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A Critical Assessment of the ICH Guideline on Photostability Testing of New Drug Substances and Products (Q1B): Recommendation for Revision
COMMENTARY A Critical Assessment of the ICH Guideline on Photostability Testing of New Drug Substances and Products (Q1B): Recommendation for Revision STEVEN W. BAERTSCHI,1 KAREN M. ALSANTE,2 HANNE H. TØNNESEN3 1
Eli Lilly and Company, Analytical Sciences Research and Development, Lilly Research Laboratories, Indianapolis, Indiana 46285
2
Pfizer Global Research & Development, Analytical Research & Development, Eastern Point Rd., Box 4077, Groton, Connecticut 06340
3
Department of Pharmaceutics, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway
Received 20 November 2009; accepted 4 December 2009 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22076 ABSTRACT: The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2934–2940, 2010
Keywords: stability
physical stability; chemical stability; analytical chemistry; stability; solid state
INTRODUCTION The ICH guideline on photostability (ICH Topic Q1B)1 was published in November 1996 and has been implemented in all three regions (US and Canada, EU, and Japan). After January 1, 1998, it is obligatory to provide photostability information constructed according to this guideline for all new drug license applications filed in these regions. The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of
drugs under conditions of patient use. It recommends a systematic approach to photostability testing on the drug substance and drug product according to a decision flow chart. The outline of the guideline is as follows:
Correspondence to: Steven W. Baertschi (Telephone: 317-2761388; Fax: 317-277-2154; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 2934–2940 (2010) ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association
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(I) General (A) Preamble (B) Light sources (C) Procedure (II) Drug substance (A) Presentation of samples (B) Analysis of samples (C) Judgment of results (III) Drug product (A) Presentation of samples (B) Analysis of samples (C) Judgment of results
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(IV) Annex (A) Quinine chemical actinometry (V) Glossary (VI) Reference The tests are pass/fail tests where ‘‘acceptable change is change within limits justified by the applicant.’’ Despite the implementation of the ICH photostability guideline, issues remain that are not specifically covered in the document and which are left to the applicant’s discretion.2,3 The guideline allows for alternative approaches assuming that these are scientifically sound. The aim of the photostability testing should be to demonstrate that exposure to irradiation does not result in an unacceptable change. It is left to the applicant to establish how the product will be used and to undertake appropriate photostability studies. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from a revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process; (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program; (iii) provide recommendations for clarification of the guideline.
FORCED AND CONFIRMATORY STUDIES The guideline calls for ‘‘forced degradation’’ studies (stress testing) and a ‘‘confirmatory’’ study. A forced degradation study is testing under forcing conditions to characterize intrinsic stability characteristics of the drug substance or drug product, to determine degradation products and reaction mechanisms, and to develop appropriate methodology for detection and quantitation. Confirmatory studies involve testing under conditions designed to generate data to predict what might happen during ambient storage, and to determine whether precautionary measures are needed during formulation, production, and storage. A confirmatory study can be regarded as a limit test, and should conclude with ‘‘acceptable’’ or ‘‘unacceptable’’ change. Comments: a. In II. Drug Substance, the first paragraph reads: ‘‘For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing.’’ DOI 10.1002/jps
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This is not stated in section III. Drug product. Additional guidance should be given to the applicant for photostability forced degradation of drug product samples. It is recommended that the guidance clearly state that photostability/photodegradation is a function of the ‘‘system’’ (i.e., the formulation plus the drug) and not just the drug molecule, as clearly evidenced by examples documented in the literature.4,5 b. In V. Glossary, drug product testing is not mentioned in the definition of forced degradation testing studies.
SEQUENTIAL TESTING A sequential testing approach is recommended. The sample should first be tested unpacked, with direct exposure to the radiation source. If necessary, a transparent (with known UV/Vis transmittance) container may be used for liquid or semisolid products. Samples that are found to be unstable should then be further tested in primary and secondary (market) packs as necessary. Products that are stable in the primary pack but unstable without it should be labeled in such a way that a transfer into a less protective pack, for example, by a pharmaceutical wholesaler or in a hospital pharmacy, is prevented. It is unnecessary to conduct tests in containers completely impenetrable to radiation (e.g., aluminum foil) when these are used for direct dispensing to the patient. Comments: c. The first paragraph of III. Drug product states: ‘‘Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light.’’ To avoid confusion, it should be clearly stated that if no light degradation is observed in the fully exposed sample, no further testing needs to be performed. This text change would more clearly support the Decision Tree diagram. d. III. Drug Product, foil/foil blisters should be added to the list of immediate packs impenetrable to light to be more complete.
IRRADIATION SOURCE The ICH guideline gives two options for the selection of the irradiation source. Option 1 addresses exposure to outdoor daylight or window glass filtered daylight. Option 1 advises exposing the samples to UVB, UVA, and visible light simultaneously. In practice, Option 1 offers the choice between three different types of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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sources. Glass-filtered daylight can be obtained by use of a ‘‘full spectrum’’ or daylight fluorescent lamp, which has both UV and Vis output, or by use of a xenon lamp or metal halide lamp, both in combination with appropriate filters. Option 2 radiation sources attempt to mimic indoor lighting conditions which (assuming that the room has a window) is composed of glass-filtered daylight and artificial radiation provided by cool white fluorescent lamps. This option allows for the use of two separate lamps; one for the UVA emission and one for the visible light. The lamps can be used in combination or sequentially. It has been noted that a combination of sources specified in Option 2 may produce little or no output between 380 and 430 nm.4 It is important to check that the sample (API or drug substance) does not absorb primarily in this region to avoid an artificial lack of photodegradation. Comments: e. The term light source is used throughout the guideline. Light refers, however, to the photopic response, i.e., radiant energy acting on the retina. Visual perception is normally taken to cover the range 400–800 nm with a maximum in response sensitivity around 550 nm. Although the term light often is recognized as having a broader meaning, the scientifically correct terms in this context are radiation, photon, or photolysis source. These will cover both the UV regions and the visible light. f. Clarity on sequential/simultaneous nature of Option 2 exposure to UVA and cool white fluorescent light is needed. The guideline gives no guidance as to whether samples should be exposed to the two Option 2 light sources simultaneously or sequentially, and if sequentially, does order matter? Clarification is needed. g. Clarity on description of Option 1 and Option 2 lamp output/emission is needed. What is ‘‘similar to’’? The guideline states ‘‘Any light source that is designed to produce an output similar to the D65/ ID65 emission standard . . .’’ D65 and ID65 are two different standards, so there is some confusion as to which should be used for studies with Option 1 light sources. It appears that the guideline is suggesting that either one of the standards (D65 or ID65) is appropriate, yet the suggestion for use of a window-glass filter to eliminate radiation below 320 nm indicates that the ID65 emission standard is preferred. Rewording of this section for clarity would be useful to the industry. The specific wording of the guideline with regard to the description of Option 2 sources is also confusing. Researchers in the industry often struggle to find a cool white fluorescent light JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
as defined in ISO10977, and some guidance would be helpful. Similarly, the description of the near UV fluorescent lamp is also vague, which can increase the risk of improper choice of near UV lamps.6 It is notable that Riehl et al.7 describe in the Pharmacopeial Forum ‘‘requirements’’ for the UVA fluorescent lamp emission that are more specific and detailed than the guideline presents. The ICH guideline simply states that the lamp provide a ‘‘spectral distribution from 320 to 400 nm with a maximum energy emission between 350 and 370 nm; a significant proportion of UV should be in both bands of 320–360 nm and 360–400 nm.’’ In contrast, Riehl asserts in his Pharmacopeial Forum article that ‘‘at least 25% of the ultraviolet-A must be between 320 and 360 nm and at least 25% must be between 360 and 400 nm.’’ Consideration should be given to incorporating these requirements into the revised guidance.
OVERALL ILLUMINATION AND EXPOSURE TIME The ICH guideline recommends a total exposure of not less than 200 W-h m 2 in the UV range (320– 400 nm) and 1.2 million lux-h in the visible range (400–800 nm) for confirmatory studies. For a lamp with a spectral output similar to the ID65 standard (i.e., Option 1) a total irradiance of 200 W-h m 2 in the UV region corresponds to 0.45 million lux-h in the visible region. A test run with the end criterion ‘‘1.2 million lux h’’ will therefore exceed the minimum requirement ‘‘200 W-h m 2’’ by a factor of 2.5–3 by use of irradiation sources that are compliant with either the D65 or ID65 standards, according to Option 1. The problem can be avoided by selecting the following approach: Option 1 and Option 2 approaches can be combined. The minimum 200 W-h/m2 could be met using an Option 1 source and the visible light exposure could then be fulfilled by exposure to a cool white fluorescent light. The Option 1 source would serve as a surrogate for the UVA component of the exposure. Further, the ICH guideline does not specify an irradiance level, only the overall illumination (i.e., end criterion). Test conditions corresponding to the maximum output of the lamp will often be the first choice as the exposure time thereby can be reduced. It is, however, important to realize that a high irradiance level can change the mechanisms of the degradation process even when the spectral distribution of the radiation source is kept constant.8,9 DOI 10.1002/jps
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Comments: h. Clarity on length of exposure when using Option 1 conditions is needed. In I. C. Procedure, the guidelines state: ‘‘For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux-h and an integrated near ultraviolet energy of not less than 200-h/m2 to allow direct comparisons to be made between the drug substance and drug product.’’ This statement is clear for exposure time when using Option 2 with separate UV and visible light sources; however, the minimum exposure of 1.2 million lux-h and 200-h/m2 needs to be specified when using Option 1. What could be made clear in the guideline is that both requirements need to be met (at a minimum), and that a combined Option 1 then Option 2 approach is acceptable (in addition to the other approaches suggested above).
PRESENTATION OF SAMPLES The presentation of samples within the test chamber can have a significant effect on the outcome of the photostability study. Important issues are alignment of the samples relative to the irradiation source, thickness of sample layer, selection of protective material, uniform exposure of the samples, change in temperature and humidity, and appropriate dark controls.2,10 Comments: j. In II. Drug substance, A. Presentation of Samples, the guideline states: ‘‘Solid drug substances should be spread across the container to give a thickness of typically not more than 3 mm.’’ We suggest removing typically stating ‘‘. . . to give a thickness not more than 3 mm.’’ k. In III. Drug Product, A. Presentation of Samples, the guideline states: ‘‘Some adjustment of testing conditions may have to be made when testing large volume containers (e.g., dispensing packs).’’ Guidance should be provided to the applicant to ensure that the samples tested are those samples with the greatest light exposure in the container. This would make the photostability testing in the containers more consistent with the direct exposure testing, where it is stated that ‘‘The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets and capsules, should be spread in a single layer.’’ An example diagram has been provided in Figure 1. l. Use of dark controls should be more firmly stated. In I. C. Procedure, the guidelines state: ‘‘If DOI 10.1002/jps
Figure 1. Illustration of sample presentation for solid oral dosage forms in their immediate packaging.
protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.’’ A suggested change to this statement is ‘‘Protected samples (e.g., wrapped in aluminum foil) should be used as dark controls to evaluate the contribution of thermally induced change to the total observed change; these should be placed alongside the authentic sample.’’ m. In II. Drug Substance, B. Analysis of Samples and III. Drug Product, B. Analysis of Samples, the last sentence states: ‘‘The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.’’ We suggest removing the clause ‘‘if these are used in the test’’ to more firmly stress the use of dark controls.
JUDGMENT OF RESULTS Photostability testing according to the ICH guideline will give an indication as to whether photochemical degradation of the drug substance or drug product is likely to occur during its synthesis, manufacture, packaging, or shelf-life. Quantitative photostability results must be evaluated together with long-term stability results. The results obtained are used to make packaging and labeling decisions as well as patient use decisions (labeling directions for use). When the combined results from photostability and thermal studies do not meet the specifications at the proposed expiry, the results must be considered as unacceptable unless a reduction in expiration date is an option. The guideline does not include the design of in-use tests or cover abridged applications. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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Comments: o. Clarity on interpretation of results is needed. In I. A. Preamble, it is stated: ‘‘Acceptable change is change within limits justified by the applicant.’’ It would be useful to have more clarity on determining an ‘‘acceptable’’ result. In II. Drug Substance, C. Judgment of Results, second paragraph, it is stated that the ‘‘confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed.’’ It would be useful to consider parsing out manufacturing, formulation, and storage/distribution for both the drug substance and drug product. The more critical area of concern is manufacturing (for both the drug substance and product); a ‘‘failure’’ of a full confirmatory test may or may not present a significant problem for manufacturing light exposures since these light exposures are typically much less than the minimum recommended confirmatory exposure. It would be useful to briefly discuss this topic to bring clarity for the industry. p. In the case of section III. Drug Product, C. Judgment of Results, the guideline states that ‘‘it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life . . .’’. Anderson11 illustrated the concepts intended by the ICH Expert Working group in a presentation in 1997, and this illustration has been published by Thatcher et al.12 (see Fig. 2). Some modification of the guideline to provide clarity as found in this illustration would be helpful.
Figure 2. Example showing how confirmatory photostability results can be used in conjunction with definitive stability results for the judgement of shelf-life of a drug substance or product. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
q. Clarity on term ‘‘equivocal’’ is needed. In II. Drug Substance, the last paragraph, and in III. Drug Product the term ‘‘equivocal’’ is used. Equivocal apparently means ‘‘doubtful,’’ ‘‘questionable,’’ or ‘‘suspicious,’’ and in the context it can be understood to mean that the results are such that it is not obvious whether or not the drug is clearly photostable or photolabile. Some clarity is needed to enable meaningful decisions regarding the assessment of whether the results of a confirmatory photostability test are ‘‘equivocal.’’ r. Clarity on use and interpretation of ‘‘dark controls’’ (section C. Procedure, last paragraph) is needed. It is inferred that the dark control is to enable differentiation between thermal degradation and photodegradation. This should be specifically mentioned under ‘‘Judgment of Results.’’ s. In-use photostability testing guidance (e.g., dermal creams, IV preparations, transdermal patches, topical agents) is not covered by the guideline. Some guidance would be helpful to the industry, but perhaps this should come in a separate guidance.
CALIBRATION The ICH guideline recommends the use of a calibrated radiometer or a validated actinometric system to monitor the exposure in the UV region. A calibrated luxmeter is recommended to determine the overall illumination in the visible range. Neither the UV filter radiometer nor the luxmeter provide information on the spectral power distribution (SPD, the plot of radiation intensity vs. wavelength) of the sources. Further, these devices cannot be used to obtain an absolute measurement of irradiance or to compare irradiance between sources unless they are calibrated specifically for each source.13 Spectroradiometric data should be provided by the lamp manufacturer upon request. A detailed estimate of the SPD is obtained by use of a spectroradiometer. The total irradiance (i.e., actual number of photons) can be determined by chemical actinometry using a reaction of known photochemical efficiency. The chemical actinometer listed in the ICH guideline (quinine hydrochloride) has its limitations and it is not suitable for calibration of Option 1 radiation sources. Comments: t. Quinine is listed in the guideline for use in a ‘‘primary actinometric procedure for monitoring exposure to the near UV region of the light source.’’ The next sentence states that ‘‘The actinometric DOI 10.1002/jps
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systems should be calibrated for the type of sources used.’’ (IV. Annex A. Chemical Actinometry, first paragraph). The third paragraph states ‘‘For near UV lamps, the length of the exposure should be sufficient to ensure a change in absorbance observed of at least 0.8.’’ There has been significant confusion in the industry around the proper use of this ‘‘actinometer.’’ The actinometer has only been validated for one particular lamp (Sylvania F20T12/BLB UVA fluorescent lamp) with a certain spectral power distribution (SPD).11,14 Other lamps with similar SPD’s should give similar results, but UVA fluorescent lamps with a different SPD will give significantly different results. This limitation needs to be made clear in the guideline. It would be useful to publish the SPD of the lamp for which quinine was calibrated in the guideline. Another problem that has been discovered since the publication of the guideline is that the timing of the measurement of absorbance at 400 nm is critical to the result. That is, Kester et al.15 has shown that the quinine absorbance at 400 nm continues to increase after the exposure to the lamp has ceased (for more than 60 h!) at approximately one-fifth the rate of increase in absorbance that is observed during exposure to the source. Significantly different results can be observed, depending on whether or not the quinine solution absorbance is measured immediately after exposure to the lamp or after a delay. This source of error should be eliminated. It should also be made clear in the guideline that Option 1 light sources are not amenable to use with quinine as an actinometer. Many researchers have spent considerable time trying to calibrate/validate quinine for Option 1 sources only to discover that this is not feasible. For example, Baertschi16 showed that with a xenon lamp that quinine is sensitive to dissolved oxygen content and temperature. Christensen et al.17 also showed the temperature dependence of the quinine actinometry system and proposed recommended maximum holding times of 2 h prior to absorbance measurement. Thatcher et al.18 and Gauglitz19 also discussed limitations of the actinometer. Brower et al.14 explicitly state that quinine is not suitable for Option 1 sources. Nonetheless, it is apparent that many in the industry are not aware of these limitations because of the absence of such critical information in the guideline. Another line in the actinometry section deserves some attention. The last line of this section states that ‘‘Alternative validated chemical actinometers may be used.’’ Coupled with the last sentence in the first paragraph, ‘‘The actinometric systems should be calibrated for the type of sources used,’’ it is DOI 10.1002/jps
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apparent that some guidance should be provided for the term ‘‘validated’’ so the researcher is not left to invent the validation procedure. Finally, only one container is recommended for the actinometric solution (a 20-mL colorless ampoule), and that container is not adequately defined by the guideline. The dimensions are given, but the type of glass, thickness of the glass, and the transmission characteristics of the glass are undefined. Such details are critically important to define since variations can lead to dramatically different results. Provision for other containers (specifically, quartz UV cells of defined dimensions and spectral characteristics) would be helpful. There has been some confusion as to whether ‘‘Option 1’’ and ‘‘Option 2’’ as listed in the Annex is intended to indicate that that these are the intended actinometric solution containers for ‘‘Option 1’’ light sources (the glass ampoule) and ‘‘Option 2’’ light sources (quartz UV cells), or if these are just two Options for containers to use with the actinometric solution.
CONCLUSION The ICH guideline on photostability has provided the industry with needed guidance on photostability testing since its approval and publication in 1996. Since then, various issues of significance have been identified by both academic and industry researchers that point to the need for the guidance to undergo the revision process as outlined by ICH. Notwithstanding, many who use the guideline are not aware of these issues and potential ramifications. We have attempted to capture the major issues in this commentary, along with suggestions for revising the guidance. It is our hope that a revised photostability guidance document will provide clarity to the industry and eliminate potential errors and misapplication.
ACKNOWLEDGMENTS The authors gratefully acknowledge helpful comments provided by Robert A. Reed and Bernard A. Olsen during the preparation and review of this commentary.
REFERENCES 1. ICH Q1B. 1997. Photostability testing of new drug substances and products. Fed Reg 62:27115–27122. 2. Tønnesen HH, Baertschi SW. 2004. The questions most frequently asked. In: Tønnesen HH, editor. Photostability of drugs and drug formulations. 2nd edition. Boca Raton: CRC Press. pp. 161–172. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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3. Tønnesen HH. 2007. The International Conference on Harmanization Photostability Guideline. A discussion of experimental conditions. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 47–60. 4. Tønnesen HH, Moore DE. 1993. Photochemical degradation of components in drug formulations. Pharm Technol Eur 5:27–33. 5. Templeton AC, Bowen WE. 2007. Unexpected photochemistry in pharmaceutical products: A review on the role of diluents, excipients, and product components in promoting pharmaceutical photochemistry. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 223–252. 6. Piechocki JT. 2007. Sources. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability stabilization and technology. Drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 99–119. 7. Riehl J, Maupin C, Layloff T. 1995. On the choice of photolysis source for the photostability testing of pharmaceuticals. Pharm Forum 21:1654–1663. 8. Tønnesen HH, Brunsvik A, Løseth K, Bergh K, Gederaas OA. 2007. Photostability of ofloxacin in the solid state and in a tablet formulation. Photoreactivity of biologically active compounds. XVIII. Pharmazie 62:105–111. 9. Sue-Chu M, Kristensen S, Tønnesen HH. 2009. Photoinduced color changes in two different qualities of riboflavin in the solid state and in various tablet formulations. Photoreactivity of biologically active compounds.XX. Pharmazie 64:428–435. 10. Sue-Chu M, Kristensen S, Tønnesen HH. 2008. Influence of lagtime between light exposure and color evaluation of riboflavin in the solid state. Pharmazie 63:545–546. 11. Anderson N. 1997. A European perspective on photostability testing. Presented at Pharmaceutical Photostability, AAI Seminar Series, Arlington, VA, February 24–25.
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12. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. 2001. Pharmaceutical photostability: A technical and practical interpretation of the ICH Guideline and its application to pharmaceutical stability: Part I. Pharm Technol US 25:98–110. 13. Tønnesen HH, Karlsen J. 1997. A comment on photostability testing according to the ICH guideline: Calibration of light sources. Pharmeuropa 9:735–736. 14. Brower JF, Drew HD, Juhl WE, Thornton LK. 1998. Quinine photochemistry: A proposed chemical actinometer to monitor UV-A exposure in photostability studies of pharmaceutical drug substances and drug products. Pharm Forum 24:6334– 6346. 15. Kester TC, Zhan Z, Bergstrom DH. 1996. Quinine actinometry studies under two light sources specified by the ICH guideline on photostability testing. Seattle, Washington. Presented at the AAPS National Meeting. 16. Baertschi SW. 1997. Commentary on the quinine actinometry system described in the ICH draft guideline on photostability testing of new drug substances and products. Drug Stability 1:193–195. 17. Christensen KL, Christensen JO, Frokjaer S, Langball P, Hansen LL. 2000. Influence of temperature and storage time after light exposure on the quinine monohydrochloride chemical actinometric system. Eur J Pharm Sci 9:317– 321. 18. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. 2001. Pharmaceutical photostability: A technical and practical interpretation of the ICH guideline and its application to pharmaceutical stability: Part II. Pharm Technol US 25:50– 62. 19. Gauglitz G, Hubig SM. 2007. Chemical actinometry. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 151– 153.
DOI 10.1002/jps
Eli Lilly and Company, Analytical Sciences Research and Development, Lilly Research Laboratories, Indianapolis, Indiana 46285
2
Pfizer Global Research & Development, Analytical Research & Development, Eastern Point Rd., Box 4077, Groton, Connecticut 06340
3
Department of Pharmaceutics, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway
Received 20 November 2009; accepted 4 December 2009 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22076 ABSTRACT: The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2934–2940, 2010
Keywords: stability
physical stability; chemical stability; analytical chemistry; stability; solid state
INTRODUCTION The ICH guideline on photostability (ICH Topic Q1B)1 was published in November 1996 and has been implemented in all three regions (US and Canada, EU, and Japan). After January 1, 1998, it is obligatory to provide photostability information constructed according to this guideline for all new drug license applications filed in these regions. The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of
drugs under conditions of patient use. It recommends a systematic approach to photostability testing on the drug substance and drug product according to a decision flow chart. The outline of the guideline is as follows:
Correspondence to: Steven W. Baertschi (Telephone: 317-2761388; Fax: 317-277-2154; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 2934–2940 (2010) ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association
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(I) General (A) Preamble (B) Light sources (C) Procedure (II) Drug substance (A) Presentation of samples (B) Analysis of samples (C) Judgment of results (III) Drug product (A) Presentation of samples (B) Analysis of samples (C) Judgment of results
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(IV) Annex (A) Quinine chemical actinometry (V) Glossary (VI) Reference The tests are pass/fail tests where ‘‘acceptable change is change within limits justified by the applicant.’’ Despite the implementation of the ICH photostability guideline, issues remain that are not specifically covered in the document and which are left to the applicant’s discretion.2,3 The guideline allows for alternative approaches assuming that these are scientifically sound. The aim of the photostability testing should be to demonstrate that exposure to irradiation does not result in an unacceptable change. It is left to the applicant to establish how the product will be used and to undertake appropriate photostability studies. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from a revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process; (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program; (iii) provide recommendations for clarification of the guideline.
FORCED AND CONFIRMATORY STUDIES The guideline calls for ‘‘forced degradation’’ studies (stress testing) and a ‘‘confirmatory’’ study. A forced degradation study is testing under forcing conditions to characterize intrinsic stability characteristics of the drug substance or drug product, to determine degradation products and reaction mechanisms, and to develop appropriate methodology for detection and quantitation. Confirmatory studies involve testing under conditions designed to generate data to predict what might happen during ambient storage, and to determine whether precautionary measures are needed during formulation, production, and storage. A confirmatory study can be regarded as a limit test, and should conclude with ‘‘acceptable’’ or ‘‘unacceptable’’ change. Comments: a. In II. Drug Substance, the first paragraph reads: ‘‘For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing.’’ DOI 10.1002/jps
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This is not stated in section III. Drug product. Additional guidance should be given to the applicant for photostability forced degradation of drug product samples. It is recommended that the guidance clearly state that photostability/photodegradation is a function of the ‘‘system’’ (i.e., the formulation plus the drug) and not just the drug molecule, as clearly evidenced by examples documented in the literature.4,5 b. In V. Glossary, drug product testing is not mentioned in the definition of forced degradation testing studies.
SEQUENTIAL TESTING A sequential testing approach is recommended. The sample should first be tested unpacked, with direct exposure to the radiation source. If necessary, a transparent (with known UV/Vis transmittance) container may be used for liquid or semisolid products. Samples that are found to be unstable should then be further tested in primary and secondary (market) packs as necessary. Products that are stable in the primary pack but unstable without it should be labeled in such a way that a transfer into a less protective pack, for example, by a pharmaceutical wholesaler or in a hospital pharmacy, is prevented. It is unnecessary to conduct tests in containers completely impenetrable to radiation (e.g., aluminum foil) when these are used for direct dispensing to the patient. Comments: c. The first paragraph of III. Drug product states: ‘‘Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light.’’ To avoid confusion, it should be clearly stated that if no light degradation is observed in the fully exposed sample, no further testing needs to be performed. This text change would more clearly support the Decision Tree diagram. d. III. Drug Product, foil/foil blisters should be added to the list of immediate packs impenetrable to light to be more complete.
IRRADIATION SOURCE The ICH guideline gives two options for the selection of the irradiation source. Option 1 addresses exposure to outdoor daylight or window glass filtered daylight. Option 1 advises exposing the samples to UVB, UVA, and visible light simultaneously. In practice, Option 1 offers the choice between three different types of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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sources. Glass-filtered daylight can be obtained by use of a ‘‘full spectrum’’ or daylight fluorescent lamp, which has both UV and Vis output, or by use of a xenon lamp or metal halide lamp, both in combination with appropriate filters. Option 2 radiation sources attempt to mimic indoor lighting conditions which (assuming that the room has a window) is composed of glass-filtered daylight and artificial radiation provided by cool white fluorescent lamps. This option allows for the use of two separate lamps; one for the UVA emission and one for the visible light. The lamps can be used in combination or sequentially. It has been noted that a combination of sources specified in Option 2 may produce little or no output between 380 and 430 nm.4 It is important to check that the sample (API or drug substance) does not absorb primarily in this region to avoid an artificial lack of photodegradation. Comments: e. The term light source is used throughout the guideline. Light refers, however, to the photopic response, i.e., radiant energy acting on the retina. Visual perception is normally taken to cover the range 400–800 nm with a maximum in response sensitivity around 550 nm. Although the term light often is recognized as having a broader meaning, the scientifically correct terms in this context are radiation, photon, or photolysis source. These will cover both the UV regions and the visible light. f. Clarity on sequential/simultaneous nature of Option 2 exposure to UVA and cool white fluorescent light is needed. The guideline gives no guidance as to whether samples should be exposed to the two Option 2 light sources simultaneously or sequentially, and if sequentially, does order matter? Clarification is needed. g. Clarity on description of Option 1 and Option 2 lamp output/emission is needed. What is ‘‘similar to’’? The guideline states ‘‘Any light source that is designed to produce an output similar to the D65/ ID65 emission standard . . .’’ D65 and ID65 are two different standards, so there is some confusion as to which should be used for studies with Option 1 light sources. It appears that the guideline is suggesting that either one of the standards (D65 or ID65) is appropriate, yet the suggestion for use of a window-glass filter to eliminate radiation below 320 nm indicates that the ID65 emission standard is preferred. Rewording of this section for clarity would be useful to the industry. The specific wording of the guideline with regard to the description of Option 2 sources is also confusing. Researchers in the industry often struggle to find a cool white fluorescent light JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
as defined in ISO10977, and some guidance would be helpful. Similarly, the description of the near UV fluorescent lamp is also vague, which can increase the risk of improper choice of near UV lamps.6 It is notable that Riehl et al.7 describe in the Pharmacopeial Forum ‘‘requirements’’ for the UVA fluorescent lamp emission that are more specific and detailed than the guideline presents. The ICH guideline simply states that the lamp provide a ‘‘spectral distribution from 320 to 400 nm with a maximum energy emission between 350 and 370 nm; a significant proportion of UV should be in both bands of 320–360 nm and 360–400 nm.’’ In contrast, Riehl asserts in his Pharmacopeial Forum article that ‘‘at least 25% of the ultraviolet-A must be between 320 and 360 nm and at least 25% must be between 360 and 400 nm.’’ Consideration should be given to incorporating these requirements into the revised guidance.
OVERALL ILLUMINATION AND EXPOSURE TIME The ICH guideline recommends a total exposure of not less than 200 W-h m 2 in the UV range (320– 400 nm) and 1.2 million lux-h in the visible range (400–800 nm) for confirmatory studies. For a lamp with a spectral output similar to the ID65 standard (i.e., Option 1) a total irradiance of 200 W-h m 2 in the UV region corresponds to 0.45 million lux-h in the visible region. A test run with the end criterion ‘‘1.2 million lux h’’ will therefore exceed the minimum requirement ‘‘200 W-h m 2’’ by a factor of 2.5–3 by use of irradiation sources that are compliant with either the D65 or ID65 standards, according to Option 1. The problem can be avoided by selecting the following approach: Option 1 and Option 2 approaches can be combined. The minimum 200 W-h/m2 could be met using an Option 1 source and the visible light exposure could then be fulfilled by exposure to a cool white fluorescent light. The Option 1 source would serve as a surrogate for the UVA component of the exposure. Further, the ICH guideline does not specify an irradiance level, only the overall illumination (i.e., end criterion). Test conditions corresponding to the maximum output of the lamp will often be the first choice as the exposure time thereby can be reduced. It is, however, important to realize that a high irradiance level can change the mechanisms of the degradation process even when the spectral distribution of the radiation source is kept constant.8,9 DOI 10.1002/jps
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Comments: h. Clarity on length of exposure when using Option 1 conditions is needed. In I. C. Procedure, the guidelines state: ‘‘For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux-h and an integrated near ultraviolet energy of not less than 200-h/m2 to allow direct comparisons to be made between the drug substance and drug product.’’ This statement is clear for exposure time when using Option 2 with separate UV and visible light sources; however, the minimum exposure of 1.2 million lux-h and 200-h/m2 needs to be specified when using Option 1. What could be made clear in the guideline is that both requirements need to be met (at a minimum), and that a combined Option 1 then Option 2 approach is acceptable (in addition to the other approaches suggested above).
PRESENTATION OF SAMPLES The presentation of samples within the test chamber can have a significant effect on the outcome of the photostability study. Important issues are alignment of the samples relative to the irradiation source, thickness of sample layer, selection of protective material, uniform exposure of the samples, change in temperature and humidity, and appropriate dark controls.2,10 Comments: j. In II. Drug substance, A. Presentation of Samples, the guideline states: ‘‘Solid drug substances should be spread across the container to give a thickness of typically not more than 3 mm.’’ We suggest removing typically stating ‘‘. . . to give a thickness not more than 3 mm.’’ k. In III. Drug Product, A. Presentation of Samples, the guideline states: ‘‘Some adjustment of testing conditions may have to be made when testing large volume containers (e.g., dispensing packs).’’ Guidance should be provided to the applicant to ensure that the samples tested are those samples with the greatest light exposure in the container. This would make the photostability testing in the containers more consistent with the direct exposure testing, where it is stated that ‘‘The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets and capsules, should be spread in a single layer.’’ An example diagram has been provided in Figure 1. l. Use of dark controls should be more firmly stated. In I. C. Procedure, the guidelines state: ‘‘If DOI 10.1002/jps
Figure 1. Illustration of sample presentation for solid oral dosage forms in their immediate packaging.
protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.’’ A suggested change to this statement is ‘‘Protected samples (e.g., wrapped in aluminum foil) should be used as dark controls to evaluate the contribution of thermally induced change to the total observed change; these should be placed alongside the authentic sample.’’ m. In II. Drug Substance, B. Analysis of Samples and III. Drug Product, B. Analysis of Samples, the last sentence states: ‘‘The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.’’ We suggest removing the clause ‘‘if these are used in the test’’ to more firmly stress the use of dark controls.
JUDGMENT OF RESULTS Photostability testing according to the ICH guideline will give an indication as to whether photochemical degradation of the drug substance or drug product is likely to occur during its synthesis, manufacture, packaging, or shelf-life. Quantitative photostability results must be evaluated together with long-term stability results. The results obtained are used to make packaging and labeling decisions as well as patient use decisions (labeling directions for use). When the combined results from photostability and thermal studies do not meet the specifications at the proposed expiry, the results must be considered as unacceptable unless a reduction in expiration date is an option. The guideline does not include the design of in-use tests or cover abridged applications. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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Comments: o. Clarity on interpretation of results is needed. In I. A. Preamble, it is stated: ‘‘Acceptable change is change within limits justified by the applicant.’’ It would be useful to have more clarity on determining an ‘‘acceptable’’ result. In II. Drug Substance, C. Judgment of Results, second paragraph, it is stated that the ‘‘confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed.’’ It would be useful to consider parsing out manufacturing, formulation, and storage/distribution for both the drug substance and drug product. The more critical area of concern is manufacturing (for both the drug substance and product); a ‘‘failure’’ of a full confirmatory test may or may not present a significant problem for manufacturing light exposures since these light exposures are typically much less than the minimum recommended confirmatory exposure. It would be useful to briefly discuss this topic to bring clarity for the industry. p. In the case of section III. Drug Product, C. Judgment of Results, the guideline states that ‘‘it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life . . .’’. Anderson11 illustrated the concepts intended by the ICH Expert Working group in a presentation in 1997, and this illustration has been published by Thatcher et al.12 (see Fig. 2). Some modification of the guideline to provide clarity as found in this illustration would be helpful.
Figure 2. Example showing how confirmatory photostability results can be used in conjunction with definitive stability results for the judgement of shelf-life of a drug substance or product. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
q. Clarity on term ‘‘equivocal’’ is needed. In II. Drug Substance, the last paragraph, and in III. Drug Product the term ‘‘equivocal’’ is used. Equivocal apparently means ‘‘doubtful,’’ ‘‘questionable,’’ or ‘‘suspicious,’’ and in the context it can be understood to mean that the results are such that it is not obvious whether or not the drug is clearly photostable or photolabile. Some clarity is needed to enable meaningful decisions regarding the assessment of whether the results of a confirmatory photostability test are ‘‘equivocal.’’ r. Clarity on use and interpretation of ‘‘dark controls’’ (section C. Procedure, last paragraph) is needed. It is inferred that the dark control is to enable differentiation between thermal degradation and photodegradation. This should be specifically mentioned under ‘‘Judgment of Results.’’ s. In-use photostability testing guidance (e.g., dermal creams, IV preparations, transdermal patches, topical agents) is not covered by the guideline. Some guidance would be helpful to the industry, but perhaps this should come in a separate guidance.
CALIBRATION The ICH guideline recommends the use of a calibrated radiometer or a validated actinometric system to monitor the exposure in the UV region. A calibrated luxmeter is recommended to determine the overall illumination in the visible range. Neither the UV filter radiometer nor the luxmeter provide information on the spectral power distribution (SPD, the plot of radiation intensity vs. wavelength) of the sources. Further, these devices cannot be used to obtain an absolute measurement of irradiance or to compare irradiance between sources unless they are calibrated specifically for each source.13 Spectroradiometric data should be provided by the lamp manufacturer upon request. A detailed estimate of the SPD is obtained by use of a spectroradiometer. The total irradiance (i.e., actual number of photons) can be determined by chemical actinometry using a reaction of known photochemical efficiency. The chemical actinometer listed in the ICH guideline (quinine hydrochloride) has its limitations and it is not suitable for calibration of Option 1 radiation sources. Comments: t. Quinine is listed in the guideline for use in a ‘‘primary actinometric procedure for monitoring exposure to the near UV region of the light source.’’ The next sentence states that ‘‘The actinometric DOI 10.1002/jps
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systems should be calibrated for the type of sources used.’’ (IV. Annex A. Chemical Actinometry, first paragraph). The third paragraph states ‘‘For near UV lamps, the length of the exposure should be sufficient to ensure a change in absorbance observed of at least 0.8.’’ There has been significant confusion in the industry around the proper use of this ‘‘actinometer.’’ The actinometer has only been validated for one particular lamp (Sylvania F20T12/BLB UVA fluorescent lamp) with a certain spectral power distribution (SPD).11,14 Other lamps with similar SPD’s should give similar results, but UVA fluorescent lamps with a different SPD will give significantly different results. This limitation needs to be made clear in the guideline. It would be useful to publish the SPD of the lamp for which quinine was calibrated in the guideline. Another problem that has been discovered since the publication of the guideline is that the timing of the measurement of absorbance at 400 nm is critical to the result. That is, Kester et al.15 has shown that the quinine absorbance at 400 nm continues to increase after the exposure to the lamp has ceased (for more than 60 h!) at approximately one-fifth the rate of increase in absorbance that is observed during exposure to the source. Significantly different results can be observed, depending on whether or not the quinine solution absorbance is measured immediately after exposure to the lamp or after a delay. This source of error should be eliminated. It should also be made clear in the guideline that Option 1 light sources are not amenable to use with quinine as an actinometer. Many researchers have spent considerable time trying to calibrate/validate quinine for Option 1 sources only to discover that this is not feasible. For example, Baertschi16 showed that with a xenon lamp that quinine is sensitive to dissolved oxygen content and temperature. Christensen et al.17 also showed the temperature dependence of the quinine actinometry system and proposed recommended maximum holding times of 2 h prior to absorbance measurement. Thatcher et al.18 and Gauglitz19 also discussed limitations of the actinometer. Brower et al.14 explicitly state that quinine is not suitable for Option 1 sources. Nonetheless, it is apparent that many in the industry are not aware of these limitations because of the absence of such critical information in the guideline. Another line in the actinometry section deserves some attention. The last line of this section states that ‘‘Alternative validated chemical actinometers may be used.’’ Coupled with the last sentence in the first paragraph, ‘‘The actinometric systems should be calibrated for the type of sources used,’’ it is DOI 10.1002/jps
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apparent that some guidance should be provided for the term ‘‘validated’’ so the researcher is not left to invent the validation procedure. Finally, only one container is recommended for the actinometric solution (a 20-mL colorless ampoule), and that container is not adequately defined by the guideline. The dimensions are given, but the type of glass, thickness of the glass, and the transmission characteristics of the glass are undefined. Such details are critically important to define since variations can lead to dramatically different results. Provision for other containers (specifically, quartz UV cells of defined dimensions and spectral characteristics) would be helpful. There has been some confusion as to whether ‘‘Option 1’’ and ‘‘Option 2’’ as listed in the Annex is intended to indicate that that these are the intended actinometric solution containers for ‘‘Option 1’’ light sources (the glass ampoule) and ‘‘Option 2’’ light sources (quartz UV cells), or if these are just two Options for containers to use with the actinometric solution.
CONCLUSION The ICH guideline on photostability has provided the industry with needed guidance on photostability testing since its approval and publication in 1996. Since then, various issues of significance have been identified by both academic and industry researchers that point to the need for the guidance to undergo the revision process as outlined by ICH. Notwithstanding, many who use the guideline are not aware of these issues and potential ramifications. We have attempted to capture the major issues in this commentary, along with suggestions for revising the guidance. It is our hope that a revised photostability guidance document will provide clarity to the industry and eliminate potential errors and misapplication.
ACKNOWLEDGMENTS The authors gratefully acknowledge helpful comments provided by Robert A. Reed and Bernard A. Olsen during the preparation and review of this commentary.
REFERENCES 1. ICH Q1B. 1997. Photostability testing of new drug substances and products. Fed Reg 62:27115–27122. 2. Tønnesen HH, Baertschi SW. 2004. The questions most frequently asked. In: Tønnesen HH, editor. Photostability of drugs and drug formulations. 2nd edition. Boca Raton: CRC Press. pp. 161–172. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010
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3. Tønnesen HH. 2007. The International Conference on Harmanization Photostability Guideline. A discussion of experimental conditions. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 47–60. 4. Tønnesen HH, Moore DE. 1993. Photochemical degradation of components in drug formulations. Pharm Technol Eur 5:27–33. 5. Templeton AC, Bowen WE. 2007. Unexpected photochemistry in pharmaceutical products: A review on the role of diluents, excipients, and product components in promoting pharmaceutical photochemistry. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 223–252. 6. Piechocki JT. 2007. Sources. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability stabilization and technology. Drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 99–119. 7. Riehl J, Maupin C, Layloff T. 1995. On the choice of photolysis source for the photostability testing of pharmaceuticals. Pharm Forum 21:1654–1663. 8. Tønnesen HH, Brunsvik A, Løseth K, Bergh K, Gederaas OA. 2007. Photostability of ofloxacin in the solid state and in a tablet formulation. Photoreactivity of biologically active compounds. XVIII. Pharmazie 62:105–111. 9. Sue-Chu M, Kristensen S, Tønnesen HH. 2009. Photoinduced color changes in two different qualities of riboflavin in the solid state and in various tablet formulations. Photoreactivity of biologically active compounds.XX. Pharmazie 64:428–435. 10. Sue-Chu M, Kristensen S, Tønnesen HH. 2008. Influence of lagtime between light exposure and color evaluation of riboflavin in the solid state. Pharmazie 63:545–546. 11. Anderson N. 1997. A European perspective on photostability testing. Presented at Pharmaceutical Photostability, AAI Seminar Series, Arlington, VA, February 24–25.
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12. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. 2001. Pharmaceutical photostability: A technical and practical interpretation of the ICH Guideline and its application to pharmaceutical stability: Part I. Pharm Technol US 25:98–110. 13. Tønnesen HH, Karlsen J. 1997. A comment on photostability testing according to the ICH guideline: Calibration of light sources. Pharmeuropa 9:735–736. 14. Brower JF, Drew HD, Juhl WE, Thornton LK. 1998. Quinine photochemistry: A proposed chemical actinometer to monitor UV-A exposure in photostability studies of pharmaceutical drug substances and drug products. Pharm Forum 24:6334– 6346. 15. Kester TC, Zhan Z, Bergstrom DH. 1996. Quinine actinometry studies under two light sources specified by the ICH guideline on photostability testing. Seattle, Washington. Presented at the AAPS National Meeting. 16. Baertschi SW. 1997. Commentary on the quinine actinometry system described in the ICH draft guideline on photostability testing of new drug substances and products. Drug Stability 1:193–195. 17. Christensen KL, Christensen JO, Frokjaer S, Langball P, Hansen LL. 2000. Influence of temperature and storage time after light exposure on the quinine monohydrochloride chemical actinometric system. Eur J Pharm Sci 9:317– 321. 18. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. 2001. Pharmaceutical photostability: A technical and practical interpretation of the ICH guideline and its application to pharmaceutical stability: Part II. Pharm Technol US 25:50– 62. 19. Gauglitz G, Hubig SM. 2007. Chemical actinometry. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology, drugs and the pharmaceutical sciences, Vol. 163. New York: Informa Healthcare. pp. 151– 153.
DOI 10.1002/jps