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A strategy to ensure product quality and consistency
Specifications are chosen to confirm the quality of the drug
substance rather than to establish full characterisation, and should focus on
those characteristics found to be useful, says J Ramnivas
Establishing specifications for active pharmaceutical ingredients
is a herculean task. If the drug substance is already in the relevant pharmacopoeia,
there is no problem in setting the specifications. Otherwise, one has to crack
hard nuts for developing the specifications followed by method development and
validation to the developed methods to meet the regulatory requirements. Unless
the method is validated, it is not suitable for the release of the material
for commercial purposes.
As ICH Q7A guidelines state, ‘‘Analytical methods should be validated
unless the method employed is included in the relevant pharmacopoeia or other
recognised standard reference.’’ The suitability of all testing methods
used should nonetheless be verified under actual conditions of use and documented
as specifications form a part of a total control strategy for the drug substance
designed to ensure product quality and consistency.
Other parts of this strategy include a thorough product characterisation during
development, upon which specifications are based and adherence to Good Manufacturing
Practices; e.g., suitable facilities, a validated manufacturing process, validated
test procedure, raw material testing, in-process testing, stability testing,
etc.
Specifications are chosen to confirm the quality of the drug substance rather
than to establish full characterisation, and should focus on those characteristics
found to be useful.
Identifying and setting specifications to establish the quality dimensions of
a drug substance represents an important aspect of project management. With
significant cost and time-to-market pressures, a well thought-out strategy regarding
a product’s specifications can have huge implications on ease of manufacturing
and ultimately, on the product’s financial return. The cost of measuring
numerous specifications on a commercial product is significant.
An evolving specification “laundry list” generated during the development
process may become “engraved in stone,” incurring unnecessary costs
year after year during the product’s life cycle. Surely, this is an undesired
situation in today’s cost-conscious marketplace. Therefore, an important
project management goal is to establish material acceptance specifications that
clearly assess the API’s quality as it is released from a validated manufacturing
process.
The following concepts are important in the development and
setting of harmonised specifications. They are not universally applicable, but
each should be considered in particular circumstances. This guideline presents
a brief definition of each concept and an indication of the circumstances under
which it may be applicable.
 Generally,
proposals to implement these concepts should be justified by the applicant and
approved by the appropriate regulatory authority before being put into effect.
(i) Periodic and skip testing
(ii) Release versus shelf life acceptance criteria
(iii) In-process tests
(iv) Design and development consideration
(v) Limited data available at filing
(vi) Parametric release
(vii) Alternative procedures
(viii) Pharmacopoeial tests and acceptance criteria
(ix) Evolving technologies
(x) Impact of drug substance on drug product specifications
(xi) Reference standards
A few recommendations for establishing API specifications have been offered
that can substantially reduce the manufacturing cost of a drug substance. Without
question, choose specifications that represent the API’s quality when produced
by a validated manufacturing process using documented analytical standards.
These specifications should, if possible, be divorced from molecular confirmation
techniques since structure determination was accomplished long before the product
reached manufacturing.
Secondly, use a statistical basis to establish the specification range based
on the process and measurement capabilities of the production facility. This
approach is dependent upon the caveat that performance requirements drive specifications,
not what the plant can, or wants to do.
The following parameters of “Specifications” module must be taken
into consideration for development of specifications for active pharmaceutical
ingredients and key intermediates or the starting materials, which are helpful
in the hazard analysis and critical controls on the product as per cGMP norms:
S= Safety
P= pH, purity, potency, polymorphic, pyrogens, physico-chemical properties and
particle size distribution
E = Efficacy study, enantiomers and endotoxin study
C = Characterisation study
I = Identification test and isomerism studies
F = Feasibility study
Forced degradation study
Freedom from contamination
I = Impurity profile and related substances
C = Clinical studies phase-I, phase-II and phase-III, chiral purity (in case
optical active substance)
C = Assay
T = Toxicity and therapeutic studies including microbial limit tests I= Inorganic
substances [elemental and metallic impurities]
O = Organic volatile impurities
N = Non-volatile matters
S = Solvents used in the process (Class-I, II, III etc. as listed in ICH Q3C
Guidelines)
The quality of drug substances and drug products is determined by their design,
development, in-process controls, GMP controls and process validation and by
specifications applied to them throughout development and manufacture.
The specifications, ie, those tests, procedures and acceptance criteria which
play a major role in assuring the quality of the drug substance at release and
during shelf life. Specifications are an important component of quality assurance,
but are not its only component. All of the considerations listed above are necessary
to ensure consistent production of drug substances of high quality.
The Q6A guideline discusses these concepts, providing recommendations on what
data should be evaluated, including decision trees describing how the data can
be evaluated when developing specifications.
Despite these efforts, there remains a lack of agreement globally concerning
the role that statistical uncertainty plays in establishing specifications.
The writer is senior manager QA, Tonira Pharma Limited,
Vadodara. Email: jramniwas@tonira.com
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