1

2
3
4

13 July 2011
EMA/CHMP/CVMP/QWP/441071/2011
Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary
Use (CVMP)

Guideline on stability testing for applications for variations

to a marketing authorisation

Draft

8
Draft Agreed by Quality Working Party

June 2011

Adoption by CHMP for release for consultation

June 2011

Adoption by CVMP for release for consultation

July 2011

End of consultation (deadline for comments)

31 January 2012

9
10

This guideline replaces Guideline on Stability Testing for Applications for Variations to a Marketing

11

Authorisation previous version (CPMP/QWP/576/96 Rev 1 & EMEA/CVMP/373/04)

12
Comments should be provided using this template. The completed comments form should be sent to
qwp@ema.europa.eu
13
Keywords

Stability, stability testing, stability data, chemical active substance,

specification, variation

14

7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
E-mail info@ema.europa.eu Website www.ema.europa.eu

An agency of the European Union

European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.

16

Guideline on stability testing for applications for variations

to a marketing authorisation

17

Table of contents

18

Executive summary ..................................................................................... 3

19

1. Introduction (background)...................................................................... 3

20

2. Scope....................................................................................................... 3

21

3. Legal basis .............................................................................................. 3

22

4. General requirements .............................................................................. 3

23

5. Type I variations ..................................................................................... 4

24

6. Type II variations .................................................................................... 4

25
26

37

6.1. Introduction of a new manufacturer of the active substance that is supported by an

ASMF (B.I.a.1.b) ...................................................................................................... 5
6.2. Change in the manufacturer of a starting material / reagent / intermediate or the active
substance that uses a substantially different route of synthesis or manufacturing conditions,
which may have a potential to change important quality characteristics of the active
substance, such as qualitative and/or quantitative impurity profile requiring qualification, or
physico-chemical properties impacting on bioavailability (B.I.a.1.c)> ............................... 5
6.3. Change in the manufacturing process of the active substance (B.I.a.2.b; B.I.a.2.d) ..... 5
6.4. Change in immediate packaging of the active substance (B.I.c.1.b) ........................... 6
6.5. Change in composition of the finished product (B.II.a.3.b.2) .................................... 6
6.6. Change in coating weight of oral dosage forms (B.II.a.4.b) ...................................... 6
6.7. Change in the manufacturing process of the finished product (B.II.b.3.b, 3.d-e).......... 6
6.8. Change in the batch size of the finished product (B.II.b.4.d) .................................... 7

38
39

6.9. Change in immediate packaging of the finished product (B.II.e.1a.3., B.II.e.1a.4.

B.II.e.1.b. 2.) .......................................................................................................... 7

40

7. Commitment batches............................................................................... 7

41

References .................................................................................................. 7

42

Annex I ....................................................................................................... 8

43

Annex II ...................................................................................................... 8

15

27
28
29
30
31
32
33
34
35
36

44

Guideline on stability testing for applications for variations to a marketing authorisation

EMA/CHMP/CVMP/QWP/441071/2011

Page 2/8

45

Executive summary

46

The following guideline provides guidance on the stability data which have to be generated in order to

47

support a variation to a Marketing Authorisation. The guideline provides general guidance on stability

48

testing in case of type I (A and B) variations and addresses the data requirements for widely

49

encountered cases of type II variations.

50

1. Introduction (background)

51

The following guideline sets out the stability testing requirements for variations to a Marketing

52

Authorisation after approval. This guideline is an extension of the CHMP and CVMP Guidelines on

53

Stability Testing of Existing Active Substances and Related Finished Products and the respective

54

ICH/VICH Guidelines for New Active Substances and Drug Products. It is intended to be applied in the

55

European Union.

56

The guideline seeks to exemplify the stability data required for variations to active substances and/or

57

finished products. It is not always necessary to follow this when there are scientifically justifiable

58

reasons for using alternative approaches.

59

The guideline provides a general indication on the requirement for stability testing, but leaves sufficient

60

flexibility to encompass the variety of different practical situations required for specific scientific

61

situations and characteristics of the material being evaluated.

62

2. Scope

63

The purpose of this guideline is to outline the stability data which have to be generated in case of

64

variations. It is applicable to chemical active substances and related finished products, herbal drugs,

65

herbal drug preparations and related herbal medicinal products, however not to radiopharmaceuticals,

66

biologicals and products derived from biotechnology.

67

Variations for active substances and finished products encompass a wide range of situations. The

68

Guideline provides general guidance on stability testing in case of type I (A and B) variations,

69

furthermore, it addresses the information required for active substances and/or finished products in

70

widely encountered cases of type II variations as listed in section 6.

71

3. Legal basis

72

This guideline has to be read in conjunction with Regulation No 1234/2008 and the introduction and

73

general principles (4) and annex I to Directives 2001/82 and 2001/83 as amended.

74

4. General requirements

75

In cases of variations which require generation of stability data on the finished product, the stability

76

studies required, including commitment batches, should always be continued up to the approved shelf-

77

life and the authorities should be informed immediately if any problems with the stability appear during

78

storage, e.g. if outside specification or potentially outside specification.

79

The scope and design of the stability studies for variations and changes are based on the knowledge

80

and experience acquired on the active substances and finished products. The available information

81

must be taken into account such as:

82

a) For active substances:

Guideline on stability testing for applications for variations to a marketing authorisation
EMA/CHMP/CVMP/QWP/441071/2011

Page 3/8

83

- the stability profile including the results on stress testing;

84

- the supportive data;

85

- the primary data of accelerated and long term testing.

86

b) For finished products:

87

- the supportive data;

88

- the primary data of accelerated and long term testing.

89

In all cases of variations, the applicant has to investigate whether the intended change will have an

90

impact or not on the quality characteristics of active substances and/or finished products and

91

consequently on their stability.

92

When stability data are required, the choice of test conditions defined in this guideline refers to the

93

CHMP/ICH Guideline on Stability Testing of New Drug Substances and Products, the CHMP/QWP

94

Guideline on Stability Testing of Existing Active Substances and Related Finished Products, the

95

CVMP/VICH Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products,

96

and the CVMP/QWP Note for Guidance on Stability Testing of Existing Active Substances and Related

97

Finished Products, respectively. Where appropriate, the concept of bracketing and matrixing as

98

described in the CHMP/ICH and the CVMP/VICH Note for Guidance on Bracketing and Matrixing Designs

99

for Stability Testing of Drug Substances and Drug Products may be applied across related products.

100

Where extrapolation of data are applicable, see Annex II for further information.

101

5. Type I variations

102

If a variation to a marketing authorisation fulfils the conditions defined in Commission Regulation EC

103

1234/2008 for Type IA variations, and if stability data are required, the minimum set of data to be

104

submitted with the variation is defined in the Guideline on the details of the various categories of

105

variations to the terms of marketing authorisations for medicinal products for human use and

106

veterinary medicinal products. The results of these studies, covering the requested time period as

107

defined in above guideline, using accelerated and long-term testing conditions, should be compared to

108

the results of studies performed on the unchanged active substance/finished product in order to ensure

109

that the change does not negatively impact the stability profile, i.e. that the specification limits of the

110

active substance/finished product will still be met at the end of the proposed retest period/shelf-life.

111

The comparison data for the unchanged product may come from earlier studies, and need not

112

necessarily be collected in combination with the study on the changed product.

113

Type IB is the new default category under the new variations Regulation. As far as the associated

114

classification guideline is concerned, some examples of different types of Type IB changes have been

115

included in the guideline, along with recommended documentation. Where a change may impact on

116

stability, the required satisfactory stability data requirements at the time of submission are specified in

117

the guideline. In case of other Type IB by default changes, which are not specifically described in the

118

classification guideline, the required stability data has to be decided on a case by case basis. However,

119
120

consideration should be given to specified requirements for any other similar changes which have
actually been included as examples in the guideline.

121

6. Type II variations

122

European Commission Regulations EC 1234/2008 define Type II variation as major variations which

123

have the highest potential impact on the quality, safety or efficacy of medicinal products. Type II
Guideline on stability testing for applications for variations to a marketing authorisation
EMA/CHMP/CVMP/QWP/441071/2011

Page 4/8

124

variations are defined in the Guideline on the details of the various categories of variations to the

125

terms of marketing authorisations for medicinal products for human use and veterinary medicinal

126

products. However data to be submitted with these variations are not defined in the majority of cases.

127
128

6.1. Introduction of a new manufacturer of the active substance that is

supported by an ASMF (B.I.a.1.b)

129

In case of an introduction of a new manufacturer of the active substance that is supported by an ASMF

130

stability data should be part of the applicants part of the ASMF. In cases where no retest period is fixed

131

(according to the relevant guidelines) the active substance has to be tested immediately prior use.

132

If the quality characteristics/impurity profile of the active substance are changed in such a way that it

133

may impact the stability of the finished product, additional stability data on the finished product, in

134

accelerated and long term conditions, six months on two batches on at least pilot scale, may be

135

required.

136
137
138
139
140
141

6.2. Change in the manufacturer of a starting material / reagent /

intermediate or the active substance that uses a substantially different
route of synthesis or manufacturing conditions, which may have a potential
to change important quality characteristics of the active substance, such as
qualitative and/or quantitative impurity profile requiring qualification, or
physico-chemical properties impacting on bioavailability (B.I.a.1.c)>

142

In case of such a variation the following approaches may be considered as acceptable:

143

If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are

144

changed in such a way that stability may be compromised, comparative stability data are required in

145

accelerated and long term testing conditions, on the active substance before and after the change:

146

- for active substances known to be stable: three months on one batch of at least pilot scale (see

147

Annex I for the definition of stable active substance).

148

- for active substances known to be unstable: six months on three batches of at least pilot scale.

149

If the quality characteristics of the active substance are changed in such a way that it may impact the

150

stability of the finished product, additional stability data on the finished product, in accelerated and

151

long term testing conditions, six months on two batches on at least pilot scale, may be required.

152
153

6.3. Change in the manufacturing process of the active substance

(B.I.a.2.b; B.I.a.2.d)

154

In case of variations to the manufacturing process of the active substance, the following approaches

155

may be considered as acceptable:

156

If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are

157

changed in such a way that stability may be compromised, comparative stability data are required in

158

accelerated and long term testing conditions, on the active substance before and after the change:

159

- for active substances known to be stable: three months on one batch of at least pilot scale (see

160

Annex I for the definition of stable active substance).

161

- for active substances known to be unstable: six months on three batches of at least pilot scale.

Guideline on stability testing for applications for variations to a marketing authorisation

EMA/CHMP/CVMP/QWP/441071/2011

Page 5/8

162

If the quality characteristics of the active substance are changed in such a way that it may impact the

163

stability of the finished product, additional stability data on the finished product, in accelerated and

164

long term testing conditions, six months on two batches on at least pilot scale, may be required

165

6.4. Change in immediate packaging of the active substance (B.I.c.1.b)

166

In case of a change to the immediate packaging of a sterile active substance the following approach

167

may be considered as acceptable:

168

Comparative stability data are required using accelerated and long term testing conditions of six

169

months duration on at least 2 pilot scale batches of the active substance.

170

6.5. Change in composition of the finished product (B.II.a.3.b.2)

171

In case of a change in the composition of the finished product, the following approaches may be

172

considered as acceptable:

173

For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the

174

active substance is known to be stable, comparative stability data, 6 months duration, long term and

175

accelerated testing conditions on two pilot scale batches are required.

176

For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be

177

unstable, comparative stability data, 6 months duration long term and accelerated stability testing

178

conditions on three pilot scale batches are required.

179

6.6. Change in coating weight of oral dosage forms (B.II.a.4.b)

180

In case of a change in the coating weight of oral dosage forms, the following approaches may be

181

considered as acceptable:

182

For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be

183

unstable, comparative stability data, 6 months duration long term and accelerated stability testing

184

conditions on three pilot scale batches are required.

185
186

6.7. Change in the manufacturing process of the finished product

(B.II.b.3.b, 3.d-e)

187

In case of variations to the manufacturing process of the drug product, the following approaches may

188

be considered as acceptable:

189

If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance or

190

an excipient are changed in such a way that stability may be compromised, comparative stability data

191

are required in accelerated and long term testing conditions, on the drug product before and after the

192

change:

193

For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the

194

active substance is known to be stable, comparative stability data, 6 months duration, long term and

195

accelerated testing conditions on two pilot scale batches are required.

196

For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be

197

unstable, comparative stability data, 6 months duration long term and accelerated stability testing

198

conditions on three pilot scale batches are required.

Guideline on stability testing for applications for variations to a marketing authorisation

EMA/CHMP/CVMP/QWP/441071/2011

Page 6/8

199

6.8. Change in the batch size of the finished product (B.II.b.4.d)

200

In case of variations to the batch size of the drug product, the following approaches may be considered

201

as acceptable:

202

If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance or

203

an excipient are changed in such a way that stability may be compromised, comparative stability data

204

are required in accelerated and long term testing conditions, on the drug product before and after the

205

change:

206

For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the

207

active substance is known to be stable, comparative stability data, 6 months duration, long term and

208

accelerated testing conditions on two pilot scale batches are required.

209

For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be

210

unstable, comparative stability data, 6 months duration long term and accelerated stability testing

211

conditions on three pilot scale batches are required.

212
213

6.9. Change in immediate packaging of the finished product (B.II.e.1a.3.,

B.II.e.1a.4. B.II.e.1.b. 2.)

214

In case of a change to the immediate packaging of the finished product the following approach may be

215

considered as acceptable:

216

In the case of less protective packaging or when a risk of interaction occurs, mainly for semi-solid or

217

liquid dosage forms, comparative stability data are required using accelerated and long term testing

218

conditions of six months duration on three pilot batches of the finished product.

219

7. Commitment batches

220

For all Type IA and IB variations that require the generation of stability data on the finished product,

221

adequate follow up studies on commitment batches need to be performed.

222

For all Type II variations that require the generation of stability data on the finished product, at least

223

the first production scale batch manufactured according to the approved variation should be placed on

224

long term stability testing using the same stability testing protocol as described in the original

225

application unless it has already been submitted as part of the variation application. Stability studies

226

need to be continued to cover the entire shelf-life. The results of these stability studies should be made

227

available on request and the authorities should be informed if any problems appear with the stability

228

studies.

229

References

230

Guideline on the details of the various categories of variations to the terms of marketing authorisations

231

for medicinal products for human use and veterinary medicinal products (OJ L 334, 12.12.2008, p. 7)

232

Guideline on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99-ICH Q1A)

233

Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products

234

(CVMP/VICH/899/99 Rev.1-VICH GL43)

235

Guideline on Stability Testing of Existing Active Substances and Related Finished Products

236

(CPMP/QWP/122/02 Rev. 1 corr)

Guideline on stability testing for applications for variations to a marketing authorisation

EMA/CHMP/CVMP/QWP/441071/2011

Page 7/8

237

Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products

238

(EMEA/CVMP/QWP/846/99-Rev.1)

239

Note for Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and

240

Drug Products (CPMP/ICH/4104/00-ICH Q1D)

241

Bracketing and matrixing designs for stability testing of new veterinary drug substances and medicinal

242

products (EMEA/CVMP/VICH/581467/2007-VICH GL45)

243

Annex I

244

An active substance is considered as stable if it is within the initial specifications when stored at 25C/

245

60 % RH or 30C/65% RH, respectively, (2 years) and 40C/75 %RH (6 months).

246

Annex II

247

Where the data submitted, long term 25C/60% RH or 30C/65% RH, respectively, and accelerated

248

40C/75% RH or, in case of aqueous products in semi-permeable containers, the respective storage

249

conditions defined in the CHMP and CVMP Guidelines on Stability Testing of Active Substances and

250

Related Finished Products, show that there is no adverse effect on the stability of the active

251

substance/finished product, the retest period/shelf life originally granted can normally be retained,

252

based on comparison with the original data submitted. However, where the data demonstrate an

253

adverse change in product stability, a new shelf life must be assigned. Based on a case-by-case

254

decision, extrapolation of data may be applied.

255

If real time data are supported by results from studies conducted under accelerated or intermediate

256

storage conditions, the retest period/shelf-life may be extended beyond the end of real time studies.

257

Normally, extrapolation to twice the length of the real time studies can be accepted. However, the

258

maximum shelf-life justified by extrapolation should not exceed 3 years. The degree up to which

259

extrapolation will be acceptable following to a change to the active substance or finished product that

260

shows an adverse effect to the stability will largely depend on the change over time, variability of data

261

observed, proposed storage conditions and extent of statistical analyses performed. It will always have

262

to be a case-by-case decision. For more detailed information on statistical evaluation of stability data

263

please refer to the CHMP/ICH Note for Guidance on Evaluation of Stability Data; similar principles are

264

also applicable to veterinary medicinal products.

265

Guideline on stability testing for applications for variations to a marketing authorisation

EMA/CHMP/CVMP/QWP/441071/2011

Page 8/8