1 TG Dekker WHO, UkraineOctober 2005 Stability Studies (emphasis on FPPs) World Health Organization...

1 TG Dekker – WHO, UkraineOctober 2005

Stability Studies (emphasis on FPPs)

World Health OrganizationTraining Workshop on Pharmaceutical

Quality, GMP and BioequivalenceKiev - Ukraine

3 to 7 October 2005

Theo Dekker, D.Sc., consultant to WHOResearch Institute for Industrial Pharmacy

North-West University, Potchefstroom, South [email protected]


Topics for discussion

1. Objective of stability studies2. Glossary / definitions

Included for completeness - self reading3. Study protocol/requirements4. TB and ARV FDC examples to show

Expression of degradants Assay / degradation analytical requirements

5. Reporting of stability data See Annex 3 and 4 of main guidelines – self reading

6. Evaluation of stability data7. Closing remarksNote: 25ºC/60%RH = 25ºC ± 2ºC / 60% RH ± 5% RH


The objective of stability studies

The purpose of stability testing is to provide evidence on how the quality of a drug substance [API] or drug product [FPP] varies with time under the influence of a variety of environmental

factors such as temperature, humidity, and light and

to establish a re-test period for the API or a shelf life for the FPP and

to recommend storage conditions ICH QA1(R2)


Glossary [ICH QA1(R2)] (1)

Re-test period The period of time during which the API is expected to remain

within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the API has been stored under the defined conditions

After this period, a batch of API destined for use in the manufacture of a FPP should be re-tested for compliance with the specification and then used immediately

A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification

For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a re-test period. The same may be true for certain antibiotics



Re-test dateThe date after which samples of the API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product [if stored under defined conditions]

Expiry (expiration) dateThe date placed on the container label of an FPP designating the time prior to which a batch of the FPP is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must

not be used {no re-testing !!}



Stress testing (API) Studies undertaken to elucidate the intrinsic stability of the

IPA. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress testing (finished product) Studies undertaken to assess the effect of severe conditions

on the finished product. Such studies include photostability testing (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).



Accelerated testing Studies designed to increase the rate of chemical degradation

or physical change of an API or FPP by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated

(real-time) conditions & to evaluate the effect of short term excursions outside the

label storage conditions such as might occur during shipping

Results from accelerated testing studies are not always predictive of physical changes

Current accelerated conditions for solid orals: 40ºC/75%RH


Example of shipping conditions(possible excursions outside storage requirements) UNICEF ↔ Kampala (1989):

Temperature Relative humidity


Stability batches (FPPs)

Stability data for three primary batches by time of submission One batch should at least be of production scale,

the remaining 2 batches at least pilot scale The formulation and manufacturing process

should be the same as proposed for marketing In container-closure system as proposed for

marketing Preferably manufactured from different API

batches Full info on batches tested (tabulated format)

Next slide


Information on stability batches requiredTablets as example

1st 2nd 3rd

Batch numberManufacturing dateManufacturing siteBatch size (kg)Batch size (number of units)Batch type (full-scale, pilot, etc.)Primary packagingDate initial analysisBatch number of API


Stability specifications

Stability studies should include testing of those attributes (parameters) of the FPP that are susceptible to change during storage and thus are likely to influence quality, safety, and/or efficacy The testing should cover, as appropriate, the physical,

chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system)

From ICH Q1A(R2)


Example - FPP specs – uncoated tablets

Attribute Release limits Stability limits

Appearance Full description Same as release

Identification At least 1 method Not required for stability studies. Not regarded as variables for product.

Dimensions Diameter, etc

Average mass w.r.t. theoretical

Mass uniformity Ph.Eur/USP/Int.Ph

Water content Product specific Same as release?

Tablet hardness* Product specific Same as release


Example of FPP specs – uncoated tabs (con.)

Attribute Release limits Stability limits

Friability * ≤ 1 % (normally) Same as releaseDissolution Set per product Same as release

Disintegration Not required if dissolution is doneRelated subs. (degradants)

Only if formed during production

Required. Limits to one/two decimal

Assay (content) 95.0-105.0%, unless justified

May be 90.0-105.0% if justified

Microbial limits Skip-testing End-of-shelf* Tests not necessary at release if done in-process


FPP stability specificationsSpecial for FDCs

Degradation products must be calculated in % with reference to the parent API, not the sum of APIs, e.g. Rifampicin / isoniazid tablets

• Rifampicin quinone (degradant) as % of rifampicin. Lamivudine + Stavudine + Nevirapine tablets

• Thymine (degradant) as % of stavudine If 2 APIs react with each other, then the degradant to

be stated with respect to worst case, e.g. Rifampicin / isoniazid tablets. Isonicotinyl hydrazone forms

from the 2 APIs. Specification: % hydrazone with respect to rifampicin (worst-case in mass balance).

Unknown degradants – with respect to worst case


Stability indicating analytical methods

Analytical methods must be suitable for the purpose of stability testing (stability indicating), particularly in the case of Assay of the API(s) in the FPP Determination of the degradants Determination of preservatives

Compendial methods May not be suitable (e.g. non-specific like titration) May not exist for the particular purpose (e.g.

degradants)


Rifampicin containing FDC products assay/degradation methods (1)

Particular degradants to consider:1. Isonicotinyl hydrazone2. Rifampicin quinone3. Rifampicin N-oxide4. 3-Formyl rifamycin (present in FDCs?)5. 25-Desacetyl rifampicin

All to be determined & expressed with respect to rifampicin


Rifampicin containing FDC products assay/degradation methods (2)

Examples of methods: USP 28 (2, 3, 4 FDC capsules/tablets)

Assay method (stability indicating when tested in our lab) No specification/test for degradants

S. Singh et al. (NIPER) Various HPLC methods, mainly related to isonicotinyl

hydrazone determination, simultaneously with rifampicin and isoniazid (one example given here)

In-house HPLC analysis For assay of rifampicin and degradants Other APIs with a separate method


Rifampicin containing FDC productsA NIPER HPLC method

S. Singh et al., Pharm. Pharmacol. Commun., 6, 405-410 (2000)


Rifampicin containing FDC productsIn-house HPLC chromatogram (spiked)

C-18: methanol/phosphate buffer pH 7.0 : 6/4Signals well separated

min0 5 10 15 20 25 30

mAU

0

10

20

30

40

50

DAD1 A, Sig=254,4 Ref=360,100 (AMR_RIF\07090407.D)

7.3

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Rifa

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Lamivudine + Stavudine + Nevirapine tablets 150 mg 40 mg 200mg

According to the WHOPAR of TRIOMUNE Lamivudine and nevirapine are compatible (stable) Stavudine shows incompatible with both APIs

The main degradation product was found to be thymine (degradant of stavudine)

HPLC (modified from literature) for sample stored at 30°C/60%RH for 12 months is shown on next page Hypothetical example & signal for thymine Assumption: all substances show similar response factor Calculate the percentage degradation for thymine How would you express the “identified related substances”


Lamivudine + Stavudine + Nevirapine tabletsHPLC chromatogram (modified from lit.)

mAU

Substance Peak Area (mAU) % degradationStavudine 1 300Lamivudine 2 970Thymine 4 6.0 → ?Nevirapine 3 524Sum of areas 1800

Thym

ine


Testing frequency & storage conditionsExample: Tablets and capsule

Zone IV is real-time condition for prequalification project, unless otherwise justified

Zone II only if justified (may be fall-back for zone IV) ASEAN proposal for zone IV: 30ºC / 75% RH

Real-time data to cover minimum of 12 months However, see Supplement 2 of guideline

• 6 month data for certain FPPs containing stable APIs

Condition▼ Month► 0 3 6 9 12 18 24 3630ºC / 65% RH (zone IV) X X X X X X X X40ºC / 75% RH (accel) X X25ºC / 60% RH (zone II) X X X X X X X


Significant changes during stability

1. A 5% change in assay from its initial value2. Any degradation product exceeding its acceptance

criterion3. Failure to meet the acceptance criteria for

appearance, physical attributes, and functionality test (e.g., colour, resuspendibility, hardness)

4. and, as appropriate for the dosage form: Failure to meet the acceptance criterion for pH; or Failure to meet the acceptance criteria for

dissolution for 12 dosage unitsDissolution specifications for release and stability must

be the same (otherwise possible BE change)


Pitfall

The assay value is still within the limits but the change during stability is more than 5.0%

Example Release assay limit: 95.0 – 105.0% Stability assay limit: 92.5 – 105.0% Release assay: 101.0% (within spec) 24-Month assay: 93.0% (within spec) Loss in potency: 8.0% !!This is a significant change !!


Evaluation of stability data

1. The data show no/little variation with time Statistical analysis is not required Proposed shelf-life = 2 x real-time data (R), but not more

than R + 12 months (30 months max)• Exception to rule: see Supplement 2 of Guideline

2. The data show trend(s) Statistical analysis required [see ICH Q1A(R2)] Proposed shelf-life depends on the statistical analysis

3. Commitment For confirmation of provisional (tentative) shelf-life, real-

time data are required First 3 production batches on stability Follow up stability testing (FUST) – one batch per year


Closing remarks

Stability testing is an essential part of the process of ensuring that the patient receives a product that meets established standards of safety, efficacy and quality

Sound planning and execution of stability studies are important Valuable time may be lost if the data are insufficient Always include all attributes which may change with time

(e.g. water content, friability & tablet strength in the case of uncoated tablets) – pay upfront and save later

Give attention to analysis and calculation of degradation products in FDCs

1 TG Dekker WHO, UkraineOctober 2005 Stability Studies (emphasis on FPPs) World Health Organization...

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