FPP Stability
Lynda Paleshnuik
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Overview
 Selection of Batches
 Container Closure System
 Specifications: Stability-indicating quality parameters
 Testing Frequency
 Storage Conditions
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Overview
 FPP Stability Commitment
 Evaluation/Extrapolation of data
 Statements/Labelling
 In-use Stability
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Overview
 Variations
 Ongoing Studies
 Assessment Tips
 Common stability deficiencies
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Selection of Batches
 Main Guide: NLT 3 (1 production and 2 at least pilotscale)
 New Guide = Q1A: NLT 3 (2 at least pilot, 1 can be
smaller*);
 New Guide only: NLT 2 pilot for conventional FPP with
stable API.
*if it is representative of production batches with regard to
critical manufacturing steps
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Selection of Batches
Main Guide: COA’s should be provided, plus composition, batch
size, batch # and manufacturing date.
Main Guide = New Guide:
- Each strength and container type/size should be studied unless
bracketing/matrixing is applied. (Q1D)
- FPP batches should use different lots of API where possible;
- Batches should be as proposed re:
– Formulation
– Container/closure system
– Manufacturing process simulates production process
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Example problem
Problem: Tablets have undergone significant formulation changes.
Applicant provides many stability studies, using batches of both the
previous and current formulations. The assessor doesn’t check
which studies use the current formulation, decides some studies are
redundant, arbitrarily chooses which studies to review. (Proposed
formulation compared to BE: reduction of starch, binder change
from PVP to gelatin)
Result: Some studies reviewed were irrelevant or could be used as
“supporting data only”. Some relevant studies were not reviewed.
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FPP Stability
Container/Closure
 Main Guide = New Guide = Q1A
 Should be the container proposed for marketing including
any secondary packaging.
 If the same container is proposed in different sizes
(container or fill size), bracketing may be applied. (Q1D)
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FPP Stability
Stability-indicating quality parameters
Monitor parameters susceptible to change:
Physical (description, moisture, quality parameters (DT,
dissolution));
• Moisture is particularly important for solid orals in blisters and
strips.
Chemical (assay, degradants, preservatives);
Efficacy of additives, AMPE;
Container/closure interactions, when applicable;
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Stability-indicating quality parameters
 The New Guide is in agreement with Q1A, plus includes
Appendix 2, “Examples of Testing Parameters” for various
FPP’s.
 More details on parameters and reporting of results are in
Main Guide and Supplement 3.
 All three guides include the requirement:
A single primary batch should be tested for AMPE at the
proposed shelf-life.
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FPP Stability
Testing Frequency
Long term (Not in Main Guide) Q1A, New Guide:
Year 1: every 3 months
Year 2: every 6 months
Subsequent years: annually
Accelerated (Main Guide, Q1A, New Guide):
Minimum three points including t0 and tfinal, eg 0, 3, 6.
Intermediate (Main Guide, Q1A, New Guide):
Four points including t0 and tfinal, eg 0, 6, 9, 12.
Matrixing or bracketing may be applied if justified.
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FPP Stability
Storage Conditions
The New Guide mentions storage with: “due regard to the
climatic conditions in which the product is intended to be
marketed”, and discusses storage facility equipment
tolerances.
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FPP Stability
Submission Requirements
At time of submission:
FPP’s containing one stable API: (see S2)
6 months at 40◦C/75%
6 months at 30◦C/65%*
Other FPP’s:
6 months at 40◦C/75%
12 months at 30◦C/65%*
*It is preferred that long term studies be conducted at 30◦C/75%
(Supp3). See “Evaluation”.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Submission Requirements
At time of submission:
FPP’s for 2nd line TB products
3 months accelerated and 3 months at long term on not
less than 2 pilot scale batches
(Data required at time of submission only. Requirements
for prequalification remain the same.)
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FPP Stability
Storage Conditions
 General Requirements (New Guide)
Long-term: 25◦C/60%, 30◦C/65% or 30◦C/75% (25◦C/60%
and 30◦C/65% are indicated in the Main Guide)
Intermediate: 30◦C/65% = Main Guide
Accelerated: 40◦C/75% = Main Guide
 Main Guide (2005): “Unless otherwise justified, 30°C ±
2°C/65% RH ± 5% RH is the real-time condition for the
prequalification project.” (API and FPP)
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FPP Stability
Storage Conditions
 Storage conditions for aqueous-based products in semipermeable containers are the same in the Main Guide
and New Guide/Q1A except for long-term study
conditions:
New Guide/Q1A: 25◦C/40% or 30◦C/35%
Main Guide: 25◦C/40% or 30◦C/65%
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Storage Conditions
 For products to be stored in a refrigerator, freezer or below -20◦C,
see Q1A and the New Guide (not in Main Guide).
 The New Guide includes tables as per Q1A, with the addition of the
Zone IV storage (30◦C/75% for general case, 30◦C/65% and
30◦C/75% for accelerated conditions for refrigerated storage, 30◦C
for freezer), and reduced minimum times for stable drugs.
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FPP Stability
Storage Conditions
 Q1A leaves long-term conditions up to the applicant; the
New Guide states it should be as per the zone “in which
the FPP is intended to be marketed”.
 Under “FPP’s in impermeable containers”, the New Guide
gives guidance as to how materials are classified as
permeable or impermeable. (Not in Main or Q1A)
(eg glass ampoules)
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FPP Stability
Storage Conditions
FPP in semi-permeable containers:
 The New Guide includes a complicated discussion of
when water loss is a significant change (similar to Q1A).
 The New Guide also includes the Q1A section, “Example
of an approach for determining water loss”. (The New
Guide includes the calculations, which are absent in
Q1A.)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Example Problem
 During the assessment period:
“Additional data accumulated during the assessment
period of the registration application should be
submitted… if requested.” [Main Guideline, Q1, New
Guide]
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Example Problem
HAxxx FDC: Proposed expiry 24 mo in bottles/blisters.
 First assessed Nov/07; 3 batches stated to be on stability; no
summary of data in report, and according to batch manufacturing
dates, the batches could only be 7 mo old. Updated data
requested.
 Response reviewed July/08, at most 12 mo would be available.
Report does not indicate the length of data provided. Applicant
states only data in bottles is being provided, but assessor’s
summary mentions both bottles and blisters. A provisional 24 mo
expiry is accepted. Three comments went out, updated stability
data was not requested.
 Response reviewed Sept/08; four comments went out, no request
for updated stability.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Example Problem
Response reviewed Nov/08; the company is now mentioning
potency drops (both API’s) of 5.5% and 6% (LT 2% observed in the
only assessment report summary), for 6mo accelerated/12 mo LT
studies, packaging unknown. No updated data was requested in
previous 2 letters therefore none provided, and can’t verify in
reports if data in both packages has been assessed. Batches
would only be 18 mo old now. LT conditions are 30◦C/75%
(according to first report), therefore there is no intermediate
condition, and significant change should result in no extrapolation
beyond long term data. The request for all updated data now goes
out.
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Example Problem
Updated stability data in all packaging formats
should always be requested if there are other
significant comments going out, unless the data
provided covers the proposed shelf-life.
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Intermediate Conditions
 Data should be submitted at intermediate conditions
when ‘significant change’ is observed at accelerated
conditions.
 Note that there is no intermediate condition when long
term conditions are 30◦C/65% or 30◦C/75%. See
“Evaluation”.
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“Significant Change”
 For an FPP, significant change is any of:
- failure of any parameter to meet the limits (exceptions
next slide);
- GT 5% change in assay from initial;
- failure to pass S2 or L2 dissolution testing, ie n=12 (solid
orals - exception next slide);.
For FPP’s in semi-permeable containers, a 5% loss of
water from initial (3 mo at 40◦C/25%) is significant change.
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“Significant Change”
Exceptions:
(Q1A/Q1E/New Guide):
Some physical changes may be expected under accelerated
conditions:
- softening of suppositories (those intended to melt at 37◦C), melting
of creams (but not phase separation), adhesion loss of
transdermals.
Also, for gel caps or gelatin-coated tablets, S2/L2 dissolution failure
is not a significant change if there is an established link to crosslinking.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Photostability Studies
 Main Guide: Data should be conducted on at least one
primary batch of the FPP; see Q1B. (New Guide and Q1A
state one batch, “if appropriate”.)
 Note: for PQP, if PhInt, USP or BP, states in the
monograph for the FPP, "Protect from light", photostability
data is not required.
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FPP Stability
Other Stress Studies
Compatibility studies:
Main Guide 3.2.1: API-excipient and API-API.
For FDC’s:
TRS 929 appendix 3 Table A.1 (2005) and Supplement 2 (2006):
1) possible conditions for stress testing (API-API and APIexcipient)
2) a format for reporting the results.
NB: Q1A and the New Guide do not mention compatibility studies.
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FPP Stability Commitment
Long-term data is required to confirm the proposed shelflife.
Main Guide, 3.11.1 and New Guide:
When available long-term stability data on primary
batches do not cover the proposed shelf-life period
granted at the time of approval, a commitment should be
made to continue the stability studies post approval in
order to firmly establish the shelf-life period.
The post-approval stability protocol for commitment
batches should also be provided and should be the same
as that for the primary batches, unless otherwise
scientifically justified.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability Commitment
 New Guide/Q1A:
Various scenarios are outlined as to when a commitment is
required. A commitment is required in all three Guides unless longterm data on batches* was provided covering the proposed shelflife.
*For the commitment, note that the Main Guide refers to primary
batches, whereas the New Guide and Q1A refer to production
batches.
Main Guide - primary batches: 3 batches, at least one production,
the other two at least pilot (See 3.11.3).
New Guide - 2 production (stable) or 3 production (not stable).
Q1A – 3 production batches.
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FPP Stability
Evaluation
 Purpose: to establish shelf-life and storage conditions.
 Main Guide: in agreement with Q1A. The New Guide
includes statements from Supplement 2 for accepting a
24 month expiration.
 Examples follow.
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FPP Stability
Evaluation
 Case 1: FPP is hard capsule or tablet containing a single
stable (as per S2) API:
A two year shelf-life can be assigned based on results of
6 months accelerated and 6 months long-term data, when
all conditions in S2 are met.
Storage conditions are based on long term study
conditions.
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FPP Stability
Evaluation
 Case 2: FPP-FDC is hard capsule or tablet containing
multiple stable (as per S2) APIs:
A two year shelf-life can be assigned based on results of
6 months accelerated and 6 months long-term data, when
all conditions in S2 are met, including API-API
compatibility studies.
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FPP Stability
Evaluation
 Case 3: Data is provided for 12 months at 25◦C/60% and
6 months at 40◦C/75%. No significant change is noted.
 A shelf-life of 24 months (12 months + 12 months) can be
assigned.
 Storage statement “Do not store above 25◦C” is required.
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FPP Stability
Evaluation
 Case 4: Data is provided for 18 months at 30◦C/65% and 6 months
at 40◦C/75%. Significant change is noted at 40◦C/75%.
 There is no intermediate storage condition.*
 A shelf-life of 18 months can be assigned. The shelf-life is based on
real time data due to significant change observed at accelerated
conditions.
 Storage statement “Do not store above 30◦C”.
*See Q1A and New Guide under, “storage in a refrigerator” for
guidance on approach when significant change is observed at
accelerated conditions, when there is no intermediate storage
condition.
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FPP Stability
Evaluation
 Case 5: The applicant provides long term studies at
30◦C/65% that cover the proposed shelf-life, but no
accelerated data. They state that accelerated data is
unnecessary because long term data covers the shelf-life.
 Accelerated data is to cover “the effect of short term
excursions outside the label storage condition, eg during
shipping or handling”. Accelerated data should be
submitted or the shelf-life cannot be granted.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Evaluation Examples
 Related example: Product is to be stored in refrigerator.
Refrigeration by the patient is recommended but not
required if used within 30 days and stored below 25°C.
The applicant only provided 30 days stability studies at
25◦C.
 Solution: 25°C is the accelerated condition for this
product, and 6 months data is required regardless of the
in-use intentions.
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FPP Stability –Example:
Calculation of Shelf-life
FPP with 24 month expiry includes premix with proposed
12 month expiry. Comment out (revised somewhat):
“It should be remembered that use of a PREMIX
approaching its 12 months expiry period will result in a
finished product with less than 12 month expiry period. In
addition, shipment and distribution will further reduce the
use period and may lead to financial losses if finished
product is not used during the assigned shelf-life period.”
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability –Example:
Calculation of Shelf-life
“You are requested to confirm your understanding of the
definition of the starting point for the expiration period of a
product, as the date of the production step of first mixing
of the API with excipient(s). In order to qualify a 12 month
expiration for the premix, the stability data required to
establish a 24 month expiration of the FPP is a study on
the FPP (3 batches), manufactured with premix at the
maximum age (ie 12 months old), stored at ICH conditions
for the period of time desired for the shelf-life product after
release. For example, 24 month data on the FPP
(produced with 12 month old premix) would be required to
support an intended 24 month shelf-life for the product
(from time of release).” Company responded by
reducing hold time of premix to 6 mo.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Extrapolation of Data
 If data (6 mo acc/x mo LT) is within specifications with no
significant change at accelerated conditions, the allowed
shelf-life is double the long-term period x, but NMT x + 12
months. [In Main Guide but not in Q1A or New Guide.
This is a generally accepted practice.]
 In PQP, a shelf-life greater than 24 months must be
supported by real-time data on production batches.
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FPP Stability
Statements/Labelling
Storage conditions depend on the stability results and the
conditions of long-term testing.
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FPP Stability
Statements/Labelling
Main Guide: (Not in Q1A or New Guide)
1) If no significant change was observed at 40◦C/75% and
30◦C/65%, the SmPC and PIL should state, “This FPP does not
require any special storage conditions.”
2) If long-term storage was at 30◦C/65% and significant change
was observed at 40◦C/75%, the SmPC/PIL should state, “Do not
store above 30◦C” or “Store below 30◦C”.
3) If long-term storage was at 25◦C/60%, the SmPC/PIL should
state, “Do not store above 25◦C” or “Store below 25◦C”.
In New Guide and Main Guide, additional statements are required
where protection from low temperatures is necessary or storage in
refrigerator/freezer is required.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
FPP Stability
Statements/Labelling
 New Guide:
1) The statement “This FPP does not require any special storage
conditions” is not an option.
2) Statements, “Store below…” are no longer an option.
Statements are, “Do not store above…” long-term storage
conditions, or store in refrigerator/freezer when relevant.
3) Additional labelling statements are described where stability
testing shows limiting factors, eg hygroscopic FPP’s, FPP’s cannot
tolerate certain factors. See Appendix 3 to the New Guide.
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FPP Stability
In-use studies
 In-use studies are for FPP intended to be diluted/reconstituted.
(multi-use FPP)
 The New Guide has a separate section on In-Use Studies (2.2.10),
and specifies using two different batches (at least pilot), one near
the end of its shelf-life. Main Guide also specifies two batches, but
not their size. (# of batches not specified in Q1A)
NB: there is no in-use requirement (eg labelling “use within 30
days”) for dispersible tablets; a single dose is intended to be
dispersed just prior to use.
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Stability - Variations
 The variation guideline (Annex 6 of TRS 943, 2007)
Appendix 1 (minor changes) and Appendix 2 (major
changes) should be considered along with:
Appendix 4: “Stability-requirements for variations and
changes to prequalifed FPPs”
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Stability – Variations
Minor Changes
API variations requiring new/additional stability data:
#15: Change in re-test or storage conditions; requires
data on 2 batches (at least pilot size), covering the
requested period or storage condition.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Stability-Variations
Minor Changes
FPP variations requiring new/additional stability data:
#16: Change in excipient; requires 3 months
accelerated and long-term data on 2 batches (at least
pilot size).*
#26: Change in primary packaging; requires 3 months
stability data on 2 batches (at least pilot size).*
#29: Change in batch size; #30: minor change in
manufacture; require 3 months stability data on 1 batch
(at least pilot size).*
*Data must be available and must be provided if OOS.
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Stability-Variations
Minor Changes
 #31: change in colour/flavour; requires 3 months stability
data on 2 batches (at least pilot size). Photostability
testing may be required.*
 #32: change in tablet coat weight/capsule shell weight;
#33: change in headspace/surface-volume ratio of
container; requires 3 months stability data on 2 batches
(at least pilot size).*
*Data must be available and must be provided if OOS.
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Stability-Variations
Minor Changes
 #38: change in pack size; requires written commitment
that studies will be conducted in accordance with WHO
guidelines where stability parameters may be affected.
 #39: change in shelf-life or storage conditions; results of
real-time studies on two production batches. Where
appropriate, microbial testing should be included.
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Stability – Variations
Minor Changes
 Appendix 4: Results of studies above should be
compared to the results of studies on unchanged
API/FPP.
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Example Situation
 There is a change, such as removal of scoreline.
 Check the variation guideline if unsure whether stability data would
be required – find a similar scenario.
 Note that there are very few situations where stability data is
requested outright.
 (HC guideline for change in score requires 1st production batch to be
added to stability protocol.)
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Stability – Variations
Major Changes
 Examples:
Change in manufacturing process of API
Change in composition of FPP
Change in immediate packaging of FPP
See Appendix 4 of Variation Guide for discussion of
requirements.
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FPP Stability
Ongoing studies
 In New Guide only (not Main or Q1A):
2.2.12: “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 programme (unless none is produced during that
year).” The protocol should be provided.
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Assessment Tips
1) If a lot of data is submitted, check packaging, batches,
conditions studied. Check that batches tested are
relevant, ie are production or pilot as required, and if there
have been formulation changes, confirm that they are the
correct formulation (for eg by searching the reports for the
batch #’s). If unclear, pose comment for clarification.
2) Stability-indicating parameters only – others such as
identity, residual solvents, content uniformity are not
relevant and do not need to be summarized.
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Assessment Tips
 Recognizing problem areas that warrant a closer
look/more questions.
Eg. Data is provided in such a way that a) trends cannot
be determined, eg range of dissolution values but no
average, or b) limits cannot be assessed, eg average
dissolution but no range of individual values.
Eg. Data shows a lack of mass balance, or variability in
results without trends - may indicate problems with
analytical methods.
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Assessment Tips
When summarizing/discussing stability data, always:
a) Reiterate the retest/shelf-life declared by the applicant
and what has been considered acceptable by
assessment of the data,
b) State what shelf-life is actually declared in the labelling
such as SmPC, and on the API/FPP specifications,
c) Clearly state the actual length of data in the various
packaging formats and storage conditions which was
provided/assessed.
d) Include the limits with reporting of results.
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Common Deficiencies
These deficiencies are commonly encountered and lead to
questions and delays in approval of a shelf life:
1. Failure to specify the formulations used in the trial, and
to state which batches are identical to the proposed
formulation.
2. Failure to state the size or scale of the batches used in
the trial.
3. Failure to describe clearly the packaging used in the
trial and to confirm whether it is identical to the proposed
pack.
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Common Deficiencies
4. Failure to accumulate stability data on the required number of
batches of the product.
5. Failure to define accurately the temperature and humidity
conditions applied during the trial.
6. Failure to fully describe test methods and sample sizes.
7. Failure to provide validation of analytical methods.
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Common Deficiencies
8. Expression of results as passes test or similar when a
quantitative figure would be available.
9. Failure to include quantitative or semiquantitative determinations
of the content of degradation products, or to provide only total
content rather than values for individual impurities.
10. Use of an HPLC assay procedure to detect impurities without
validation for the purpose. HPLC assay procedures as used for
determination of the API are often unsuitable for separation and
detection of impurities as they use too short a run time. Such a
procedure would be acceptable if validated for impurity detection.
Note, however, that long run times do not in themselves ensure
good separation.
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Common Deficiencies
11. Failure to comment or conduct additional tests when there is a
lack of mass balance between the formation of degradation
products and the loss of the active substance. For example, are the
assay procedures sufficiently specific? Is the API volatile? Is it
adsorbed on to the container wall?
12. Failure to conduct additional tests to investigate the significance
of obvious alterations in the characteristics of the product. For
example a distinct change in the colour of the product may
necessitate additional investigation for degradation products.
13. Failure to include information on the physical
characteristics of the product during storage, such as
dissolution characteristics, homogeneity, particle size etc.
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Common Deficiencies
14. Failure to include stability studies under conditions of high
humidity for products that are to be registered in moisturepermeable containers, and especially for those which are
potentially labile to moisture (for example, many antibiotics).
15. Failure to provide results from intermediate time stations to
facilitate assessment of any trends in the parameters measured.
16. Failure to provide results for individual dosage units where
these are available (for example, dissolution profiles).
17. Attempting to extrapolate data obtained in the trial beyond
reasonable limits.
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Questions?
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