1 TG Dekker – WHO, MalaysiaFeb 2005 Stability Studies (emphasis on FPPs) Workshop on GMP and...

1 TG Dekker – WHO, MalaysiaFeb 2005

Stability Studies(emphasis on FPPs)

Workshop on GMP and Quality Assurance of

Multisource Tuberculosis MedicinesKuala Lumpur – Malaysia

21-25 February 2005

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

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


Abbreviations

API Active pharmaceutical ingredientBP British PharmacopoeiaCEP EU certificate of suitabilityEOI Expression of interestFDC Fixed dose combinationFPP Finished pharmaceutical productICH International Conference on HarmonizationInt.Ph. International PharmacopoeiaR&D Research and developmentTB TuberculosisUSP United States Pharmacopeia25ºC/60%RH 25ºC ± 2ºC / 60% RH ± 5% RH etc.


The perspective

Pharmaceutical R & D provides the foundation of the activities aimed at ensuring that the patient receives an FPP (product) that consistently meets established standards & specifications of Safety Efficacy Quality

The FPP should be stable - and thus retain these standards – throughout the shelf-life, if kept in the original packaging and when correctly distributed, stored & handled


Topics for discussion

1. Objective of stability studies

2. Glossary / definitions

3. Example of transport monitoring

4. Study protocol/requirements

5. Rifampicin containing FDCs to exemplify Expression of degradants Assay / degradation analytical requirements

6. Closing remarks


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 (drug substance) or

a shelf life for the FPP (drug product) and recommended storage conditions.

ICH QA1(R2)


Glossary [ICH QA1(R2)]

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


Glossary (2)

Re-test date

The 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) date

The 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 !!}


Glossary (3)

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).


Glossary (4)

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 (1)

UNICEF ↔ Kampala (1989): Temperature


Example of shipping conditions (2)

UNICEF ↔ Kampala (1989): Relative humidity


Stability protocol/report

The following elements (see Guidelines, Annex 2)1. Info on batches tested (commercial formula)2. Unit composition (or cross-reference)3. Container-closure system (commercial!!)4. Literature and/or supporting data5. Stability specifications (only for FPPs)6. Analytical methods – stability indicating (cross-reference)7. Stability plan (schedule)8. Tabulated test results (including specifications)9. Analysis/discussion of data (statistical if negative trend)10. Re-test or shelf-life proposal (including storage condition)11. Post approval commitments


Stability batches

Stability data for three primary batches The formulation and manufacturing process should be

the same as proposed for marketing In container-closure system proposed for marketing Preferably manufactured from different API batches

Full info on batches tested (tabulated format) e.g.: Batch number Manufacturing date Manufacturing site Batch size (in kg & in number of units) Container-closure (primary packaging) Date of initial analysis (release) API batch number


Tablets – stability batches data - example

1st 2nd 3rd

Batch number

Manufacturing date

Manufacturing site

Batch size (kg)

Batch size (number of units)

Batch type (full-scale, pilot, etc.)

Primary packaging

Date initial analysis

Batch 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)


Tablets – stability specifications

Parameters for tablets that are often omitted: Tablet strength, friability and moisture can change

with time– if not in release specs, include in stability– these are interrelated, also with dissolution– these are inexpensive

Microbial limit at release and end-of-shelf Dissolution specification must be same as for

release


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 release

Dissolution Set per product Same as release

Disintegration Not required if dissolution is done

Related subs. (degradants)

Only if formed during production

Required. Limits to one 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 specs. – special for FDCs

Degradants (related substances) must be stated & calculated in % with respect to the parent API, not the sum of the APIs, e.g. Rifampicin / isoniazid tablets. Rifampicin quinone

(degradant) as % of rifampicin (not of all peaks in HPLC)

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 Dissolution – include all APIs (e.g. FDCs in the USP)


Isonicotinyl hydrazone expression

The reaction (simplified):Isoniazid + rifampicin → hydrazone

+ ..

Rel. MM 137 829 845

MM Ratio (÷137) 1.0 mg 6.0 mg 6.2 mg

FDC mg 75 mg 150 mg

FDC ratio 1.0 mg 2.0 mg

At 100% reaction, no rifampicin left, 67% isoniazid intact Hydrazone to be expressed with respect to rifampicin Rifampicin worst-case in mass balance


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 (related substances) Determination of preservatives

If the same as release testing methods, a reference will suffice Release methods should include validation for stability

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 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

Assay method(s) must be specific (considering degradants)

A method for degradants to be developed


Rifampicin containing FDC assay/degradation methods (2)

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

Assay method (stability indicating when tested in our lab) C-18 column, gradient chromatography (see USP) 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)

RIIP analysis (Research Institute for Industrial Pharmacy) For assay of rifampicin and degradants – other APIs with

a separate method


USP FDC assay method

Isonicotinyl hydrazone in area of gradient “switch”, difficult for quantification

min0 5 10 15 20 25

mAU

0

50

100

150

200

250

300

350

DAD1 A, Sig=238,4 Ref=360,100 (C:\HPCHEM~1\ASTERIX\AMR\03060406.D)

2.6

43

3.0

42

3.6

26

4.1

82

-

Iso

nia

zid

5.4

43

-

Py

ra

zin

am

ide

9.6

95

10

.01

0

10

.37

9

10

.99

9

11

.55

5

11

.87

2

13

.04

4 -

R

ifa

mp

icin

16

.54

4

16

.99

3

19

.58

5

29

.73

2

switch

Rifampicin

Isoniazid

Pyrazinamide


A NIPER HPLC method

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


RIIP HPLC chromatogram

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

Signals 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

89

-

Rifa

mp

icin

N-O

xid

e

14

.17

1 -

H

yd

raz

on

e

18

.86

1 -

R

ifam

pic

in Q

uin

on

e

24

.07

0 -

3

-Fo

rmy

lrifa

my

cin

27

.41

3 -

R

ifam

pic

in

rifampicin

N-O

xid

e

Hyd

razo

ne

Qu

ino

ne

3-F

orm

yl r

ifam

ycin

Oth

er 3

AP

Is


4FDC products – degradation results

The 4FDC tablets instable: Isonicotinyl hydrazone main degradantContainer permeability may play a role (Alu/Alu > Pvdc/Alu?)

Product A B C

Primary container Pvdc/Alu HDPE securitainer

Pvdc/Alu

Age (months) 10 8 8

N-oxide (%)

Hydrazone (%) 7.2 5.0 10.2

Quinone (%) 1.3 2.6

3-Formyl (%)

Total related subs. 8.5 5.0 12.8


Testing frequency & storage conditions

Solid oral dosage forms (tablets, capsules):

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

Condition▼ Month► 0 3 6 9 12 18 24 36

30ºC / 65% RH (zone IV) X X X X X X X X

40ºC / 75% RH (accel) X X

25ºC / 60% RH (zone II) X X X X X X X


Stability storage facilities

RIIP facilities (110 m3)

Three rooms: 25ºC/60%RH; 30ºC/65%RH; 40ºC/75%RH


Significant changes during stability

1. A 5% change in assay from its initial value (or failure to meet acceptance criteria when using biological methods)

2. Any degradation product exceeding its acceptance criterion3. Failure to meet the acceptance criteria for appearance,

physical attributes, and functionality test (e.g., colour, phase separation, resuspendibility, hardness, dose delivery per actuation);

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 units5. Dissolution 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 !!


Reporting of stability data

Stability should be presented in well constructed tables (stability data sheets) See Annex 2 for an example Relevant administrative information must appear

on sheet Acceptance criteria for each attribute must be

included in the table for quick reference purposes Result sheets must bear date and responsible

person signature / QA approval


Evaluation of stability data

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

than R + 12 months (30 months max)

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

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