Policy Document 英国药典(吸入药章节) 2012年 9月 17日

BP Inhaled Products Working Party

Policy Document

This document contains recommendations on the content of British Pharmacopoeia (BP) monographs for inhalation. The recommendations are supported by rationale given immediately following the recommendation in italicised text.

Introduction

Inhaled products provide a number of peculiar and unique characteristics that make common specifications difficult. This is due to the variety of devices, accessories and formulations that can be used to deliver the active pharmaceutical ingredient (API). The efficient delivery of the API is also dependent on the operator’s (patient’s) ability to use the inhaler correctly as well as the inhaler dosage form.

Safety and efficacy are critical considerations; the Working Party has taken the view that the inhalation monographs would ensure products that are safe and efficacious by maintaining a standard set of quality tests which should be determined. These are defined within the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671). It is worth noting that the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671) makes reference to several other relevant general monographs, hence these are not listed specifically here, but are part of the overall policy recommendations.

Safety and efficacy are most affected by the delivered dose and fine particle dose. These quality tests are crucial in ensuring that the safety and efficacy of the inhaled product is maintained. Therefore, the quality tests must focus on the current best practices, especially with respect to test methodology. This last point underpins the recommendations. Removal of the opportunity for poor quality inhaled products reaching the British market is also seen as necessary. In order to ensure quality standards are up to date some older product monographs may need revision of their tests and limits.

Recommendations

1. Terminology should be aligned with the Ph. Eur. for the naming of inhalation dosage forms and test

methods.

a. Specific product monograph titles should use the relevant EDQM Standard Term for the dosage

form, with the BP legacy title included as a subsidiary title for revised monographs.

The naming of inhalation products and dosage forms would usefully be aligned with

EDQM (Ph. Eur.) Standard Terms. This would avoid the risk of confusion by both

manufacturers and competent authorities. This can be achieved by using the Ph. Eur.

Standard Term as the primary name and the current BP terminology as the subsidiary

title. This would ensure that older product titles are maintained within the BP as they are

now, but that harmonisation occurs and new monographs follow best practice.

b. Test method titles should use the relevant Ph. Eur. term in both the monographs and

Appendices.

This would remove the current inconsistencies, for example Preparations for inhalation:

aerodynamic assessment of fine particles (Ph. Eur.) versus Aerodynamic Assessment of

Fine Particles – Fine Particle Dose and Particle Size Distribution (BP).

2. The BP ‘Preparations for Inhalation of the British Pharmacopoeia’ general monograph and individual

inhalation product monographs should be aligned with the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671). The following specific points are highlighted to add clarity to specific BP tests that would be affected.

Alignment of BP monographs with the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671) provides the most appropriate quality attribute tests that can ensure safety and efficacy of inhaled products. Further, the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671) provides the current best practice test methodology that is well established. The Ph. Eur.

‘Preparations for Inhalation’ general monograph (0671) makes reference to several other relevant inhaled product monographs, hence these are not listed specifically here, but would form an

integral part of the overall alignment process with Ph. Eur. 0671.

Alignment would also provide clear guidance to manufacturers on the requirements that are

needed within a BP specific product monograph and remove ambiguity and inconsistencies

between the inhaled product monographs due to historical requirements and therefore progress harmonisation across the European marketplace. Further, it would give the BP a consistent

approach with other key pharmacopoeias, as the Ph. Eur. and United States Pharmacopeia

(USP) Aerosol [601] monograph are harmonised. This should not be an underestimated

advantage given the very global nature of inhaled product manufacturing. Also, other countries that apply the BP monographs to their marketed products would equally benefit by revision of the BP monographs.

By aligning the BP requirements with the Ph. Eur. ‘Preparations for Inhalation’ general

monograph (0671) an additional benefit would be harmonisation with the EMA Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products where it makes reference to the Ph.

Eur. quality tests.

a. The Aerodynamic Particle Size Distribution Test and Fine Particle Dose Test should be aligned

with Ph. Eur. ‘Preparations for inhalation: aerodynamic assessment of fine particles’test (2.9.18).

The particular test methodologies for aerodynamic particle size distribution and fine

particle dose should be updated to be consistent with the best practice and established

methods defined in Ph. Eur. monograph 2.9.18.

b. The requirement for the BP ‘Deposition of emitted dose’ test(defined as the Ph. Eur.

‘Preparations for inhalation: aerodynamic assessment of fine particles’ (2.9.18) apparatus A) should be replaced by the ‘Fine particle dose’ test in specific product monographs.

The BP ‘Deposition of the emitted dose’ test using the Ph. Eur. 2.9.18 apparatus A

(actually a twin stage impinger apparatus for determining aerodynamic particle size with

numerous parts) should be discontinued as it is no longer considered an appropriate

‘dose’ collection apparatus. The current methodology allows dose to be stated in a

number of ways, e.g. ‘metered’, ‘emitted’ or ‘pre-metered’, this inconsistency within the BP

monographs can then also be removed.

c. Specific product monographs should include a ‘Fine particle dose’ test. For new monographs a

test and limits will be included under the tests section. For existing monographs a test method will be provided under the production section with no limit. Products must be compliant with the manufacturer’s Marketing Authorisation (MA) specification for ‘Fine particle dose’.

As a quality test, the ‘fine particle dose’ should be specified as a requirement in each

inhaled product monograph. The significance of this test to safety and efficacy is critical,

the fine particle dose is very important when assessing dose proportionality of a product

‘strength’ range and may correlate or provide a relationship to the in vivo response.

Following stakeholder feedback inclusion of limits would be beneficial for new

monographs to act as a driver for product standardisation and to lead to enhancement of

generic products. There would be a further benefit to patients and prescribers, as this

would minimise any labelling misunderstanding.

It is difficult to add limits to existing products as multiple products have already been

approved and retrospective change is not likely to add value. Given these products are in

a mature lifecycle stage they are likely to be superseded, consequently the emphasis of

this policy is on new products.

d. The ‘Uniformity of delivered dose’ test should be aligned with the Ph. Eur. ‘Preparations for

Inhalation’ general monograph (0671). This will remove the BP requirement for ‘Content of active ingredient delivered by actuation of the valve’ from the ‘Preparations for Inhalation of the British Pharmacopoeia’ general monograph and ‘Uniformity of weight’ test from the specific product monographs.

The uniformity of delivered dose test within the Ph. Eur. ‘Preparations for Inhalation’

general monograph (0671) should be applied and the outdated BP test that collects the

emitted dose ex valve under solvent should be removed. The uniformity of delivered dose

test would include the limits as specified in the Ph. Eur. monograph (0671).

e. An Assay (content of active test) for all inhalation dosage forms is required.

Following the removal of ‘Content of active ingredient delivered by actuation of the valve’

test, an appropriate Assay test should be included in the monograph.

3. The dose (and its limits) should be stated in terms of the Delivered Dose.

The significance of collecting the delivered dose in an appropriate manner is that it closely

represents the way an inhaler would be used by a user and hence the dose received by the

patient. This would also link with the label claim which, in the next Ph. Eur. revision, will be

derived from the delivered dose.

4. Monograph templates for each category of preparation for inhalation that reflect the above policy are

provided and should be used as the basis to draft new BP monographs, Appendix A and to revise existing BP monographs, Appendix B.

It is proposed that a set of templates for the various inhaled dosage forms are prepared and

made available to provide an Aide Memoire to those Expert Advisory Groups (EAGs) developing new BP and revising existing BP inhaled product monographs. The templates will include the

standard features of a monograph for a formulated preparation as indicated in Supplementary Chapter III C. Monograph Development: Guidance to Manufacturers in addition to the formulation specific tests mentioned above. This will ensure a consistent approach across the EAGs. The use of templates will also aid adherence to these recommendations.

5. The BPC should advocate to the Ph. Eur. Commission that a general monograph providing

information for the testing of spacers, holding chambers and facemasks should be developed through the Pharmacopoeial Discussion Group (PDG) harmonisation process.

Many inhaled products also require the use of accessories to provide effective and safe drug

delivery to the patient, particularly for vulnerable groups in paediatric and geriatric patient

populations, e.g. inhaled steroids. These accessories include spacers, holding chambers and

facemasks. The presence and use of these accessories affect the delivered dose and fine

particle dose of the drug. Therefore, it is imperative that the drug delivery (delivered dose and fine particle dose) of inhaled products when used in conjunction with an accessory is determined.

Currently there is no pharmacopoeial guidance on the need to assess the product when used in conjunction with an accessory. Since there is a significant gap ensuring safety and efficacy of inhaled products the Working Party concludes that a monograph should be elaborated to provide test guidance. Consequently it is advised that a request should be made by the UK delegation to the European Pharmacopoeia Commission for elaboration of a monograph. It is noted that a

stimuli to revision has been published (Pharmacopoeial Forum 2011; 37 (4)) for comment in the USA. It is recommended that this process could become a harmonised activity through the PDG harmonisation programme.

6. The ‘Preparations for Inhalation of the British Pharmacopoeia’ general monograph to be reviewed

and revised as necessary for the BP 2014 and to be omitted from the BP 2015.

With the alignment to the Ph. Eur. ‘Preparations for Inhalation’ general monograph (0671) the

‘Preparations for Inhalation of the British Pharmacopoeia’ general monograph requirements

become obsolete. Therefore, it is recommended that this is revised to clarify the requirements and published in the BP 2014, and then subsequently omitted from the BP 2015. This would

specifically include removal of duplication of Ph. Eur. text and obsolete storage requirements for the BP 2014.

7. All BP inhalation product monographs should be reviewed and revised according to this policy. A BP

monograph revision programme is proposed, Table 1.

We recommend that the BPC initiates a revision programme for, 1) the ‘Preparations for

Inhalation of the British Pharmacopoeia’ general monograph and 2) all inhaled product

monographs, in line with the recommendations in this policy document.

The timing of the proposed revision programme is prioritised according to the importance of the products in the market place, the API and with some consideration to current EAG work plans and is shown in Table 1. The revision programme should also consider whether the published monographs are still required.

8. Inhalation product monographs developed following approval of this policy document should be

reviewed for compliance with the policy at a suitable period to be defined by the BPC. The process for this review should also be defined by the BPC.

This will ensure that all monographs are developed in a consistent style according to this policy and determine if revisions to the policy are required.

Appendix A – Draft New Monographs

1016075

British

[ACTIVE] Nebuliser [Solution/Suspension/Emulsion]{ XE \b "[ACTIVE] Nebuliser

[Solution/Suspension/Emulsion]"}

[ACTIVE] Preparations

Action and use

xxx.

Definition

[ACTIVE] Nebuliser [Solution/Suspension/Emulsion] is a [solution/suspension/emulsion] of [ACTIVE] in [a suitable vehicle/Water for Injections].

The nebuliser [solution/suspension/emulsion] complies with the requirements stated under Preparations for Inhalation and with the following requirements.

Production

The active substance delivery rate and the total active substance delivered are determined using the methods described in Appendix XII C. 8. Preparations for nebulisation: characterisation. Where justified and authorised, a different apparatus and procedure may be used.

Note: This is a copy/paste of the Ph Eur Production statement with the Ph Eur reference changed to BP reference. The particle-size distribution is determined using an apparatus and procedure described in general chapter Appendix XII C. 8. Preparations for nebulisation: characterisation. Where justified and authorised, a different apparatus and procedure may be used.

Note: This is a copy/paste of the Ph Eur Production statement with the Ph Eur reference changed to BP reference. Note for EAG: This statement should only be included for Nebuliser Solutions and Nebuliser Suspensions.

Content of [ACTIVE], C x H x O x

[x to x]% of the stated amount.

Identification

A. [IR/TLC/UV]

B. [Peak ID in HPLC method]

Tests

Acidity

pH, [3 to 10], Appendix V L.

Aerodynamic assessment of nebulised aerosols

Note for EAG: This test should only be included for Nebuliser Suspensions.

Carry out the test for aerodynamic assessment of nebulised aerosols, Appendix XII C. 8, determining the content of active ingredient as described below.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the mass of [ACTIVE, C x H x O x] collected using the declared content of [C x H x O x] in [ACTIVE BPCRS]. Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

LIMITS

xxx

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions, protected from light.

(1)

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [C x H x O x] in the nebuliser [suspension/solution/emulsion] using the declared content of [C x H x O x] in [ACTIVE BPCRS].

1016075

British

[ACTIVE] Powder for Nebuliser [Solution/ Suspension/Solution or Suspension]{ XE \b "[ACTIVE] Powder for Nebuliser [Solution/ Suspension/Solution or Suspension]"}

[ACTIVE] Preparations

Action and use

xxx.

Definition

[ACTIVE] Powder for Nebuliser [Solution/Suspension/Solution or Suspension] consists of [ACTIVE] with or without excipients. It is supplied in a sealed container.

The contents of the sealed container comply with the requirements stated under Preparations for Inhalation and with the following requirements.

Content of [ACTIVE], C x H x O x

x to x% of the stated amount.

Identification

A. [IR/TLC/UV]

B. [Peak ID in HPLC method]

Tests

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

LIMITS

xxx

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions, protected from light.

(1)

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [C x H x O x] in the container using the declared content of [C x H x O x] in [ACTIVE BPCRS].

8169

British

{[ACTIVE] Pressurised Inhalation{ XE \b "[ACTIVE] Pressurised Inhalation" }

[ACTIVE] Preparations

Action and use

xxx.

Definition

[ACTIVE] Pressurised Inhalation is a [solution/suspension/emulsion/solution, suspension or emulsion] of [ACTIVE] in a suitable liquid in a pressurised container fitted with a metering dose valve.

The pressurised inhalation complies with the requirements stated under Preparations for Inhalation and with the following requirements.

Production

The size of aerosol particles to be inhaled is controlled so that a consistent portion is deposited in the lung. The fine-particle characteristics of powders for inhalation are determined using the method described in Appendix XII C.

7. Preparations for inhalation: aerodynamic assessment of fine particles.

Note: this is a copy/paste of the Ph Eur Production statement with the Ph Eur references changed to BP references.

Content of [ACTIVE], C x H x O x

[95.0 to 105.0]% of the stated amount.

Identification

A. [IR/TLC/UV]

B. [Peak ID in HPLC method]

Tests

Uniformity of delivered dose

Complies with the requirements stated under Pressurised Metered-dose Preparations for Inhalation using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Collect single doses of the preparation being examined using the procedure described under Pressurised

Metered-dose Preparations for Inhalation, Uniformity of delivered dose and dissolve the collected dose in

sufficient [solvent] to produce a solution containing the equivalent of [target concentration]% w/v of

[ACTIVE].

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [ACTIVE, C x H x O x], per delivered dose using the declared content of [C x H x O x] in [ACTIVE BPCRS]. Repeat the procedure as described under Pressurised Metered-dose Preparations for Inhalation, Uniformity of delivered dose.

Fine particle dose

Carry out the test for aerodynamic assessment of fine particles, Appendix XII C. 7, using Apparatus C, D or E but determining the content of active ingredient as described below.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the amount of [ACTIVE, C x H x O x] per aliquot of solvent using the declared content of [C x H x O x] in [ACTIVE BPCRS]. The mass of the active substance less than 5μm is not less than [x]% of the delivered dose.

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

solution

(1) Test

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

LIMITS

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity () is not greater than the area of the principal peak in the chromatogram obtained with solution () (%);

the sum of the areas of any other secondary peaks is not greater than () times the principal peak in the chromatogram obtained with solution () (%).

Disregard any peak with an area less than () times the area of the principal peak in the chromatogram obtained with solution () (%).

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Prepare the sample in an appropriate manner and dissolve the sample in sufficient [solvent] to produce a

solution containing the equivalent of [target concentration]% w/v of [ACTIVE].

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [ACTIVE, C x H x O x], using the declared content of [C x H x O x] in [ACTIVE BPCRS].

8169

British

{[ACTIVE] Inhalation Powder { XE \b "[ACTIVE] Inhalation Powder" }

[ACTIVE] Preparations

Action and use

xxx.

Definition

[ACTIVE] Inhalation Powder consists of [ACTIVE] in microfine powder either alone or combined with a suitable carrier. It is administered by a dry-powder inhaler.

The inhalation powder complies with the requirements stated under Preparations for Inhalation and with the following requirements.

Production

7. Preparations for inhalation: aerodynamic assessment of fine particles.

Note: this is a copy/paste of the Ph Eur Production statement with the Ph Eur references changed to BP references.

Content of [ACTIVE], C x H x O x

[95.0 to 105.0]% of the stated amount.

Identification

A. [IR/TLC/UV]

B. [Peak ID in HPLC method]

Tests

Uniformity of delivered dose

Complies with the requirements stated under Inhalation Powders using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Collect single doses of the preparation being examined using the procedure described under Inhalation

Powders, Uniformity of delivered dose and dissolve the collected dose in sufficient [solvent] to produce a solution containing the equivalent of [target concentration]% w/v of [ACTIVE].

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [ACTIVE, C x H x O x], per delivered dose using the declared content of [C x H x O x] in [ACTIVE BPCRS]. Repeat the procedure as described for reservoir systems under Powders for Inhalation, Uniformity of delivered dose.

Fine particle dose

Carry out the test for aerodynamic assessment of fine particles, Appendix XII C. 7, using Apparatus C, D or E but determining the content of active ingredient as described below.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

solution

(1) Test

(2)

(3)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

LIMITS

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity () is not greater than the area of the principal peak in the chromatogram obtained with solution () (%);

the sum of the areas of any other secondary peaks is not greater than () times the principal peak in the chromatogram obtained with solution () (%).

Disregard any peak with an area less than () times the area of the principal peak in the chromatogram obtained with solution () (%).

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Prepare the sample in an appropriate manner and dissolve the sample in sufficient [solvent] to produce a

solution containing the equivalent of [target concentration]% w/v of [ACTIVE].

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [ACTIVE, C x H x O x], using the declared content of [C x H x O x] in [ACTIVE BPCRS].

8169

British

[ACTIVE] Inhalation Powder, hard capsule/[ACTIVE] Inhalation Powder, pre-dispensed{ XE \b "[ACTIVE] Inhalation Powder, hard capsule/[ACTIVE] Inhalation Powder, pre-dispensed" }

[ACTIVE] Preparations

Action and use

xxx.

Definition

[ACTIVE] Inhalation Powder, hard capsule consists of [ACTIVE] in microfine powder either alone or combined with a suitable carrier. The capsule is loaded into a dry-powder inhaler to generate an aerosol.

[ACTIVE] Inhalation Powder, pre-dispensed consists of [ACTIVE] in microfine powder either alone or combined with a suitable carrier. The [blister/disk/etc] is loaded into a dry-powder inhaler to generate an aerosol.

The [inhalation powder, hard capsule/inhalation powder, pre-dispensed] complies with the requirements stated under Preparations for Inhalation and with the following requirements.

Production

7. Preparations for inhalation: aerodynamic assessment of fine particles.

Note: this is a copy/paste of the Ph Eur Production statement with the Ph Eur references changed to BP references.

Content of [ACTIVE], C x H x O x

[95.0 to 105.0]% of the stated amount.

Identification

A. [IR/TLC/UV]

B. [Peak ID in HPLC method]

Tests

Uniformity of delivered dose

Complies with the requirements stated under Inhalation Powders using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Collect single doses of the preparation being examined using the procedure described under Inhalation

Powders, Uniformity of delivered dose and dissolve the collected dose in sufficient [solvent] to produce a solution containing the equivalent of [target concentration]% w/v of [ACTIVE].

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE

xxx

SYSTEM SUITABILITY

xxx

DETERMINATION OF CONTENT

Calculate the content of [ACTIVE, C x H x O x], per delivered dose using the declared content of [C x H x O x] in [ACTIVE BPCRS]. Repeat the procedure as described for pre-dispensed systems under Powders for Inhalation, Uniformity of delivered dose.

Fine particle dose

Carry out the test for aerodynamic assessment of fine particles, Appendix XII C. 7, using Apparatus C, D or E but determining the content of active ingredient as described below.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1)

(2)

CHROMATOGRAPHIC CONDITIONS

(a)

(b)

(c)

(d)

(e)

(f)

MOBILE PHASE