1. World Health Organization
19 April, 2017
Stability Principles and Case Studies: Active Pharmaceutical Ingredient (API) and Finished Pharmaceutical Product (FPP)
Gabriel K. Kaddu
WHO Prequalification of Medicines Programme
Assessment training, Copenhagen
May 2014

2. Overview Purpose of stability
Section 2.3.S.7.1(a)/ 2.3.P.8.1(a): Stress Testing
Section 2.3.S.7.2/ 2.3.P.8.2: Post approval Stability commitments
Storage conditions
Section 2.3.S.7.3/ 2.3.P.8.3: Stability Data
Stability data
Other stability studies
Assessment Tips

3. Purpose of stability
the purpose of stability testing is to: “provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.”
The stability programme also includes the study of product related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.

4. API- 2.3.S.7.1 (a): Summary of stress testing
Stress testing: can help identify the likely degradation products which, in turn, can help to
establish the degradation pathways and the intrinsic stability of the molecule
and validate the stability-indicating power of the analytical procedures used.
Stress testing may be carried out on a single batch of the API

5. API- 2.3.S.7.1 (a): Summary of stress testing
The objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10–30% loss of API
by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products.
For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor.
In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.

6. API- 2.3.S.7.1 (a): Summary of stress testing
Stress conditions
Treatment
Results
Heat
Humidity
Oxidation
Photolysis
Acid
Base
Other

7. FPP- Section 2.3.P.8.1(a): Stress testing
Formal stress testing for the FPP is not required, except:
Light stressing should be shown for the FPP (ICH Q1B)
If the API was not demonstrated to be light stable, and
If the packaging has not been demonstrated to be light protective
Stress testing is required as part of method validation, to show the assay and/or related compounds method is stability-indicating.

8. Generic Guideline
“The quality guideline (TRS 970 Annex 4, Section P.8.1) states, “If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP, it is sufficient to state “protect from light” on labelling, in lieu of photostability studies when the container-closure system is shown to be light protective.”

9. Light stress testing or photo-protective packaging
We can look at:
 “Protect from light” warnings in monographs
 “Protect from light” in APIMF
 Photo stress testing
 Packaging

10. FPP
photostability testing should be conducted on at least one primary batch of the FPP if appropriate.
If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state “protect from light” on labelling, in lieu of photostability studies, when the container-closure system is shown to be light protective.

11. Light stressing/Light transmission
What is needed:
Note that photostability testing according to ICH Q1B is “required”, however we use a pragmatic approach.
Either photostability demonstration (progression of API, FPP exposed, FPP in package) or
light transmission data.
photostability testing should be conducted on at least one primary batch of the FPP if appropriate.

12. Conclusion: Light stressing
Product should be shown to be light stable by photostability studies
showing the dosage form or dosage form in packaging is photostable.
By light transmission studies showing adequate protection of the packaging.
for blisters, which are not light protective, store blisters in carton (must be clear in QIS and on labels)
If product is not light stable; label should state that protect from light and container should be light protective – light transmission tests should be carried out on the container closure system

13. Storage Conditions Climatic Zones Zone I: 21ºC/45% RH
Zone II: 25ºC/60% RH (subtropical)
Zone III: 30ºC/35% RH(hot/ dry)
Zone IVA: 30ºC/65% RH (hot/ humid)
Zone IVB: 30ºC/75% RH (hot/very humid)
Long term stability studies should cover all climatic zones if possible

14. 3.2.S.7.1(b)/ 3.2.P.8.1(b): Accelerated and Long term testing
Stability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries.
Effective as of September 2011, the required long-term storage conditions for the WHO Prequalification of Medicines Programme are 30ºC ± 2º C/75% ± 5% RH. The use of alternative long-term conditions should be justified and should be supported with appropriate evidence.

15. When the API or FPP stability studies were not conducted at PQ conditions:
The required long-term stability condition within the WHO Prequalification programme is 30ºC/75%RH for both API and FPP (Note: 30±2°C/ 65±5% RH is also acceptable for API), unless documented evidence can be provided that storage under these conditions is not possible due to the inherent chemical instability of the API.  In light of this, please provide long-term stability data for your API at 30C/75%RH or provide documented evidence that such storage conditions are inappropriate. 

16. When the API or FPP stability studies were not conducted at PQ conditions: API
If long-term stability data at 30±2°C/ 65±5% RH or 30ºC/75%RH is not available for API, please commit to generating such data on the next three production scale batches of XXXXXXXX; provide a signed detailed protocol describing this stability programme; and commit to providing an amendment to alter the recommended storage conditions and retest period once 24 months stability data has been generated.

17. FPP
In cases where the delay in accepting the dossier in order to obtain the stability data at 30ºC/75%RH is unacceptable:
The required long-term stability condition within the WHO Prequalification programme is 30ºC/75%RH, unless documented evidence can be provided that storage under these conditions is not possible due to the inherent instability of the product.  In light of this, please provide long-term stability data for your product at 30C/75%RH or provide documented evidence that such storage conditions are inappropriate. 

18. FPP
If long-term stability data at 30ºC/75%RH is not available, you are required to commit to initiating studies at 30ºC/75%RH on the required number of primary batches; provide a signed detailed protocol describing the stability programme including a commitment for the date of initiation of studies, no more than 60 days from today’s date.

19. Storage directions - temperature
Sometimes the applicant wants “store below 25°C” when they have demonstrated stability at 30°C.
Example comment to applicant: As of September 2011 we require stability data at 30C, and when this is demonstrated “store below 30C” is encouraged on labelling. Additionally, you should be aware that procurement agencies prefer products labeled, “store below 30C” as it indicates that stability was demonstrated at 30C. You are requested to reconsider the decision to label the product, “store below 25C”.
We suggest and can explain, we cannot insist.

20. 3.2.S.7.1(b)/ 3.2.P.8.1(b): Accelerated and Long term testing
Condition
Storage temperature (ºC)
Relative humidity (%)
Minimum time period
(months)
Accelerated
40 ± 2
75 ± 5 6
Long-term
30 ± 2
(for both API and FPP)
65 ± 5
(for API)

21. Exceptions: Reproductive Health and 2nd line TB drugs 1
the requirement for stability at the time of submission only, may be reduced to;
no less than 3 months accelerated,
plus 3 months long-term data,
for not less than two primary batches of at least pilot scale or in the case of an uncomplicated1 FPP (e.g. immediate-release solid FPPs (with noted exceptions), non-sterile solutions), not less than one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, or tablets or capsules) of each proposed strength of the FPP.

22. Exceptions: Reproductive Health and 2nd line TB drugs 2
One of the primary batches (also called exhibit, pre-approval, registration, submission, or test batches) should be the batch that was used for bioequivalence studies.
All prequalification requirements for final acceptability of the dossier remain in effect, without exception;
the submission of updated stability data during the assessment period as it becomes available, and
a commitment to provide:
stability data on three production batches, and
process validation of three consecutive production batches, to be completed prior to marketing.

23. 3.2.S.7.1(b)/ 3.2.P.8.1(b): Accelerated and Long term testing
Other storage conditions are outlined in the WHO stability guidelines:
for FPPs packaged in impermeable and semi-permeable containers and
those intended for storage in a refrigerator and in a freezer.
FPPs intended for storage below −20°C should be treated on a case-by-case basis.
Weight loss from plastic containers should be reported over the shelf-life (Liquids only).

24. Stability of aqueous liquids
Aqueous Liquids in semi-permeable containers – ICH Q1 and TRS953: long term studies should be at 25°C/40%RH or (for PQ) 30°C/35%RH plus 40°C/25%RH
Q1A: “Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability…Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-permeable containers can withstand low relative humidity environments. ”

25. Container closure systems 1
Semi-permeable (ICH and TRS 953):
Containers that allow the passage of solvent, usually water, while preventing solute loss […]
Examples of semi-permeable containers include plastic bags and semi-rigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.
HDPE bottles are considered semi-permeable for storing liquids.

26. Container closure systems 2
Impermeable
Containers that provide a permanent barrier to the passage of gases or solvents, e.g. sealed aluminium tubes for semisolids, sealed glass ampoules for solutions (ICH/TRS 953) and (TRS 953 only) aluminium/aluminium blisters for solid dosage forms. (Be careful of Al/Al, it depends on the sealing.)

27. Container closure systems 3
TRS 953: “Sensitivity to moisture or potential for solvent loss is not a concern for FPPs (for liquids) packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus stability studies for products stored in impermeable containers can be conducted under any controlled or ambient relative humidity condition.
Note: This does not apply to AL/ Al blisters. For Al-Al blisters, humidity in stability studies is just as important as for bottles.  It is just that moisture permeability does not have to be tested for the package.

28. Section 3.2.S.7.2/ 3.2.P.8.2 Post-approval stability commitment
2.3.P.8.2(a): Primary stability study commitment
2.3.P.8.2(b): Commitment stability studies
2.3.P.8.2(c): Ongoing stability studies
Parameter
Details
Storage conditions(s) (ºC, %RH)
Batch number(s)/ Batch Size(s)
Tests and acceptance criteria:
Description
Assay etc
Testing frequency
Container closure system

29. Section 3.2.S.7.2/ 3.2.P.8.2: Post-approval stability protocol
number of batch(es) and different batch sizes, if applicable;
relevant physical, chemical, microbiological and biological test methods;
acceptance criteria;
reference to test methods;
description of the container-closure system(s);
testing frequency;
description of the conditions of storage

30. Information on stability studies
– storage conditions;
– strength;
– batch number, including the API batch number(s) and
manufacturer(s);
– batch size;
– completed (and proposed) test intervals.
– container-closure system including orientation (e.g. erect, inverted, on-side) where applicable; important for liquids and semi-solids (e.g. erect, inverted, on-side): This is to study the possible interaction of the container closure system (the container and the closure) with the product.

31. Section 3.2.S.7.3/ 3.2.P.8.3: Stability data
Results of the stability studies should be presented in an appropriate format :
tabular,
graphical,
Narrative
Summary of analytical methods
Information on the analytical procedures used to generate the data and validation of these procedures should be included.

32. Stability reports
General information: name, manufacturing sites, date of manufacturing; batch number, batch size.
Container closure system, tests and acceptance criteria , test frequency, storage conditions—should in line with the protocol
Evaluation of stability data-- any significant change? Out of specification? out of trend?
Conclusions
retest period for drug substance, or shelf life, if applicable
storage condition

33. API: Retest period
A retest period should be derived from the stability information and should be displayed on the container label.
After this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period.

34. Change in specifications
A change in specifications is a stability issue.

35. Stability issue – specifications have changed
Often during assessment specs are revised (by request usually) but there is no attention paid to whether stability data supports the change.
[This is another reason why it is so important to compare previous specs to the revised version provided.]
It is not sufficient to accept only a commitment for results for the new specification.
When we accept a shelf-life we are saying we are satisfied that the specifications will be met based on data we have assessed.

36. Stability issue – specifications have changed
If the revised limits can be assessed using current data, just ensure the new limits are met by most recent stability data.
Example tightened impurity limits: we can usually tell whether the new limits have been met by reviewing the available data
Imp A: up to 0.2% reported; meets new limit of NMT 0.1%
Exception in this case is TLC: semi-quantitative results were provided:
Imp A: < 0.2% reported; can’t tell if new limit (0.1%) is met

37. Stability issue – specifications have changed
The revised limits may require new testing/reporting, such as inclusion of a limit for a new impurity or a different dissolution timepoint. In these cases, the available data is insufficient: 1. If studies are completed: Request available data on retained samples if not far beyond expiry, or available new studies 2. If studies are ongoing: Request that data at subsequent stations include the revised limits.

38. Stability-indicating parameters
Stability-indicating parameters must be understood for the API and FPP.
API: any parameter susceptible to change (appearance, assay, impurities*, others specific to the API e.g. polymorphism if necessary)
Why all specified impurities, and not just degradation products for the API? The way to determine if an impurity is also a degradant is to do the stability and monitor known impurities.  A process impurity could also turn out to be a degradant. The degradants for an API by one manufacturing process may differ from that of another, for example due to the presence of trace metals or other reagents.

39. Stability-indicating parameters
FPP:
Physical (description, moisture, quality parameters (DT, dissolution));
Moisture is particularly important for solid orals in blisters and strips, and moisture-sensitive products in bottles.
Chemical (assay, degradants, preservatives);
Efficacy of additives
Container/closure interactions, when applicable (e.g. liquid in plastic);

40. Evaluation and Extrapolation of results
if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months
The proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided. The recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines

41. Provisional shelf-lives 1
Ideally, these would not exist. As long as there are significant question(s) and the data did not cover the proposed shelf-life, updated data should be requested/provided.
Example problem: 12 mo data provided in blisters and then the study was discontinued. A provisional 24 mo shelf-life was accepted. Is this okay?
No. You can’t extrapolate based on data for batches when the study on these batches will not be continued over the extrapolated period.

42. Provisional shelf-lives 2
Never accept extrapolation for cancelled studies. ICH Q1E:
“a retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data as soon as these data become available.”
WHY? 1) we don’t know why the studies were cancelled. 2) we don’t have the normal assurance of the “primary stability commitment”, and 3) if they cancelled studies (in the above case they claim because of low market potential), the odds of them starting a new study are slim.
This is very risky and against all practices.

43. Updated stability data and extrapolation – what NOT to say
“Please provide update stability data. In order to support of 24 months shelf life of the product, long term stability data up to at least 12 months should be provided, with commitment to continue long term testing for a period of time sufficient to cover the whole proposed shelf life.” The above suggests that we will accept 12 months data, and extrapolate on this, even if longer data is available. What TO say: “In order to support the proposed shelf-life, you are requested to provide available updated stability data.”

44. Extrapolation
Ask for the available updated stability data each time comments are going out.
Don’t imply that extrapolation is a guarantee as in the example question. It depends on the actual data provided.
Don’t offer extrapolation unless it has specifically been proposed by the applicant.

45. 2.3.S.7.1(b)/ 2.3.P.8.1(b): Summary of accelerated and long term testing
Summary of stability results observed
Storage conditions (ºC, % RH)
Strength and Batch number
Batch size
Container closure system
Completed (and proposed) test intervals
Test
Results
Description
Moisture
Impurities
Assay

46. Other stability studies
Hold time studies: validate holding times - how long an intermediate can be stored, including bulk product prior to final packaging In-use studies: studies to show that normal in-use of the product will not result in significant changes in the product Transport studies: studies to show a bulk product will still meet the release limits after transportation to the packaging site Each of these studies have their own requirements.

47. Hold time Studies 1 Summary of acceptable hold times
A maximum processing time of one month (30 days) is acceptable without validation. (industry standard) Any hold time for an intermediate or the bulk product >30 days must be supported by stability studies. In addition, cumulative hold times should not exceed 90 days, or additional supporting data is required.
A maximum processing time of one month (30 days) is acceptable without validation. (industry standard)
Maximum processing from dispensing to the final coating
Any hold time for an intermediate or the bulk product >30 days must be supported by stability studies.
In addition, cumulative hold times should not exceed 90 days, or additional supporting data is required.
Example from previous QA talk: 16.5 months for a CR tablet (shelf-life 24 months)
Blend days
Compressed tablets 90 days
Seal coated tablets 7 days
CR coated tablets 90 days
Laser drilled tablets 90 days
Bulk tablets 6 months

48. Hold time studies 2
These are a type of stability study to determine hold times for example for blend, cores and final coated tablets in bulk.
Necessary when hold time > 30 days or there are multiple hold times (e.g ).
All stability-indicating parameters should be included in the studies.
The applied limits are important. Release limits should be applied to final tablets, not just shelf-life.

49. Hold time studies 3
Beware of even short hold times for liquid intermediates.
Example comment:
The API-loaded suspension is allowed to be stored for three days before being further used for processing. The suspension contains HPMC and lactose, both of which could promote microbial growth. Please provide the supporting data for microbial stability of the suspension and the chemical stability of the API for the proposed waiting period of three days during processing.

50. Hold time studies 4
Common issue: a number of intermediates have hold times
Beware of cumulative hold times, even if separately validated
The date of production of a batch is defined as the date that the first step is performed involving combining the API with other excipients.
Even if appropriate hold studies have been provided to support hold times, the hold times still may be unacceptable.

51. Hold time studies 5 Recent example (controlled release (CR) tablet):
Blend days
Compressed tablets 30 days
Seal coated tablets 5 days
CR coated tablets 30 days
Laser drilled tablets 30 days
Bulk tablets months
Total hold time > 5 months before packaging! Shelf-life is only 24 months. This should be questioned! E.g. Flag this if >3 months total

52. Hold time studies 6 Comment out:
You have indicated cumulative hold times prior to the stage of packaging of the product that add to over 5 months. You are reminded that the start of shelf-life is defined as the time of first mixing of an excipient with the API. You are requested to significantly reduce the hold times so that the maximum processing time will be kept at a reasonable duration (e.g. 30 days) or provide additional evidence that a product subject to the cumulative effect of the largest hold times would still meet release specifications as well as shelf-life specifications over the remaining shelf-life.

53. In-use studies 1
TRS 970 Annex 4 states: Any in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution of any sterile and/or multidose products or after first opening of FPPs packed in bulk multidose containers (e.g. bottles of 1000s*). If applicable, the in-use period and storage conditions should be stated in the product information. *only for rifampicin containing products and highly hygroscopic products. In use period of 28 days generally accepted without data (most products).

54. In-use studies 2
Standard comment out: It is noted that a two month in-use period is claimed for the product. As outlined in the quality guideline (TRS 970 Annex 4, P.8.1 p. 184), any in-use period and associated storage conditions should be justified with experimental data. A minimum of two batches of at least pilot scale* should be subjected to the test. At least one of the batches should be chosen towards the end of its shelf-life. * May use lesser requirement for uncomplicated FPPs

55. In-use studies 3
As far as possible the test should be designed to simulate the use of the product in practice (i.e. the same bottle opened at each interval), taking into consideration the filling volume of the container. At intervals comparable to those that occur in practice, appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature. In the case where the package size is inadequate for the full study: One unit (tablet or capsule) may be withdrawn and then replaced.

56. In-use studies 4
Rather than just opening the bottle, the protocol should specify that at least one capsule is picked out each time it is opened, and then it may be immediately returned to the bottle for future analysis. This is to ensure that air moves in the bottle as it is expected to during normal use.

57. Transport studies 1
It is transportation of bulk product that requires transport studies. Transportation of packaged product is not normally required (may be requested in special cases). If there are stability issues with the FPP, then study results may be requested.

58. Transport studies 2
If there are no stability issues with the FPP, we do not pursue study results. Instead a protocol is sufficient, including:
 at least one batch of at least pilot scale;
 confirmation of whether the product will be shipped in a controlled environment, with or without transportation logging devices; and
 If not a controlled environment, assessment of environmental conditions to which the product will be exposed during transportation, and studies to support the stability of the product in the bulk package at the extremes of the likely conditions.

59. Tips for Assessment of Stability Studies
CASE STUDY ON STABILITY STUDIES

60. Assessment Tips for stability 1
Has the applicant provided the stability protocol? Check the conditions used in the stability studies
Has the applicant submitted accelerated stability studies? 40±2°C/ 75±5% RH.
Has the applicant submitted long term stability studies? 30±2°C/ 75±5% RH for API and FPP (30±2°C/ 65±5% RH is also acceptable for API) except for justified cases.

61. Assessment Tips for stability 2
Check the period of the stability studies submitted: atleast 6 months for both accelerated stability studies and long term stability studies. Exceptions: RH products and 2nd line TB drugs
Check the number of batches used in the stability studies
Check the batch size of the batches used in the stability studies. Are they acceptable: atleast 2 batches of pilot scale or for an uncomplicated FPP, one of pilot scale and second batch which may be smaller

62. Assessment Tips for stability 3
Check the type of the container closure system including the type of the material of the cap used in the stability studies: What is the type of packaging type used including the type of cap, if applicable? Is it the same as that declared in section 2.3.P.7?
Check the conditions used in the stability studies
Check the period of the stability studies submitted: atleast 6 months for both accelerated stability studies and long term stability studies. Exceptions: RH products and 2nd line TB drugs

63. Assessment Tips for stability 4
Are all the stability indicating tests included?
Check the shelf life specifications against the specifications used in the stability studies.
Check the results for each parameter at each test station to confirm whether the results are all within the limits (specifications). No failured
Is there any significant change observed in the stability study results?
Summarize the trends for each parameter.

64. Assessment Tips for stability 5
Is there mass balance in the stability study results?
Do the stability studies submitted support the proposed shelf life?
Do the stability studies support the proposed storage condition? Does the compendia state any special storage condition for the product?
The storage condition should include the provisions stated in the compendia. The container closure system should provide the necessary protection.

65. Assessment Tips for stability 6 Stability Commitments
Has the applicant submitted written and signed stability study commitments (primary stability study commitment, commitment stability study commitments and ongoing stability study commitments)?
Check the batches stated under the primary stability commitment: primary batches
Check the batches stated under the commitment stability studies: first three consecutive commercial batches.
Check the batches stated under the ongoing stability study commitment: atleast one batch per year

66. References TRS_970- Annex 4 Generic Guideline
QA Talks by L. Paleshnuik, Lead Quality Assessor PQP.
Presentation- EAC Joint Session July 2013: Assessment part XIV section P.8, L. Paleshnuik, Lead Quality Assessor PQP.
Presentation- EAC Joint Session July 2013: Process of Assessment – API areas S.5, S.6, S.7, Hua Yin
ICH Q1A, Q1B, Q1D, Q1E, Q2,
WHO Technical Report Series, No. 953, Annex 2

67. World Health Organization
19 April, 2017
Thank you