Best Practices and
Application of GMPs for
Small Molecule Drugs
in Early Development
IQ Workshop, Feb 4-5, 2014, Washington, D.C.
Specifications Breakout Session 2
Pete Yehl and Mike Coutant, moderators
Best Practices and GMPs in Early Development
Problem Statement
• Improved clarity in definition of GMP expectations for early development
(Phase I to 2a) would advance innovation in drug product development
– Potential to improve cycle times and reduce costs, while maintaining
appropriate product quality and always ensuring patient safety
• Each company in Industry interprets existing GMP guidances according to
its own culture and risk tolerance
– In part, this is due to the vague nature of the guidances available regarding
GMP expectations in early dev (e.g. Q7A, Phase 1 GMPs, etc)
• Internal Industry debates between QA and CMC groups often result in
conservative “one-size fits all” interpretations across the dev continuum
– Feedback from the previous 2007 PhRMA initiative: Biggest roadblock to
achieving greater flexibility in early development is “ourselves” in Industry
A common approach to best practices and GMP expectations for early
development is needed to build alignment with regulatory agencies and
internal stakeholders
IQ Webinar: GMPs in Early Development
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Highlights of the IQ Specifications Paper
– Scope
 Small molecules (biologics not included)
 Relevant to solid oral dosage forms
 US Regulatory filings (concepts should be applicable to rest of world)
– General Concepts
 ICH Q6A appropriate for commercial not Early Development
 Commercial specifications should be tied to final process validation results
 Process, formulation, and method changes expected in early Dev so Specs evolve
 During late development, maturing product and process understanding
 Risk based approach: Early clinical has safety focus ⇒ wider acceptance criteria (AC)
 High attrition rate for compounds in early development
 Late development growing product and process understanding ⇒ maturing specs
 Differentiating Early Phase Spec Testing by standardizing typical tests and AC
 Release (submitted in regulatory filings)
 Stability (to establish DS and DP retest dates)
 Internal (for informational purposes only, but can have tighter AC)
IQ Specs paper intended to be provocative starting point to stimulate
discussion
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Topic 1: General Control Strategies
– IQ proposal: In-Process control vs. Internal Target vs. Regulatory Specification
 In addition to release and stability tests, consideration is given to internal tests and
acceptance criteria that are not normally part of formal specifications.
 These internal tests can be performed to collect information for product and
process understanding, or to allow for tighter control (i.e., target criteria tighter
than the release testing criteria) to ensure product quality will be maintained
throughout the product’s retest period.
 Based on the information obtained in early development, additional tests and
acceptance criteria for other attributes (e.g. water content) can be included as
the late development focus shifts to process and product performance and
consistency; eventually aligning the available ICH guidelines.
– Discussion: Use of IPCs vs. formal internal targets vs. registered specifications
throughout development
 When does something move from being an internal target to registered
specification?
 For PIC/PIB formulations, can purity be assigned through API testing?
Agreement on the general use of internal targets as a means of impurity control in Early Development.
Understanding when it is and isn’t acceptable to monitor internally vs. having a formal regulatory
specification
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Topic 1: General Control Strategies
– IQ proposal: Use of IPCs to control chemical, chiral, solvent and residual
metal/inorganic impurities in final API and Drug product
 DP intermediates (i.e. spray dry, HME) control of solvents and degradation products
 Consider intermediate testing for residual solvents, chiral purity
 Methods in place to control chemical impurities in API through RSM control
 Acceptability of using internal tests to obviate the need to submit additional test
data and methods for health authority review would be contingent on product
and materials knowledge level
 Balance of upfront effort to qualify IPC or intermediate test methods in lieu of
testing API and validation would be a business decision
– Discussion: Use of IPCs vs. formal internal targets vs. registered API
specifications and methods through various development stages
 Could this be applied DP intermediates?
 Early QBD approach to development – is this a business risk that companies would
consider?
 Would internal testing and control of intermediates be sufficient?
Agreement on the general use of internal targets as a means of impurity control in Early Development.
Understanding when it is and isn’t acceptable to monitor internally vs. having a formal regulatory
specification
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Topic 2: Impurity Control Strategies
 IQ proposal: 3x ICH limits for ID and qualification for Phase I and
Phase II, transition to ICH specifications for pivotal studies
 Staged approach aligns with other industry initiatives (i.e., staged TTC
PGI’s)
 Subject exposure lower and study durations are shorter. Subject
population closely monitored
 IQ Proposal: Specification of synthetic process related impurities
only in API, not in DP
 Discussion: Qualification threshold for early development ID vs.
commercial/pre-commercial
 Does a staged approach have merit based on exposure arguments?
 Do internal impurity qualification thresholds differ from filed specifications? Any
special considerations given for oncology drugs?
 General acceptance of process related impurity specifications limited to API unless
they grow or change in the DP?
Agreement on development stage/phase based approach to impurity control and specifications
based on overall patient exposure and clinical care
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IQ Specifications Paper: DS Summary
– Single set of tests and acceptance criteria (AC) for Phase 1 and 2a DS Specs
Proposed Acceptance Criteria
Release
Testing
Internal
Testing
Stability
Testing
Description
Range of color description e.g., White to almost-white to
light yellow powder
X
-
X
ID by Spectroscopy
Spectrum conforms to that of reference
X
-
-
Counterion
Report results
X
X
-
Assay
97.0 - 103.0% “anhydrous basis” or “anhydrous and
solvent free basis” if compound is a solvate
X
-
X
X
X
X
Attribute
Impurities/ Degradation
Products
Individual NMT 1.0% (can be higher if qualified )
Chiral Impurity
NMT 1.0% (can be higher if qualified)
X
X
X
Residual Solvents
ICH Limits or other justified limits for solvents used in the
final step
X
X
-
Mutagenic Impurities
Follow existing guidance until ICH M7 is finalized
-
X
-
Inorganic Impurities
Water Content
Solid Form
NMT EMEA Limits/ADI
Report results
Report results
-
X
X
X
X
X
Particle Size
Report results
-
X
-
ROI
NMT 1.0%
-
X
-
Total NMT 3.0%
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IQ Specifications Paper: PIB/PIC DP Summary
– Single set of tests and AC for PIB/PIC formulations (rely primarily on DS results)
Attribute
Proposed Acceptance Criteria
Release
Testing
Internal
Testing
Stability
Testing
X
-
X
Same as DS for PIB
Description
Capsule shell description for PIC
Identification
Same as DS
X
X
-
Assay
90.0 – 110.0%
X
-
X
Degradation Products
Use data from DS release (list degradation products only)
X
-
X
Uniformity of Dosage Units
Conforms per USP<905>
-
X
-
Disintegration or Break Test
Disintegration: Per USP <701> for capsules, NMT 15 min
X
X
X
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IQ Specifications Paper: Capsule/Tablet Summary
– Single set of tests and AC for Phase 1 and 2a capsule/tablet Specs
Attribute
Description
Proposed Acceptance Criteria
Describe color, shape and dosage form (e.g. white to
almost-white round tablets)
Release
Testing
Internal
Testing
Stability
Testing
X
-
X
Conforms to standard
Identification
For HPLC-based methods: “The retention time and UV
absorption conforms to the standard”
X
-
-
Assay
90.0 - 110.0%
X
-
X
X
-
X
Individual unspecified NMT 1.0%
Degradation Products
Total NMT 5.0%
Uniformity of Dosage Units
Complies with USP<905>
X
-
-
Water Content
Report results
-
X
X
Dissolution: Report results
-
X
X
Disintegration: Per USP <701> for capsules, NMT 15 min
X
-
X
Dissolution or
Disintegration
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Topic 3: Dissolution vs. Disintegration
– IQ proposal is that for rapidly dissolving immediate release formulations, it is
recommended to include disintegration as a regulatory filed specification
 Dissolution may be performed as an internal specification (i.e., report results without
defined acceptance criteria) to gather product knowledge during early development
(e.g., for poorly soluble drugs).
 As additional knowledge is gained, dissolution acceptance criteria should be
established in later development (i.e., Phase 2b and beyond).
 For rapidly dissolving immediate release formulations, it is recommended to include
disintegration as a regulatory filed specification.
– Discussion: When is dissolution an appropriate registered specification?
 Have companies been filing disintegration successfully? Any country specific
challenges?
 What API and DP properties or development milestones would trigger development
of a dissolution method?
For Early Development, Disintegration is an appropriate drug product specification for rapidly
dissolving immediate release formulations. Dissolution data may be generated to gather product
knowledge.
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Topic 4: Microbiological Testing
– IQ proposal is that micro testing on either API or DP is not required in early
development for oral products.
 Manufacturing usually takes place in non-sterile facilities
 Since human GI is non-sterile, limited patient risk
 Testing sterility of API is business risk, even if used in parenteral
 Other bases for omitting micro testing on DP:
 Process water activity testing is an industry standard
 Capsule shells, other excipients are micro tested prior to use
– Discussion: What are the risks and strategies around microbiological testing for
oral products in early development?
 Ancillary IV formulas produced using API made for oral use (for example in absolute BA
studies) will still be micro tested (endotoxins and sterility)
An agreement that sterility testing for oral products is not needed in US in early development. A
broader n industry perspective on experiences with other health authorities WRT micro testing
Especially in early development
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Bonus Slides
Purpose and Publication Timing of the GMPs in
Early Development Position Papers
• Intended as stimuli articles
– Serve as a starting point to stimulate further discussion at
a future workshop
– Should not be perceived as final Industry position or
recommendation
• Publication timing in Pharmaceutical Technology
–
–
–
–
–
Overarching Summary – June 2012
Analytical Methods – July 2012
Drug Product Manufacturing – August 2012
Stability – September 2012
Specifications – Anticipated October 2012
IQ Webinar: GMPs in Early Development
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IQ Workshop Objectives
• Provide a broader public forum for further discussion of the application of
GMPs in Early Development as outlined in the position papers published in
Pharmaceutical Technology in 2012
• Build alignment with health authorities and industrial CMC stakeholders
(QA, CMC development scientists, regulatory CMC) on the best practices
outlined in the position papers.
• Discuss the impact of applying these concepts in early development for
different therapeutic areas/disease states.
• Publish workshop proceedings integrating feedback based upon the
discussions.
IQ Webinar: GMPs in Early Development
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Best Practices and GMPs in Early Development:
Scope and Strategy
• Limit initial scope to US filings to help build momentum
• Focus on Early Development (Phase I to 2a)
– Early = Supporting exploratory human clinical studies
– Late = Supporting pivotal human clinical studies
• Limited to small molecules (biologics excluded)
• Emphasis on 4 topics:
–
–
–
–
Analytical method qualification/validation
Drug product manufacturing
Stability
Specifications
IQ Webinar: GMPs in Early Development
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GMPs in Early Development Part 5:
Specifications
• To be published in October 2012 issue of Pharmaceutical Technology
• Volume 36, Issue 10, pp. 84-93
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