Specifications

1. Specifications Breakout Session I&II Michael Coutant (Pfizer), Michael Szulc (Biogen Idec), Peter Yehl (Genentech)

2. Topics Covered • Two breakout sessions on specifications were held following the presentations of Kirby Wong-Moon (Amgen) and Stephen Miller (FDA). Breakout session discussion included: • Modified approach to establishing impurity ID and qualification thresholds in early phase studies • Use of API tox batch as first clinical batch • Specifications for chiral impurities • Use of internal tests or “for information only” tests • Disintegration testing as an alternative to dissolution testing in early phase formulations • Specifications for early phase drug product formulations • Safety limits on reagents not listed in ICH guidelines • Generally speaking, proactively providing justification for specifications (or lack thereof) in regulatory filings has been successful and is an encouraged health authority approach • See presentation slides from Drs. Wong-Moon and Miller for additional perspectives on these topics

3. Impurities • The proposal presented in the Pharm. Tech. paper was discussed at length for different perspectives: • For doses up to 2 g, ID threshold for impurities in drug substance used in early phase studies should be 3x ICH guidelines (0.3% or 3 mg). • For doses up to 2 g, qualification threshold for impurities in drug substance used in early phase studies should be 3x ICH guidelines (0.5% or 3 mg). • During the discussion, several companies outlined their approach as being consistent with ICH guidelines. Others outlined their justifications for using a staged approach that exceeds ICH guideline limits (indication, daily dose, length of study). • An alternative approach that arose from the discussion and discussed in more detail on the next two slides is to propose structures for impurities present above 0.1%, and use knowledge of the structure, synthesis, and use of the API in drug product to justify qualification levels above 0.15%.

4. Impurities – ID Threshold • The proposal presented in the Pharm. Tech. paper was discussed at length for different perspectives: • For doses up to 2 g, ID threshold for impurities in drug substance used in early phase studies should be 3x ICH guidelines (0.3% or 3 mg). • Most companies are assigning/proposing structures to impurities when present at 0.1-0.2% levels by LC/MS and exact mass determinations. • Confirmation of structure is performed later in development through synthesis and characterization of an impurity standard.

5. Impurities – Qualification Threshold • The proposal presented in the Pharm. Tech. paper was discussed at length for different perspectives: • For doses up to 2 g, qualification threshold for impurities in drug substance used in early phase studies should be 3x ICH guidelines (0.5% or 3 mg). • Several companies do have standards for defining when qualification thresholds may exceed 0.15%, but some in attendance thought a defined 0.5% limit was too high a risk at their companies, with a concern that any questions of the qualification of impurities could delay clinical trials. • Companies that do routinely use qualification limits greater than 0.15% in early phase studies do so considering many factors in the use of the drug product. Factors considered may include: • Consultation with colleagues in toxicology • Proposed structure of impurities and knowledge of synthetic route • Indication – cancer or other life threatening illness (S9 exception) • Duration of study; single dose study or short duration (align with chronic exposure philosophies set for in draft M7 guidance) • Daily Dose; consideration that ICH drug product guidelines Q3B allows 0.5% impurity up to 40mg dose, and 1.0%impurity for up to 5mg dose without qualification. • Commitment to qualify impurity in later phase clinical studies or tox studies

6. Use of Same API Lot for Tox and Clinical Studies • Majority of companies in the discussion use the same API batch as tox and clinical batch. • Advantage: with few exceptions, all impurities are qualified for use. • Specifications based on multiples of dosing in tox studies can be derived for future batches. • What if impurity is in clinical batch but not at all in toxicologybatch? • Oncology products frequently have resupply requests. • Justify specifications for new impurities based on consultation with toxicology colleagues, proposed structure of impurity, knowledge of synthetic route, clinical indication, drug product dose, and duration of study.

7. Chiral Impurities • Most in discussion control chiral impurities with the same limit as any other related substance. • Method capabilities in chiral separations may not allow as low an LOD/LOQ compared to HPLC related substances methods, though. • Confirm through knowledge of synthetic route and characterization testing (forced deg) to determine if the test may be omitted from stability studies • Consideration of the likelihood of the presence of a particular diastereomer or enantiomer is a legitimate justification for not specifying chiral impurities, especially in multi-chiral center actives • When there are multiple chiral centers, alternate approaches may be considered: • Control chiral purity upstream in intermediates or starting material. • Optical rotation of the final material.

8. ID/Qualification Levels • Where should impurity data be discussed in a filing? • Priority should be to discuss impurities not qualified and not present in tox batch. • Include discussions in both the Impurities section and the Justification of Specifications. • In general companies are not stating their ID and qualification thresholds but rather justifying impurity levels.

9. Internal Tests • Most companies do perform internal tests, additional testing not listed on specifications • In process control with tighter limit than final spec • “Information gathering” in early phase to inform future control strategies in Phase III and marketing application • Some report this data on CoAs, some mention in specification justification, and some do not include in filing. If included in the filing, “for information” is a common specification • Tests that are part of internal testing vary from company to company (XRPD, KF, disso)

10. Internal Tests • Balancing what information about internal tests is part of a ED filing was discussed. Companies frequently consider the following: • Is the information useful for a reviewer to evaluate as support for an early phase study? • Good to show what companies are considering and monitoring, but if it adds no value to the critical evaluation of the ED study (i.e. unrelated to safety), is it useful to include? Some companies continue to monitor but not include in filing. • Sometimes additional testing is determined not to provide critical information, and some participants were concerned that disclosing these additional tests in a filing might commit them to continued testing, even after it has been shown not to provide value. In those cases, statements may be included in the filing, such as “data is being gathered by tests x,y,z to gain process understanding, but may be changed or discontinued as necessary” • Need to maintain balance on level of information between what is useful to reviewer and what would be too much detail.

11. Dissolution vs disintegration • Most companies target simple formulations in early development (powder in bottle, powder in capsule, immediate release tablets). • Most companies perform disintegration over disso in ED • Desire is gathering clinical data to inform dissolution development • Those that do perform dissolution in ED do so generally to inform formulation development and solubility testing for poorly soluble APIs • In some cases, dissolution methods that are very informative about formulation development may be quite different from a typical regulatory method (e.g., non-sink conditions, multi-phase, unusual medium, etc.) • Many companies introduce disso during development of intended final formulation • Utilization of platform technologies with historical performance can inform selection of disintegration over dissolutions.

12. Other key consensus of Dosage Units and Purity in Early Development • For powder in bottle( PIB) and powder in capsule (PIC) formulations, most companies use knowledge of the API and the lack of excipients in the formulation to use a simpler control strategy for drug product: • uniformity of dosage units - manufacturing batch records for filled capsule weights used as an in process test to demonstrate uniformity of dosage units, test is not performed at product release. Use of tablet weight uniformity as surrogate for UDU using HPLC can be justified if blend uniformity is confirmed. • Purity; API release data may be used. Several in discussion also used API stability data in place of DP stability testing. • Disintegration used as an alternative to dissolution. Disintegration/dissolution should be justified for poorly soluble compounds. • Microbial limits testing; Most do not do MLT for drug product and drug substance for oral solid dosage forms. Two companies do test drug product for MLT in early development, all others do not. Justification of no MLT is low water activity in OSDF’s and non-sterile manufacturing environment

13. Other reagents • Many reagents and solvents are in common use in early development processes but no limits are proposed in ICH guidelines. • For example, t-butanol, methyl THF and DIPEA limits vary by company • Can information be shared through IQ, or can IQ propose to update guidelines?