Implications of In-Use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products, Part 1: Drug Products Administered by Injection

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Implications of In-Use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products, Part 1: Drug Products Administered by Injection STEVEN W. BAERTSCHI,1 DAVID CLAPHAM,2 CHRIS FOTI,3 PATRICK J. JANSEN,1 SOLVEIG KRISTENSEN,4 ROBERT A. REED,5 ALLEN C TEMPLETON,6 HANNE HJORTH TØNNESEN4 1

Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285 GlaxoSmithKline Pharmaceuticals, Ware, SG12 0DP, UK 3 Pfizer Inc., Analytical Research and Development, Groton, Connecticut 06340 4 School of Pharmacy, University of Oslo, Oslo, 0316, Norway 5 Celsion Corporation, Lawrenceville, New Jersey, 08648 6 Merck Research Laboratories, Merck & Company, Inc., West Point, Pennsylvania, 19486 2

Received 30 April 2013; revised 6 August 2013; accepted 7 August 2013 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23717 ABSTRACT: Basic guidance on the photostability testing of pharmaceuticals, designed to cover manufacturing and storage over shelf life, has long been established within ICH Q1(ICH,B10 , but the guideline does not cover the photostability of drugs during or after administration (i.e., under conditions of use). To date, there has been a paucity of guidance covering the additional testing that would be of value during the clinical preparation and use of products. This commentary suggests a systematic approach, based on realistic “worst case” photoexposure scenarios and the existing ICH Option 1 and 2 light sources, to provide valuable data to pharmaceutical manufacturers C 2013 Wiley Periodicals, Inc. and the and compounding pharmacists for the safe and effective use of photosensitive injection products.  American Pharmacists Association J Pharm Sci Keywords: stability; preformulation; photodegradation; photochemistry; injectables; chemical stability; physical stability

INTRODUCTION The importance of photostability testing within the pharmaceutical industry is well established, and numerous papers have sought to clarify, as well as improve upon, existing regulatory guidance. One aspect of clarification has been to provide practical interpretations of the regulatory guidance to assist pharmaceutical applicants in satisfying requirements.1–6 Another area that has received attention is the need for experimental design and data interpretation to support various manufacturing, packaging and testing operations to preserve product integrity.7,8 As has been noted in the literature, one area that remains significantly underdeveloped is an understanding of photostability testing needed to support the administration of photosensitive pharmaceutical products.9 Such testing is important because the product may be exposed to a variety of conditions that could adversely impact the efficacy and safety of the product, not only during the handling in the pharmacy, but also during administration. Improved testing approaches will support more effective labeling and allow patients and practitioners to be better able to manage risks associated with photosensitive pharmaceutical products. Correspondence to: Steven W. Baertschi (Telephone: +317-276-1388; Fax: +317-277-2154; E-mail: [email protected]); David Clapham (Telephone: +44 1920 883943; Fax: +44 1920 882552; E-mail: [email protected]) Baertschi, Clapham, Jansen, Kristensen, Reed and TØnnesen are Member of CIE TC6-50 expert group. Journal of Pharmaceutical Sciences

 C 2013 Wiley Periodicals, Inc. and the American Pharmacists Association

There are over 300 monographs of injectable products listed in the United States Pharmacopeia (USP). Of these products, there are approximately 100 with “Protect from Light” restrictions. There is often ambiguity surrounding this restriction and limited instructions on the in-use photostability during administration of these injectable products. Pharmaceutical injections are particularly susceptible to degradation in the presence of light owing to the drug being either suspended or (more frequently) in solution. This physical state of solution or suspension formulations allows for greater molecular mobility that tends to enhance the rate of photochemical reactions and also generally renders a larger proportion of molecules present in the formulation available for light absorption relative to the solid state. Moreover, these products are often administered in clear packaging in a clinical setting where intense lighting may be used to aid visibility for surgical or other medical procedures. It is important to establish a definition of what constitutes product in-use light exposure conditions for the various types of potential product configurations and to establish the typical lighting conditions to which these products may be exposed. From this information, a set of photostability testing conditions can be recommended, the results of which will yield sufficiently detailed information that can be used to support product labeling, manage photostability risks, and support correct product usage. The variety of clinical practice, light exposure conditions, and administration conditions renders it impossible to cover every possible situation. Rather, what is proposed here is a set of realistic “worst case” conditions that should allow evaluation of Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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the potential photostability behavior of particular products in a reasonable diversity of environments. The guidance is intended to allow practitioners in the pharmaceutical industry, and compounding pharmacists, to undertake appropriate photostability testing, and thus gain an understanding of the photostability of the particular product/diluents combination that will allow appropriate product labeling and use. The paper is organized into sections that (1) provide an overview of relevant light sources to consider; (2) outline the considerations for in-use photostability testing; (3) recommend testing conditions; and (4) discuss the implications of in-use photostability in terms of product labeling and risk mitigation. This document does not cover the analytical aspects of testing, nor issues such as sample presentation, how to interpret “acceptable change,” and so on; these issues are dealt with, to some extent, in the official ICH Q1B guidance and more extensively in the literature references given above.

Table 1.

RELEVANT LIGHT SOURCES TO CONSIDER FOR EVALUATING IN-USE PHOTOSTABILITY

The literature speaks to both the practical aspects, relative advantages, and challenges with using these two options and the ICH Q1B guidance in general.1,4,6,10,11 What is important to note, relative to in-use photostability considerations, is that Option 1 addresses exposure to outdoor daylight (D65) or window glass-filtered daylight (ID65),12,13 whereas Option 2 attempts to mimic indoor lighting conditions using a particular type of cool white fluorescent lamp. It is clear that these two Options are not equivalent, and of course this can have particular importance when considering in-use photostability. The spectral power distribution standards for these sources are covered by ISO 18909 (formerly ISO 10977). Owing to the sheer diversity of light sources in the “real world,” which will almost certainly differ from those stated in ICH Q1B, it is impossible to give a comprehensive review in this manuscript of all types of lamps and illuminance levels (often dependent on manufacturer, wattage rating of bulb, and associated power usage) used in homes, businesses, and clinical settings.14 Moreover, the spectral power distribution (intensity as a function of wavelength) of these sources varies quite substantially.15,16 They can however be subdivided, as per the ICH Q1B guidance, into the broad categories of artificial indoor lighting, outdoor daylight from the sun, and window-filtered daylight from the sun. The sun has a well-defined spectral power distribution (though the proportion of different wavelengths reaching various altitudes has an influence) with an irradiance output that varies as a function of the earth’s orbit, rotational pattern, atmospheric layer thickness, latitudinal location on the planet, and temporal weather conditions. Thus, a primary characteristic of light delivered from the sun onto the surface of the earth is its highly variable nature. Illuminance from the sun (which pertains only to the visible region of the spectrum as perceived by the human eye) ranges from approximately 3,000 lux on a winter day with a cloudy sky to 10,000–25,000 lux on an overcast day to as much as 120,000 lux on a bright summer day17,18 (see Table 1). As light absorption and undesirable drug product changes are generally not influenced by illuminance (which represents a photopic response to visible light), it is important to consider the photopic uncorrected irradiance values, particularly for UV radiation. For example, Miami has reported an average total daily irradiance of 5000–5500 (midpoint 5260) W-h/m2 ,17–19 whereas Oslo, Norway, has reported an average irradiance level of

There are a diverse set of light sources that are relevant to understanding the in-use photostability of pharmaceutical products. These include the light sources used for photostability testing options in ICH Q1B,10 but also extend to a broad range of possible light sources that the product might be exposed to during in-use conditions. Given the large number of unique light sources that this encompasses, it is more practical to consider the classes or types of light sources to which a product might be exposed and typical light doses that might be expected. By understanding the exposure scenarios for the most common and relevant sources, an understanding of the impact of in-use light exposure on a product can be ascertained, and guidance can be derived for product usage in these cases. In particular, care needs to be exercised where it is known that a particular range of wavelengths has a disproportionate effect on the photostability of the product in question (otherwise known as “causative” wavelengths) and the light source to which the sample is exposed has a relatively high proportion of those particular wavelengths. In such a case, the degradation may be more extensive than would be expected simply from an evaluation of the overall visible light intensity and a specific experiment under the actual light source used may be required. A cursory overview of the ICH Q1B sources is worthwhile before exploring light sources for in-use settings. Formal confirmatory photostability testing, unlike in-use conditions, is performed in a well-controlled experiment that requires an appropriate light source(s) and chamber, requisite exposure measurement capabilities, and often, although not specified by Q1B, temperature/relative humidity control. With respect to sources, the Q1B guidance describes two different options:

r Option

r

I: Exposure to a single lamp light source with output similar to D65 (international standard for outdoor daylight) or ID65 (equivalent indoor indirect daylight standard, window glass filtered). It is suggested that light below 320 nm be filtered out. Option II: Exposure to two lamps that combined cover the requisite exposure wavelengths: a “cool white” fluorescent lamp conforming to ISO 10977 and a near UV fluorescent lamp with output from 320 to 400 nm and having an

Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

Typical Illuminance Values

Illuminance (lux) 120,000 110,000 20,000 10,000–25,000 3000 <200 400 40 <1

Example Brightest sunlight Bright sunlight Shade illuminated by entire clear blue sky, mid-day Typical overcast day, mid-day Winter day with cloudy sky Extreme of darkest storm clouds, mid-day Sunrise or sunset on a clear day (ambient illumination) Fully overcast, sunset/sunrise Extreme of darkest storm clouds

emission maximum in the 350–370 nm range. These may either be used simultaneously or in sequence.

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Xenon Lamp Emission with D65 or ID65 Filters 4.0E–01 3.5E–01 3.0E–01 2.5E–01 2.0E–01 1.5E–01

D65 filter (outdoor sunlight simulation)

1.0E–01 5.0E–02

ID65 filter (sunlight filtered through window glass simulation)

0.0E+00

300

350

400

450

500

550

600

650

700

750

800

– 5.0E–02

Wavelength (nm) Figure 1. Spectral irradiance for the Atlas Suntest Photochamber for filtered sunlight (D65) and window-filtered sunlight (ID65)21 showing the primary change in the irradiance occurs between 300 and 350 nm resulting from the glass absorption of light in this wavelength region.

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Relative Spectral Power Distributions of Representative Fluorescent Lamps 80

120 100

Relative spectral power D (%)

2270 W-h/m2 .20 Assuming that 6.8% of the radiation is in the region of 295–400 nm (based on Ref. 21, Table 5), which is considered worst case, this corresponds to an average daily UV irradiance of 358 and 154 W-h/m2 , 295–400 nm, in Miami and Oslo, respectively. The spectral power distribution for D6522 (Fig. 1) corresponds roughly to a mid-day, mid-summer sun, in Western/ Northern Europe (color temperature 6500 K) and is tabulated in 5 nm increments from 300 to 830 nm.5 Window-filtered indirect daylight (ID65, Fig. 1) represents the spectrum of sunlight that is transmitted through standard window glass, wherein lower, more energetic wavelengths of UVB radiation (i.e., <350 nm) are cut off. As the thickness of window glass increases, the cut off shifts toward progressively longer wavelengths. Products could be exposed to a significant level of sunlight in use if they are stored/administered near a window. The distance of penetration of sunlight into a building is dependent on the elevation and angle of the sun relative to the window; thus, light often penetrates further into a building during the winter than in the summer, even though the light intensity just inside the window may be lower. Artificial light sources can vary both in spectral power distribution and illuminance (see Fig. 2 for examples23 owing to a number of factors, such as: lamp type, lamp size, lamp shape, number of lamps employed, housing or other shading/diffusing elements associated with the lamp, and distance/angle of the object from the light source. As a result, it is a complex task to understand the quantitative implications of the variety of light sources and conditions on the photostability of pharmaceutical products in use. Given the impracticality of covering all scenarios, one approach would be to use, as a general guide, the illuminance values recommended by the Illuminating Engineering Society of North America (IESNA) for architectural design.14(chapter 4) Although one cannot guarantee that a product would not be exposed to substantially more light than advocated by IESNA, particularly if the product is stored/administered close to the light source (e.g., if the sample is stored on a high shelf near a light fixture), it represents a useful benchmark for making decisions related to in-use pharmaceutical product photostability. For cases of ex-

80

70

D65 F2

60 40 20

60

0

300

400

500

600

700

800

Wavelength (nm)

50

F2 F7 F11

40 30 20 10 0 380

430

480

530

580

630

680

730

780

Wavelength (nm)

Figure 2. Relative spectral power distributions of various representative fluorescent lamps plotted from published CIE data. F2 represents a cool white fluorescent source that is compliant with ICH Q1B option II; F7 represents a typical “broad band” fluorescent source; and F11 represents a tri phosphor or three band cool white fluorescent source. The inset shows the spectral power distribution of one source (F2) relative to daylight (D65).

treme product photosensitivity, additional precautions might be warranted. Table 2 is an adaptation of information from the IESNA Handbook14(chapters21–34) describing recommended illuminance levels for many common environments, including detailed recommendations for settings such as health care facilities, residences, and retail locations. These values are derived from studies assessing how well the light supports the visual activities common to each setting and take into consideration the age of observers. Other factors that impact lighting levels are subjective and include not only visibility but also mood and atmosphere, visual comfort, aesthetic judgment, health, safety, local building regulations, social norms14(chapter 4) , as well as energy efficiency objectives. As one can see from Table 2, the Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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Table 2. Recommended Illuminance Targets from IESNA Along with Age Considerations, Typical Applications, and Visual Performance Description Lux For Median Age of Observers (in Years) IESNA Category

<25

25–65

>65

A

0.5

1

2

H

10

20

40

K

25

59

100

O

100

200

400

R

250

500

U

750

1500

Y

5000

10,000

Table 3. Light

Applications • • • • • • • • • •

• • • • 3000 • • • 20,000 • 1000

Visual Performance Description

• Orientation, relatively large scale, physical Dark adapted situations (less cognitive tasks) Basic convenience situations Very low-paced activities Moderate- to fast-paced situations • Visual performance is typically not work related, High-density situations but related to dark sedentary social situations Typical indoor very subdued circulation situations Typical indoor social situations Typical outdoor commerce situations • Common social activity and large- and/or high-contrast tasks Indoor social situations • Visual performance involves higher-level Indoor commerce situations assessment of surroundings, can be work related • Common, relatively small-scale, more cognitive, Typical indoor education situations or fast-performance visual tasks Other indoor commerce situations • Daily life and work related Typical indoor sports situations Typical indoor industrial situations Typical sports situations • Small-scale, cognitive visual tasks Other indoor commerce situations • Work or sports related, close fine inspection, Other typical indoor industrial situations very small detail Typical health care procedural situations • Unusual, extremely minute, and/or life-sustaining cognitive tasks • Visual performance is of the highest order

In-Use Photostability Categorization of Drug Products Intended for Injection by Product Form and Packaging Protection Offered to

Formulation Type Solution or dispersion

Product Form Concentrate

Clear viala , amber viala , clear syringe, or amber syringe

Secondary Packaging Required for Light Protection?

Relevant Product Presentation

Removal from package After dilution in diluent During administration

In vial or syringe

No

After dilution in diluent During administration Removal from package During administration During administration

In diluent, IV bag

Removal from package After dilution in diluent During administration After dilution in diluent During administration Removal from package After reconstitution in diluent After dilution in diluent During administration After reconstitution in diluent After dilution in diluent During administration

In vial

Yes

Ready for use after Clear viala , amber reconstitution viala

Yes

No

No

Clear viala , amber Requires further dilution prior to viala administration

Initiation of the In-Use Product Period

Yes

Clear viala , amber viala , clear syringe, amber syringe, or clear bag

Ready for use

Lyo for reconstitution

Primary Packaging

Yes

No

Vial or bag In diluent, IV bag

In diluent

In vial

In diluent, IV bag

a Ideally made from borosilicate glass and complying with USP or Ph Eur specification for Type I glass containers for pharmaceutical use. Such containers also comply with JP requirements.

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Table 4. Recommended Light Protection (X) of Active Pharmaceutical Ingredients Intended for Infusion or Parenteral Administration After Reconstitution (Including Injections That are Regularly Diluted Prior to Administration) Active Pharmaceutical Ingredient Alteplase Amphotericin B Anileridine Argatroban Ascorbic acid Atenolol Atracurium besylate Aurothioglucose Azaperone Bevacizumab Biperiden lactate Bleomycin sulfate Brompheniramine maleate Bumetanide Buprenorphine HCl Butorphanol tartrate Calcitriol Carboplatin Cefalotin Na Cefepime Ceftazidime Ceftriaxone Na Cefuroxime Na Chlordiazepoxide HCl Chlorpheniramine maleate Chlorpromazine HCl Ciprofloxacin lactate Cisplatin Cladribine Cloprostenol Cloxacillin Na Codeine phosphate Colchicine Cyanocobalamin Cytarabine Dacarbazine Dantrolene Na Daunorubicin HCl Desoxycorticosterone acetate Desoxycorticosterone pivalate Diatrizoate meglumine Diatrizoate Na Diazepam Diazoxide Dibucaine HCl Diethylstilbestrol Digitoxin Dihydroergotamine mesylate Diphenhydramine HCl Dipyridamole Docetaxel Doxorubicin HCl Dyphylline Emetine HCl Epinephrine tartrate

Formulation

Immediate Container

Light Protection of Formulation

Light Protection of Ready-to-Use Preparation

Sourcea

Powder for infusion Concentrate for infusion Injection Concentrate for infusion Injection Injection Injection Injectable suspension Injection Concentrate for infusion Injection Powder for infusion Injection

Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial

X X X X X X X X X X X X

B B A B A A A, B A A B A B A

Injection Injection Injection Injection Concentrate for infusion Powder for infusion Powder for injection Powder for infusion Powder for infusion Powder for injection Injection Injection

Glass vial Ampoule Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial

X X X X X X X X X X X X

A B A A A, B B A A, B B B A A

Injection Infusion Concentrate for infusion Concentrate for infusion Injection Powder for infusion Injection Injection Injection Powder for injection/infusion Infusion Injection Powder for injection/infusion Injection Powder for infusion Injection

Glass vial Infusion bag Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Brown glass vial Plastic flask Glass vial Brown glass vial Glass vial Glass vial Glass vial

X X X X X

X

A B A, B B A, B B A A A B B A B A A, B A

Injectable suspension

Glass vial

X

A

Injection Injection Injection Injection Injection Injection Injection Injection

Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial

X X X X X X X X

A A A A A A A A

Injection Injection Concentrate for infusion Concentrate for infusion Injection Injection Injection

Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass ampoule

X X X X X X X

A A B A, B A A B

X

X

X NO X

X X X X X X X X

X X

X

Continued DOI 10.1002/jps.23717

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Table 4.

Continued

Active Pharmaceutical Ingredient Epirubicin HCl Epoprostenol Na Eptifibatide Estradiol cypionate Etoposide Fentanyl citrate Floxuridine Fluorouracil Flupentixol decanoate Fluphenazine HCl Folic Acid Furosemide Gallamine triethiodide Haloperidol Histamine phosphate Human albumin Hydroxocobalamin Hydroxyzine HCl Imiglucerase Immunoglobulin, human Indigotindisulfonate Na Iodipamide meglumine Iophendylate Iopromide Iothalamate Na Ioversol Ioxilan Irinotecan HCl Isoflupredone acetate Isoproterenol HCl Ketamine HCl Labetalol HCl Leucovorin Ca Levomepromazine HCl Linezolid Lorazepam Mepivacaine HCl Metaraminol bitartrate Methadone HCl Methotrexate Metoclopramide HCl Metoprolol tartrate Metronidazole benzoate Metronidazole Midazolam HCl Mitomycin Morphine HCl Naloxone HCl Nandrolone decanoate Natalizumab Neostigmine methylsulfate Nimodipine Norepinephrine bitartrate Ofloxacin HCl Olanzapine Ondansetron Ondansetron HCl Orphenadrine citrate Oxaliplatin

Formulation

Immediate Container

Light Protection of Formulation

Light Protection of Ready-to-Use Preparation X X NO

Sourcea

Injection Powder for infusion Concentrate for infusion Injection Concentrate for infusion Injection Injection Injection Injection Injection Injection Injection Injection Injection Injection Infusion Injection Injection Powder for infusion Infusion

Glass vial Glass vial Glass vial Glass vial Glass vial Glass ampoule Glass vial Glass vial Glass ampoule Glass vial Glass vial Glass vial/ampoule Glass vial Coloured glass ampoule Glass vial Glass flask Glass vial/ampoule Glass vial Glass vial Glass vial

X X X X X X X X X X X X X X X X X X X

B B B A B B A A, B B A A A, B A A, B A B A, B A B B

Injection Injection Injection Infusion Injection Injection/infusion Injection Concentrate for infusion Injectable suspension Injection Injection Injection Injection Injection Infusion Injection Injection Injection Injection Concentrate for infusion Concentrate for infusion Injection Infusion Injection/infusion Infusion Injection Injection Injection Injection Concentrate for infusion Injection

Glass vial Glass vial Glass vial Glass vial, ampoule, or flask Glass vial Glass vial/flask Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial/ampoule Glass vial Glass ampoule Infusion bag Glass vial Glass ampoule Glass vial Glass vial Glass vial Glass ampoule Glass vial Infusion bag Glass or plastic vial, bag, or flask Glass or plastic ampoule Glass vial Glass vial or plastic ampoule Glass vial/ampoule Glass vial Glass vial Glass vial/ampoule

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

A A A A, B A A, B A B A A B A, B A B B A B A A A, B B A B A, B B A A, B A, B A B A, B

Infusion Injection

Brown glass vial Glass vial

X X

B A

Infusion Powder for infusion Injection Injection Injection Concentrate for infusion

Glass flask Glass vial Glass vial/ampoule Ampoule Glass vial Glass vial

X X X X X X

B B A, B B A B

X

Continued Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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Table 4.

Continued

Active Pharmaceutical Ingredient

Formulation

Immediate Container

Light Protection of Formulation

Light Protection of Ready-to-Use Preparation

Sourcea

Oxymorphone HCl Oxytetracycline Paclitaxel Paracetamol Perphenazine Phenylbutazone Phenytoin Na Physostigmine salicylate Phytonadione Piperacillin and tazobactam Piperacillin Na and tazobactam Na Plicamycin Promazine HCl Propofol Pyridostigmine HBr Raltitrexed Rasburicase Remifentanil HCl Rituximab Sufentanil citrate Sulfamethoxazole and trimethoprim Tacrolimus Testosterone cypionate Tetracaine HCl in dextrose Tetracycline HCl Tirofibran HCl

Injection Injection Concentrate for infusion Infusion Injection Injection Injection Injection

Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial Glass vial

X X X X X X X X

A A B B A A A A

Injectable emulsion Injection

Glass vial Glass vial

X X

A A

Powder for infusion

Glass vial

X

B

Injection Injection Infusion Injection Powder for infusion Powder for infusion Powder for infusion Concentrate for infusion Injection Injection

Glass vial Glass vial Glass vial or ampoule Glass vial Glass vial Glass vial or ampoule Glass vial Glass vial Glass ampoule Glass vial

X X X X X X X X X X

A A B A B B B B B A

Concentrate for infusion Injection Injection

Glass ampoule Glass vial Glass vial

X X X

B A A

Injection Concentration or infusion

X X

A B

Topotecan HCl Trifluoperazine HCl Triflupromazine HCl Vancomycin HCl Verapamil HCl Verteporfin Vinorelbine tartrate Warfarin Na Zidovudine Ziprasidone HCl

Concentrate for infusion Injection Injection Powder for infusion Injection Powder for infusion Concentrate for infusion Injection Injection Powder for injection

Glass vial Glass vial or polyethylene infusion bag Glass vial Glass vial Glass vial Glass vial Glass ampoule or vial Glass vial Glass vial Glass vial Glass vial Glass vial

X X X X X X X X X X

B A A B A A, B A, B A A B

X

a

Source is either: (A) United States Pharmacopeia 36, National Formulary 31; or: (B) the Norwegian Medicines Agency. Summary of product characteristics.33 NO, light protection not necessary.

illumination levels recommended vary substantially, with higher illuminance recommended as more detailed and critical tasks are performed. Importantly, illuminance values of up to 20,000 lux are recommended for some health care procedural situations, an area of direct relevance to in-use pharmaceutical product photostability. Actual measurements from four Philadelphia hospital emergency rooms found that illuminance levels (emanating from low-pressure mercury cool white fluorescent bulbs) varied from 300 to 2000 lux.24 The values in Table 2 represent only a reference point as it pertains to the amount of illuminance that might be observed during inuse scenarios and purposely do not take into consideration the wide range of lighting that might occur in individual settings. In addition, the quoted illuminance values, by definition, consider only the visible portion of the light and do not include the DOI 10.1002/jps.23717

UV portion, especially UVA, which may of course be the most relevant portion of the spectrum in terms of photostability. In the following section, we will consider how the implications of product light exposure translate to photostability testing approaches and risk mitigation.

CONSIDERATIONS FOR IN-USE PHOTOSTABILITY TESTING OF DRUG PRODUCTS ADMINISTERED BY INJECTION Administration of injectable pharmaceutical products comprises a number of presentations and administration routes, each with implications for the possible extent and duration of light exposure. For example, it is clear that the risk of light exposure is substantially lower for (1), a bolus injection prepared Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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Table 5.

Light Exposure, Hold Times, and Recommended Testing Conditions for Drug Products Intended for Injection

Light Source(s) Indoor artificial lighting

Product Location or Time of Day

Typical Light Intensity

Relevant Product Presentation

Typical Hold or In-Use Times (h)

Realistic Worst-Case Light Exposurea (lux h)

Recommended Photostability Testing Approach

Home

400–1000 lux (visible)a

Vial, bag, or syringe after removal from carton

4

4000

Cool white fluoresesent as per ICH Option 2b

Vial, bag, or syringe after dilution in diluent Bag or syringe during product administration Vial, bag, or syringe after removal from carton

12

12,000

24

24,000

4

40,000

12

120,000

24

240,000

Clinic

400–10,000 lux (visible)a

Vial, bag, or syringe after dilution in diluent Bag or syringe during product administration Indoor lighting with windowfiltered daylight

Home

Clinic

Outdoor lighting

Average location on earth and worst-case time during day

400–1000 lux (visible), 17 W/m2 (UVA)c

Vial, bag, or syringe after removal from carton

4

4000 lux h, 70 W-h/m2

12

12,000 lux h, 200 W-h/m2

24

24,000 lux h, 200 W-h/m2

400–10,000 lux (visible), 17 W/m2 (UVA)c

Vial, bag, or syringe after dilution in diluent Bag or syringe during product administration Vial, bag, or syringe after removal from carton Vial, bag, or syringe after dilution in diluent Bag or syringe during product administration

4

40,000 lux h, 70 W-h/m2

12

120,000 lux h, 200 W-h/m2

24

240,000 lux h, 200 W-h/m2

1

100,000 lux h, 60 W-h/m2

2

200,000 lux h, 120 W-h/m2

4

400,000 lux h, 240 W-h/m2

100,000 lux (visible), 60 W/m2 (UVA)d

Vial, bag, or syringe after removal from carton Vial, bag, or syringe after dilution in diluent Bag or syringe during product administration

Cool white fluoresesent as per ICH Option 2b

ICH Option 1 or Option 2

ICH Option 1 or Option 2

ICH Option 1 recommended

a Artificial lighting lamps produce limited emission in the UV with typical intensity of 0.1–0.3 W/m2 at 1000 lux and this should be factored for products with severe sensitivity to UV light. Option 1 could also be used but the UV intensity delivered will be far higher than using Option 2. Filters could be employed with Option 1 to attenuate the UV exposure received. b Visible light exposure only. c UV light exposure calculation based on ICH Q1B guidance approach of 200 W-h/m2 (300–400 nm) equivalence to 1 to 2 days of window-filtered UV light exposure. Assuming 1 day corresponds to 12 h of daylight, and 1 day corresponds to a UV light exposure of 200 W-h/m2 , an intensity of 16.7 W/m2 is calculated. d Value based on measured data from the Eppley Total UV Radiometer, Miami, FLA July 24, 1996 (the clearest, highest UV day in 1996), the UV dose recorded (295–400 nm) for the entire day was 473 W-h/m2 ; between 10 am and 2 pm the total was approximately 245 W-h/m2 . Information provided by Atlas Material Testing Technology, LLC, 4114 N. Ravenswood Avenue, Chicago, Illinois 60613.

by reconstitution from a solid supplied in a crimp capped vial within a cardboard outer (secondary) package at the patients bed side than for (2), a solution in a large volume parenteral injected via a slow infusion using a narrow bore/high surface

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area transfer line into a vein over many hours. In addition, some products may be ready to use, whereas others may require significant manual manipulation and preparation in a local pharmacy prior to administration.

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Prior to the pharmacy preparation and administration step, it is assumed that the pharmaceutical manufacturer has considered implications of API (Active Pharmaceutical Ingredient) and formulation photostability to ensure that undesirable changes do not take place during the various process steps, including manufacturing, filling, primary packaging, labeling, and testing. The concept of a “light budget” to account for light exposure in these settings has been discussed in the literature.25 When removed from the custody of the pharmaceutical manufacturer, a wide diversity in light exposure conditions can result, as described in Section Relevant Light Sources to Consider for Evaluating In-Use Photostability. The sequential steps in the supply chain that leads from pharmaceutical manufacturer through drug administration are as follows. At each step the potential light exposure risk should be considered: 1. Secondary (or light protective) packaging and/or labeling activities. 2. Shipment from pharmaceutical manufacturer to various geographically distributed warehouse locations. 3. Shipment to mail order pharmaceutical distribution center, hospital pharmacy, or commercial pharmacy. 4. Distribution to storage shelves in original primary or secondary packaging to be staged for distribution. 5. Product distribution to the administering health care professional or in some limited cases to patients, for administration. 6. Dilution or reconstitution (and associated hold times) followed by product administration. This may include reconstitution, admixture, or other manipulations in a central pharmacy location or hospital ward, followed by storage either frozen or at room temperature and/or distribution to one or more locations within the hospital. During step 1, procedures can be put in place to effectively control light exposure, whereas during step 2, the product is typically contained in light-resistant secondary packaging such as a cardboard box. Product light exposure for steps 1 and 2 of the supply chain can therefore usually be considered either negligible or controllable by the manufacturer. In steps 3 and 4, the product is stored on the shelves within a pharmacy setting until usage. The product may be stored in original secondary packaging or may be stored in vial or bag primary packaging until use. Professional organizations such as the American Pharmacists Association (APhA) have published specific guidance to assist pharmacists in ensuring that the repackaged product is protected from light.26 Importantly, the ICH Q1B photostability guideline is intended to cover steps 1– 4, unless repackaging occurs. If repackaging is performed, care should be taken to ensure that the light-protective properties of the new package configuration are equal to, or greater than, the original package. In some cases, secondary packaging may be required for adequate light protection and precautionary labeling should indicate whether this is the case. In steps 5 and 6, the product is now in the hands of the health care professional, and there are a number of important considerations for the in-use photostability of injectable drug products. The dispensing pharmacist has the responsibility for understanding photostability implications and conveying this important information to health care providers at DOI 10.1002/jps.23717

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the point of distribution. The formal labeling requirements for photosensitive drug substances and drug products are not uniform and are established by regional and/or national regulatory authorities.10,27 When present, the label verbiage can be ambiguous and lacking in detail. Further details and instruction beyond “Protect from Light” may be needed for photosensitive parenteral drugs to ensure that the patient or health care provider can properly handle the drug product and thus avoid undesired change during preparation and administration. A special case to consider is that of large volume parenterals that are shipped from the pharmacy to the clinical setting without secondary packaging. Table 3 tabulates the major types of injectable formulations and provides guidance concerning the appropriate presentation of the formulation to test. If the primary package provides adequate protection from light, then the in-use period commences either when a manipulation is undertaken (e.g., a dilution is made) or the product is administered to the patient (whichever is the earliest). On the other hand, if sufficient protection is not afforded by the primary package, then the in-use period commences as soon as the product is removed from the lightprotective secondary package (e.g., a carton) and continues until completion of the product administration. Identifying the “initiation of the in-use product period” allows one to identify the “relevant product presentation” for photostability testing. It is important to generate specific photostability information for each relevant product presentation and product concentration of a particular compound; however, it may be possible to reduce testing based on a sufficiently detailed knowledge of the influences on the photostability behavior of the product. In the case where there is a strong understanding of the causative wavelengths that drive photochemistry, the presentation that is predicted to be most vulnerable to photodegradation could, for example, be tested; if this presentation has adequate stability, then stability of other similar presentations may be inferred. One example of how to identify the initiation of the in-use period, and the formulation presentations to consider, is Dacarbazine for injection, USP, which is indicated for the treatment of metastatic malignant melanoma, or Hodgkin’s disease. Dacarbazine is commercially supplied as a lyophile that requires reconstitution in sterile water for injection (WFI). The reconstituted solution may be further diluted with 5% dextrose or 0.9% sodium chloride solution for injection and administered as an intravenous infusion. Two primary packaging configurations are available for this product: one consists of 10 individual 20 mL vials in a box that is labeled “protect from light” and the other consists of a single vial in an individual carton, also labeled “protect from light”. Both the reconstituted solution and solution for infusion require refrigeration and protection from light during storage because of the thermal and photolability of the API. The initiation of the in-use period starts at the removal of the vial from the individual carton, and continues through until administration, including the initial reconstituted solution and final further diluted solution for infusion. As a second example, carboplatin injection is a chemotherapeutic agent, which is supplied as a sterile, ready-to-use, 10 mg/mL aqueous solution in multidose vials with controlled room temperature and “protect from light” storage conditions. Each vial is provided in an individual secondary cardboard package that indicates “protect from light”. The 10-mg/mL carboplatin solution can be further diluted to as low as 0.5 mg/mL Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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solution in 5% dextrose or in 0.9% sodium chloride injection, USP. The recommended storage condition for the diluted carboplatin solution is 8 h at room temperature (25◦ C) with no additional comments pertaining to in-use photostability. Again, the initiation of the in-use period begins with removal of the drug product from the secondary package. Consideration of exposure to light for the vial once removed from the pack includes its multidose use, and the effect of significant dilution in 5% dextrose or 0.9% saline for up to 8 h. Table 4 provides further examples of injectable products with known photolability. Even if the API alone is photostable, this does not mean that injectable formulations will be. Several examples from the literature show that degradation in injectable formulations can be promoted by excipient components28,29 or impurities present in the diluent28,30–32 ; thus, predictions about drug product photostability based on an understanding of the photostability of the drug substance, or other drug product types, maybe misleading. For example, glucose and metabisulfite have been implicated in the photodegradation of drug products in solution. Similarly, iron impurities in citrate buffers have been observed to cause drug product photodegradation. Thus, if an API is formulated using an injection diluent that it has not been previously assessed with, it is important that the API in the formulated injection diluents be directly tested for photostability. All relevant formulations encountered in the pharmacy and during clinical practice should therefore be considered. It will probably not be sufficient to test only the commercial formulation. When translating photostability data into an in-use shelf life, it is important to remember that information about the chemical stability of the formulation may not be adequate alone. Physical effects, such as, viscosity changes, appearance effects (such as a change of color), precipitation from solution, nonhomogeneity of a suspension, embrittlement of the container, and so on, must be taken into account. Similarly, it is also important to take into account the presence and level of any photodegradation product that may have a marked toxic effect.

SUMMARY OF RECOMMENDED PHOTOSTABILITY TESTING CONDITIONS Table 5 combines the data presented in Tables 2 and 3 and the ICH option light sources into recommendations for some realistic “worst case” photoexposure scenarios in various in-use environments to ensure that the majority of administration situations will be covered by the testing. Table 5 contains the broadest light source category to which the product will be exposed, the likely location, the typical light intensities in those locations, and typical hold times. This information is used to determine the realistic worst-case light exposure conditions for each product type that can be used to provide recommended light sources for mimicking the exposure conditions in a laboratory test. The user should move step wise from the left of the table identifying the most likely condition to which the sample will be exposed in use and then expose the relevant product presentation (Table 3) to the “Realistic Worst Case Light Exposure” using the “Recommended Photostability Testing Approach” provided in Table 5. The data obtained from these experiments can be used to derive cautionary label and/or instructions to ensure that product integrity is maintained during preparation for administration and during dosing. The conditions chosen Baertschi et al., JOURNAL OF PHARMACEUTICAL SCIENCES

in Table 5 will cover the majority of conditions that will be encountered. For example, exposure to indoor lighting with or without window-filtered daylight could happen in either home or clinical settings. Although injectable products are used predominantly in clinical settings, the use of such products in home settings has increased as a result of an increasingly aging population, escalating costs for clinical treatment, and more prominent availability of home health care providers and domiciliary care regimens. A notable example is the treatment regimen for some types of diabetes that require regular insulin injections. The outdoor usage of injectable products, while uncommon, does occur. In some cases, ambulatory patients bring their infusion bags outdoor, hanging unprotected in the direct sunlight. Given the intensity of outdoor lighting and presence of high energy wavelengths, it is particularly critical to perform relevant in-use photostability testing for products that might be employed in an outdoor setting. For example, the absorption spectrum of 5-hydroxymethyl furfural (a photosensitizing impurity in glucose-containing infusions) has its maximum in the UVB (280–320 nm), and thus has been shown to be of concern for the photostability of products exposed to outdoor lighting.32 For outdoor lighting, the most important considerations are geographic location on the earth and time of day, as these two variables can play a major role in the amount of sunlight that impinges on the product. The typical lighting intensities for indoor artificial, home, clinical, and outdoor lighting environments are identified in Table 3 and represent reasonable estimates of lighting in each area per literature references. In addition, as discussed in the prior section, consideration of the light protection of the primary and secondary packaging, preparation steps performed in the pharmacy, hold times prior to dosing, storage temperatures prior to use, and the time of administration allows one to define the worst-case light exposure that would be required to evaluate the overall impact on the product quality. This worst case should be the guiding quantity for consideration in recommended photostability testing conditions. For injectable drugs whose use extends to emergency or surgical settings, additional testing with more intense light sources representative of those conditions is also needed.

DISCUSSION AND CONCLUSIONS Photostability testing should be conducted to ensure the safety and efficacy of injectable pharmaceutical products during the time course of use. In this manuscript, we have provided some guidance concerning how to design and conduct a suitable test. The first task is to understand when the in-use photoexposure begins and ends so that an appropriate photostability test can be designed to mimic such exposure. Often, the course of use starts with removal of the product from secondary packaging and ends with the completion of administration in the relevant in-use product configurations. Table 3 provides guidance in this area. Table 5 takes the product configuration understanding from Table 3 and combines this with information about product location to arrive at proposed photostability testing conditions. Subjecting the product to testing as described in Table 5 should be a good starting point in developing an understanding of the overall in-use photostability risks. Understanding the effect(s) that light exposure has on product performance and safety allows for a mitigation plan to be developed and implemented. DOI 10.1002/jps.23717

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A risk identification/risk mitigation exercise34 should form the basis for analyzing control of undesired photoexposure during use. For every major photostability risk identified, an appropriate risk mitigation strategy should be put in place. This could be the inclusion of label language, protective detailed instructions, or inclusion of protective materials (e.g., light-protective colored sleeves) as part of the product kit to ensure successful product usage. Particular attention should be paid to the points during this handling chain when the product is most vulnerable to photolysis. Owing to the timeframes required for administration of some products, often resulting in prolonged exposure to light in the clinical setting, it is important to have established criteria for managing the in-use photostability concerns associated with photosensitive parenteral products. If the product does display loss of quality upon exposure to light, one mitigation strategy with respect to light exposure would be to minimize the overall cycle time from removal from protective packaging to conclusion of the administration step. In the case of photosensitive products where the secondary package is integral to the light protection system, labeling should indicate the importance of the product being retained in the packaging whenever possible. Upon reconstitution or dilution and during hold periods prior to administration, consideration of light protection is required (e.g., return to light protective packaging or keep in the dark) until needed for administration. Upon administration, the use of protective measures such as placing a light-protective outer bag or sleeve (e.g., a colored, UV absorbing, or opaque cover) over the diluent bag and/or employing light-protective IV tubing that protects the product from light exposure during administration should be considered. Highly photosensitive parenteral products should contain, in a simple yet detailed manner, instructions that the administering healthcare practitioner can follow to ensure adequate product stability during the time course of administration. As discussed in Section Relevant Light Sources to Consider for Evaluating In-Use Photostability, clinical settings can employ intense light exposures to support detailed manipulations such as surgical procedures. As a result, it is even more critical that healthcare practitioners are made aware of potential issues with photosensitive parenteral products via correct labeling and instructions. Several points of labeling guidance can be derived from the cumulative data:

r If the product is not adequately protected within primary r

r

packaging, a label designation to store the product within secondary packaging should be indicated. If the product is subject to undesired change in the presence of appropriate lighting when reconstituted or diluted in qualified administration vehicles, guidance should be provided to ensure that time of exposure is kept as short as is reasonably practicable and/or to use protective tubing and containers (as necessary). For photosensitive parenteral products that could be subjected to intense lighting in clinical setting or even outdoor lighting for emergency use, appropriate testing should be conducted and precautions noted.

Greater awareness of the issues described in this guidance document should be considered for incorporation into current DOI 10.1002/jps.23717

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regulatory practice around photostability testing and labeling language. Another important aspect of risk mitigation is to ensure that appropriate education and awareness of product photostability issues are included in the product label. Furthermore, educational demonstrations for use of the product should be considered for pharmacists and healthcare personnel that are responsible for ensuring successful product administration. Taken together, this will ensure that labeling language and instructions are understood and can be followed correctly. Communication flow from pharmaceutical manufacturer to provider is an important aspect of successful practices utilized for in-use handling of photosensitive parenteral products. Finally, avenues for improved education should be incorporated as part of initial or continuing pharmacy education, particularly for those that work in alliance with the clinical setting.

ACKNOWLEDGMENT ¨ The authors would like to thank Dr. Oliver D. Rahauser of Atlas Material Testing Technology for valuable support regarding spectral outputs of lamps.

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