Synthesis to Clinic 14 C studies in man a Chemistry. Stephen Lewinton Managing Director Chemistry & Metabolism Feb 2013

Size: px

Start display at page:

Download "Synthesis to Clinic 14 C studies in man a Chemistry. Stephen Lewinton Managing Director Chemistry & Metabolism Feb 2013"

Cassandra Stafford
6 years ago
Views:

1 Synthesis to Clinic 14 C studies in man a Chemistry perspective Stephen Lewinton Managing Director Chemistry & Metabolism Feb 2013

2 Synthesis-to-Clinic 14 C API synthesis Preclinical Data Regulatory affairs IMP production Clinical conduct Sample analysis Biometrics Tightly integrated supply chain Single vendor Single project manager Integrated Quality process Continuity of the science Removal of management burden Relevant to all 14 C containing study types Microdose, microtracer, human ADME

3 GMP The Regulatory Framework General Provisions European Clinical Trials Directive 2001/20/EC (EUCTD) Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) UK MHRA APIs and Drug Products for Use in Very Early Phase Studies Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies, January 2006 cgmp for Phase 1 Investigational Drugs; Food and Drug Administration, July 2008 The Clinical Trials Authorisation (CTA) application The Investigational Medicinal Product Dossier (IMPD) The Investigational New Drug application (IND) 3

4 GMP GMP or not GMP? [ 14 C]IMP (Drug Product) must be manufactured to GMP [ 14 C]API (Drug Substance) for use in clinical trials is the starting material for manufacture of the [ 14 C]IMP administered in the clinical trial It does not have to be prepared to GMP but appropriate GMP concepts should be applied 4

GMP Appropriate GMP Concepts Clinical radiosynthesis laboratory (minimise risk of cross-contamination) Quarantine and identity testing of raw materials (BSE/TSE statements, CoAs) Equipment maintained

5 GMP Appropriate GMP Concepts Clinical radiosynthesis laboratory (minimise risk of cross-contamination) Quarantine and identity testing of raw materials (BSE/TSE statements, CoAs) Equipment maintained and calibrated Clinical project glassware washed and inspected before use Analytical methods should be scientifically sound Production data documented QA review of analytical and production data QA Batch Release [ 14 C]API for clinical trials prepared at Quotient released with a GMP CoA The final scope of [ 14 C]API project is agreed with the customer 5

6 GMP Is GMP for 14 C labelled API really GMP? Not all GMP controls are appropriate for the manufacture of [ 14 C]API for clinical trial use: Process validation for [ 14 C]API production is not required Analytical methods may not be fully validated The objective is to produce [ 14 C]API using a procedure that: satisfies regulatory requirements allows the material to be accepted into a [ 14 C]IMP manufacturing procedure Compliance is not Science 6

7 Preparing 14 C Labelled Compounds for Clinical Use A Representative [ 14 C]API Radiosynthesis Synthesis of [ 14 C]DSM Technical [ 14 C]API synthesis 1 Analytical method transfer Storage stability study IMPD Submission Clinical / GMP [ 14 C]API synthesis 1 = Technical batch is not mandatory 7

8 Preparing C14 Labelled Compounds for Clinical Use [ 14 C]IMP for Oral Administration Process Overview Formulation Development Cold Drug Substance Cold Trial Manufacture IMPD Submission Hot Trial Manufacture 14 C Drug Substance Clinical Trial Manufacture Heidelberg GJ

9 Some Key Considerations Analytical Release & Impurity profiles Radiosynthesis route should mimic cold route as far as practical. Helps ensure toxicological coverage for impurities Radiosynthesis scale typically <0.5g and so compound requirement for analytical release must factor in calculations of required production scale. Cold analytical method must be adapted for radiodetector to allow determination of radiochemical purity. Radiotrace 9

challenges with moving to clinical dosage form (oral solid most commonly) Ensure physico form of radiolabelled matches clinical API.

10 Some Key Considerations Proposed drug product Majority of these studies are undertaken using oral solutions. Advantages include: Concerns about form of drug substance avoided Easy to demonstrate homogeneity of the Drug Product Ensures good bioavailability Key challenges with moving to clinical dosage form (oral solid most commonly) Ensure physico form of radiolabelled matches clinical API. Most milling techniques require multi grams of material. Achieving homogeneity co-crystallisation versus blending Program design requires early decision on whether to mimic clinical dosage form and the strategy for doing so. 10

11 Some key considerations Determination of Dose for Human AME Need to determine safe radioactive dose for Human AME study 28-day Quantitative Whole Body Autoradiography study (QWBA) in pigmented rats. Data used for human dosimetry calculation. Combining safe radioactive dose with the proposed clinical dose allows calculation of the specific activity of the Drug Product (IMP). Dose for microdose study determined from ICH M3 Dosimetry is not required to support these studies Rapid determination of required specific activity possible 11

12 Some key considerations Why is the specific activity important? Stability Stability often depends upon the specific activity and form of storage. Stability can vary depending on label position. Not possible to use cold data and structure to predict impact of labelling on stability. Stability studies need to be conducted at the appropriate or a higher specific activity and in correct form. Stability data is important in allowing assignment of an expiry date. If the specific activity of the Drug product is high and so the level of cold dilution is low then importance of characterisation of the radiochemical API is increased. Early discussions around dose and degree of dilution are therefore important in planning 12

13 Stability Example Dominant effect of solution storage here lies in the suppression of formation of impurities Radiochemical purity specification of 97% both the - 80 C solid and -80 C solution remain in specification Radiochemical impurity specification is no single impurity >1.0% only the -80 C solution remains in specification after 4 weeks Analysis Time Points (weeks) -80 C Solid Radiochemical purity % -80 C Solution Radiochemical Purity % -80 C Solution Radiochemical Purity % -20 C Solution Radiochemical Purity % Analysis Time Points (weeks) 13

14 Typical Time-lines for GMP[ 14 C]API Start Clinical Program QA GMP[ 14 C]API Synthesis GMP Facility Commissioning Stability Trials [ 14 C] Technical Batch Synthesis Customer approves Batch Documentation Customer approves Protocol Analytical Method Transfer [ 14 C]DSM Synthesis Week 14

15 Summary In undertaking studies using 14C the early planning of radiosynthesis plays a key role. Some of the key early decision include: Proposed dose product Radioactive and cold dose Analytical release criteria Understanding importance of physico form to absorption In considering Chemistry requirements QA/QPs should consider for: AME studies: Single dose, Clinic based, ~6 volunteers and normally healthy. Requirements for exploratory studies for Microdose studies 15

16 Thank you 16

Pharmaceutical Development (Drug Substance & Drug Product) for Visceral Leishmaniasis candidate DNDI-6148

Request for Proposal Pharmaceutical Development (Drug Substance & Drug Product) for Visceral Leishmaniasis candidate DNDI-6148 Dated: October 12 th 2015 Page 1 Table of Contents 1. PURPOSE... 3 2. RFP