Quality Workshop

Copenhagen January 2012

Assessing
specifications:
API

1|

Lynda Paleshnuik | January 2012

Outline
Compendial versus in-house standards:
When compendial standard is claimed
When in-house standard is claimed
When compendial methods are used
When in-house methods are used but compendial
standard is claimed
2|

Lynda Paleshnuik | January 2012

Outline
Specific parameters in brief
Unnecessary tests in specifications
Exceptions to full testing (reduced testing, retesting,
skip testing)
Example specifications exercise
Review tips
3|

Lynda Paleshnuik | January 2012

Specifications
The set of criteria to which an API should
conform to be considered acceptable for its
intended use.
A list of tests, reference to analytical procedures,
and acceptance criteria (numerical limits, ranges
or other criteria)
Confirm the quality, rather than fully characterize,
the API
[ICH Q6A]
4|

Lynda Paleshnuik | January 2012

Officially recognized pharmacopoeia

PhInt, USP, BP, EP, JP are recognized standards in PQP

PhInt S2 available as CD-ROM or on-line

5|

Lynda Paleshnuik | January 2012

Compendial Standards
Other compendia which may be referenced for information:
WHO Index of pharmacopoeias (next page)
Korean Pharmacopoeia now added to the list of freely
available pharmacopoeia
(Argentina removed as was up for comment only.)

6|

Lynda Paleshnuik | January 2012

Pharmacopoeias With Free Access

Argentina

FamacopeaArgentina,8thEdition(Volume1,2,3,4),2010
[nolongerthecase]

Brazil
Croatia

FarmacopiaBrasileira,5thEdition,2010

HrvatskaFarmakopeja,2007

Japan
Slovak
Republic
WHO
7|

TheJapanesePharmacopoeia

CodexPharmaceuticusSlovacus
MMVII,2007

TheInternationalPharmacopoeia

Lynda Paleshnuik | January 2012

Validation, verification, equivalency, SST

(assay and purity methods)
Validation: full validation required for in-house methods
(impurities, assay, residual solvents), generally specificity,
linearity, accuracy, repeatability, intermediate precision, plus for
purity: LOD/LOQ.
Verification: required for most compendial methods
Equivalency: required for an in-house method, when
compendial standard is claimed
SST: part of methodology, parameters determined via
robustness; tested every time the method is run to ensure
adequate performance
8|

Lynda Paleshnuik | January 2012

When compendial standard is claimed

1. Generally, the monograph tests and limits should be adopted.
2. The monograph is the minimum standard; the authority can
impose additional requirements (e.g. ICH IT for individual
unspecified impurities)
3. All monograph methods, tests and limits need not be included
in specifications. (may use in-house methods, provide justification
for not including certain parameters)
But The product must comply with the monograph, if tested
(see equivalence testing).
9|

Lynda Paleshnuik | January 2012

When compendial standard is claimed

BP Official Standards and EP General Statements:
An article is not of pharmacopoeial quality unless it
meets all monograph requirements. However,
performance of all tests is not necessarily required to
assess compliance before release. Assurance of
pharmacopoeial quality may instead be obtained from
validation studies of the manufacturing process and
from IPCs.

10 |

Lynda Paleshnuik | January 2012

When in-house standard is claimed

1. Generally, the tightest available monograph limits for
assay and purity should be adopted (assay) or justified
(specified impurities).
Exception: monograph titration vs in-house HPLC
assay
as

11 |

Available monographs can still be used

as a general guideline for requirements

Lynda Paleshnuik | January 2012

When compendial methods are claimed

(purity and assay methods)
Ensure they have really adopted the method as is. If not:
Check the deviations against published accepted deviations:
USP <621> Chromatography
EP 2.2.46 Chromatographic separation techniques
Note that there are specific SST RSD limits for EP and USP
methods. If these methods are adopted, so should be the SST
requirements.

12 |

Lynda Paleshnuik | January 2012

When compendial methods are adopted

Full validation is not required, but verification data is required:
The compendial methods as published are typically validated
based on an API originating from a specific manufacturer.
Different sources of the same API can contain impurities and/or
degradation products that were not considered during the
development of the monograph. Therefore the monograph and
compendial method should be demonstrated suitable to control the
impurity profile of the API from the intended source(s).

13 |

Lynda Paleshnuik | January 2012

When compendial methods are adopted

(purity and assay)
Verification data:
Assay method: generally not required for API assay methods but
may require specificity if additional (to the monograph) impurities
are specified
Impurity method: full validation for any additional (to the
monograph) specified impurities. If there is no monograph limit
on individual unknowns (or it is higher than the IT/acceptable
limit), repeatability of the API at the limit for unknowns (or
LOQ of API) should be established.

14 |

Lynda Paleshnuik | January 2012

Compendial standard claimed,

but in-house method used
Full validation is required for an in-house purity/assay method.
In addition, if compendial standard is claimed, equivalence must
be demonstrated compared to the compendial method (assay:
assaying aliquots of the same samples using the two methods;
impurities: as above, spiking samples with specified impurities at
the limits)
If they can not demonstrate this, they may claim in-house standard
but not compendial standard
Note that a compendial method becomes an in-house method
when adjustments are made outside the allowable adjustments
15 |

Lynda Paleshnuik | January 2012

Specification Parameters
The solubility of the API is the most important API CQA.
For BCS low solubility APIs (DSV > 250 mL):
Polymorphism and particle size distribution are critical parameters,
and must be representative of the biolot characteristics.
Polymorphism should be investigated. If no data is found in a
literature search, the applicant should perform screening studies. If
polymorphism is a factor, a test is required in specs.
PSD limits (d10, d50, d90) are required in the API specs, based on
the results of the lot used in biostudies.

16 |

Lynda Paleshnuik | January 2012

Specification Parameters
Polymorphism
Q: A common oversight: polymorphism has been found to be a
critical parameter. The API specs include an XRD comparison to
reference standard (RS). What else needs to be considered for this
test to be sufficient?
A: Before the RS lot serves as reference for polymorphism, it
needs to be ascertained that the polymorphic form of the RS lot (or
at least the primary standard, against which in-house standards are
qualified) is the same as that of the lot in the biobatch.

17 |

Lynda Paleshnuik | January 2012

Specification Parameters
Assay and Related Compounds
Assay: may be tested using a non-specific method, e.g.
titration, but need to achieve overall specificity, e.g.
non-specific assay plus suitable impurity test.
Related compounds: need limits on specified (identified
and unidentified*), unspecified (individual unknowns)
and total impurities. Limits must be suitably qualified.
*specified unidentified = structurally unidentified. It is
identified in the specs by means of e.g. RT.
The specifications should have a key identifying
impurities.
18 |

Lynda Paleshnuik | January 2012

Specification parameters
Related compounds
Qualification of limits: adopt limit QT, or qualify:
If a limit refers to a significant metabolite, it is considered
qualified (confirm it is a metabolite, e.g. WHOPAR, EPAR,
SmPC).
Level used in safety studies and/or clinical studies (ICH Q3A)
Literature i.e. ORP limits for specified related compounds are
considered qualified; an unspecified/unknown limit in a
monograph is not qualified.
Limit is similar to levels found in unstressed innovator product.
19 |

Lynda Paleshnuik | January 2012

Specification Parameters
Residual Solvents
ICH Q3C limits are acceptable.
When EtOH, MeOH, toluene or acetone are used
(especially last two steps), benzene may be present
(often used as an azeotropic agent to remove water). A
limit should be included in specs (API or intermediate)
unless shown to be absent. In PQP, this may be
conditionally included in specs eg as a skip test, to be
re-established in case of (for e.g.) change in supplier.

20 |

Lynda Paleshnuik | January 2012

Specification Parameters
Identification
Identification should be specific to the API, i.e. should be
able to discriminate between compounds of closely
related structure (Q6A)
Identification tests in pharmacopoeia sometimes gives
clues as to whether polymorphism may be a factor for the
API (sample prep).

21 |

Lynda Paleshnuik | January 2012

Specification Parameters
Identification
Caution regarding pharmacopoeial identity testing:
First and second identification:
Second identification is intended only for pharmacies and only
under certain circumstances (API is fully traceable to a batch
certified to meet all other monograph requirements).
Issue: if 2nd id tests are allowed in specifications as the routine
tests for an API, when they do periodic/reduced testing where they
test a batch only for identification, they will be using non-specific
testing.

22 |

Lynda Paleshnuik | January 2012

Specification Parameters
Identification
When the API is present as a salt, the salt moiety must be included
in the specifications:
Example identity test: (e.g. abacavir (as sulfate) PhInt):
A 10 mg/ml solution yields reaction A described under2.1 General
identification tests, as characteristic of sulfates.
Example identity test: (e.g. bupropion HCl USP):
IDENTIFICATION TESTSGENERAL, CHLORIDE 191 :
Meets the requirements for the silver nitrate precipitate test
23 |

Lynda Paleshnuik | January 2012

Specification Parameters
Identification
The applicants API specifications for bupropion HCl dont
include the chloride identification. What to check for before
posing the question?
Check if specs include an assay of the salt.
Example content of chloride: Not less than 12.6% and not more
than 13.1% of chloride, calculated on the anhydrous basis
[Physical method, USP monograph].
Generally acceptable to have identification or assay.

24 |

Lynda Paleshnuik | January 2012

Minor Tests
ROI (USP)/Sulfated Ash (EP/BP):
The Residue on Ignition/Sulfated Ash test measures the amount
of residual substance (usually inorg imps in an org substance)
not volatilized from a sample when the sample is ignited in the
presence of sulfuric acid.
Not universally required, should be looked at case-by-case, e.g.
an inorganic reagent (e.g. NaBH4) was used to prepare the API
When required (above), compendial limits can be accepted
(usually 0.1%).
25 |

Lynda Paleshnuik | January 2012

Minor tests
Heavy Metals vs a specific test for a residual metal:
Substances that typically will respond to this test are lead,
mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper,
and molybdenum. But it is not specific to any of these metals.
In the case of environmental contamination through exposure to
reaction vessels etc, this risk exists for almost all API preparations
and every API specification should include a test for heavy metal
content, even if the monograph does not specify one.
Generally NMT 10 ppm (insoluble API) or 20 ppm (soluble API).
26 |

Lynda Paleshnuik | January 2012

Minor tests
Heavy Metals vs a specific test for a residual metal:
Where a specific metal is used in the manufacturing process (e.g.
as catalyst), EMA guidance on the control of metal residues of
specific metals should be followed
Note that ICH Q3D is also under development (now at step 1)
Special cases: organo tin compounds watch for this with
valsartan, losartan (tetrazole group)

27 |

Lynda Paleshnuik | January 2012

Minor tests
Water versus LOD
LOD is adequate to control class 3 residual solvents (if NMT
0.5%)
Water (KF) is specific to the determination of water.

28 |

Lynda Paleshnuik | January 2012

Unnecessary tests in specifications

Solubility critical to know this about the API, but not
necessary in specs
Characters or Characteristics items in a EP/BP monograph
appearance (description is an important parameter, but the
appearance need not be exactly as in the monograph)
e.g. solubility, decomposition point, odour, melting point
polymorphism may be stated for information only, e.g. it
shows polymorphism; whether a test is necessary depends
on API solubility
29 |

Lynda Paleshnuik | January 2012

Exceptions to full testing

Reduced testing test results taken from the API
manufacturers COA
Generally not accepted but there are situations where this may be
acceptable.

Retesting parameters
Skip testing
In all cases, the API should meet the full specifications if tested.
Note: specific tests may also be contracted out, but the contract
test site(s) must be GMP compliant
30 |

Lynda Paleshnuik | January 2012

Example specifications
See separate handout. Full result slides will be provided after
the workshop.

31 |

Lynda Paleshnuik | January 2012

Review tips
Focus review time on the important elements:
Low solubility APIs: PSD, polymorphism
All APIs: assay, purity, residual solvents
When reviewing method validation, the validation protocol is of
much less importance than the validation study results
Ensure the API specs you review for the dossier are those of the
FPP manufacturer (particularly when the API supplier and FPP
manufacturer are from the same corporate structure but different sites)

32 |

Lynda Paleshnuik | January 2012

Review tips
Updated specs should always be compared to the previous
version submitted, or at minimum the change history should be
reviewed. The result of the comparison must be in the
report, with a discussion of the acceptability of any solicited
and unsolicited changes.

33 |

Lynda Paleshnuik | January 2012

Thank you

34 |

Lynda Paleshnuik | January 2012