
redispersability, rheological properties , mean
size , and distribution of particles.
– Small-Volume Parenterals: Color , Clarity of
solutions, particulate matter , pH, sterility ,
endotoxins . Powder for injectable solution:
color, reconstitution time, water content. After
reconstitution: clarity, color, pH, particles,
sterility, endotoxins/pyrogens, and particulate
matter. Suspensions for injection should include
additional particle size distribution, re
dispersability , and rheological properties.
Emulsions for injection should include phase
separation, viscosity , mean size , and
distribution of dispersed globules.
-Large-Volume Parenterals: Color , Clarity of
solutions, particulate matter , pH, sterility ,
endotoxins/pyrogens , and volume.
-Suppositories: softening range , dissolution at
37degreesC.
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-Topical ,ophthalmic, and otic preparations:

Clarity, homogeneity, pH , resuspendability (for
lotions), consistency , viscosity,
microbial bio burden , and water loss
should be tested. For ophthalmic and
otic products additional attributes
should include sterility, particulate
matter and extractable.
-Metered-Dose inhalers and Nasal Aerosols:
content uniformity, aerodynamic
particle size distribution, microscopic
evaluation, water content, leak rate ,
microbial bio burden, valve delivery ,
extractable , leachable from plastic and
elastomeric components.

The batches must have same:

1. Formula
2. Packaging
3. Raw material source
4. Manufacturing process
If one of these parameters change : other
stability studies are required.
Bracketing
In some cases , we can use :

• Bracketing :
– bracketing is the design of a stability schedule
such that only samples on the extremes of
certain design factors
(e.g., strength, container size and/or fill) are
tested at all time points as in a full design.
– The design assumes that the stability of any
intermediate levels is represented by the
stability of the extremes tested.

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And :

Matrixing
Design of a stability schedule such that a
selected subset of the total number of possible
samples for all factor combinations would be
tested at a specified time point.
At a subsequent time point, another subset of
samples for all factor combinations would be
tested.
The design assumes that the stability of each Matrixing
subset of samples tested represents the stability
of all samples at a given time point.
The differences in the samples for the same
drug product should be identified as, for
example, covering different batches, different
strengths, different sizes of the same container
closure system, and possibly, in some cases,
different container closure systems.
When a secondary packaging system contributes
to the stability of the drug product, matrixing
can be performed across the packaging systems.
Each storage condition should be treated
separately under its own matrixing design.

3.2.P.8.3.1 Real Stability NB: If we have real stability data for only two

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Data. commercial batches and if the active

ingredient is stable and if the dosage form is
conventional we can accept.

NB: For an injectable liquid which is stable at

refrigerator storage conditions 5degrees+/-3
degrees for long term, we can accept it , even
if it is not conform for accelerated :
25degrees+/- 2degrees .
Accelerated Definitions of significant changes of data stored
3.2.P.8.3.2 Stability. at accelerated conditions
API
Significant change is defined as failure to meet
the specification
Drug product
1. A 5% potency change from the initial assay
value;
2. Any specified degrading exceeding its
acceptance criteria
3. Failure to meet acceptance criteria for
appearance and physical
properties (e.g., color, phase separation,
resuspendability, delivery per actuation, caking,
hardness); and as appropriate to the product
type;
4. The pH exceeding its acceptance criteria; and
5. Dissolution exceeding the acceptance criteria
for 12 dosage units.

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Critical Remarks:

Some problems found:

-The stability data for long term conditions are provided completely for three batches but one bath has expiration date sixth months later!
- Stability data for three commercial batches are provided for 6 months of accelerated conditions and only for 6 months long term.(not complete)
- The quantity (pilot batch) followed for stability data for each conditions (less than 10% of the commercial or production batch).
-The protocol of stability and annexure are not provided.
- There is no comparison with the innovator drug, that we do not Know it sometimes.
- There is no pharmaceutical or formulation development.
- There is no description of excipients compatibility.
-Parts are not provided: all the 3.2.P.5- Appendix about specifications and analytical methods –the tests procedures and results for packaging materials-
-No dissolution tests studies.
-No certificates of analysis, or not signed.
-No excipient in the formulation but it is mentioned in the leaflet!
-In sterilization, heat penetration studies provided for another product.
-Several tape mistakes: for example: for suppositories, they mention appearance of tablets…
-Data are missing on paper and we must find them on the CD rom or vice versa.

Recommendations:
The part P of module 3will be:
Approve or not or on "Pending" for clarifications and more information or details.
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ANNEXES
Brief Summary of the ICH Guidelines for testing of Drug Substances and New drug Products :

Examples of stability data sheet:

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