FDA S GUIDANCE FOR INDUSTRY ANDAS: STABILITY TESTING OF DRUG SUBSTANCES AND PRODUCTS

Transcription

1 FDA S GUIDANCE FOR INDUSTRY ANDAS: STABILITY TESTING OF DRUG SUBSTANCES AND PRODUCTS 02-December-2014 San Diego, CA Kim Huynh-Ba Executive Director PHARMALYTIK Kim.huynhba@pharmalytik.com Overview Stability goals Roles in Drug Development Stability Program of NDA Stability requirements for anda Key considerations of anda stability Impact to the Generic Industry 2 1

2 Stability Goals ACTIVE PHARMACEUTICAL INGREDIENT (API) To establish a retest date for API Data to support submission of drug product DRUG PRODUCT To establish a shelf life for the commercial product Length and storage condition 3 Drug Product Stability Stability characteristics of API or Drug Product is a critical quality attribute of pharmaceutical product Stability Studies are used to: Establish how product changes over time under critical environmental factors (temperature, humidity and light) Determine appropriate product specifications Select marketing container closure system Determine appropriate storage conditions Justification of expiry of commercial product Provide necessary medical supplies 4 2

3 Development of Generics Rx Drug Products Generic Products 5 Drug Registration IND NDA Market anda 6 3

4 Critical Role of Drug Stability Quality is established for identify, strength, quality and purity (CFR ) ANDA products must show equivalency with innovator products. Clinical Phases are not done. Risk of ANDA product: Safety and efficacy of drug product are established during development via clinical studies. If drug product stability changes beyond established acceptance criteria, established safety and efficacy are no longer applicable. Change of Drug Stability would risk patient safety Quality of finished products decrease Potential sub potent or over dose products Potential toxic unknown impurities Uncontrolled process product inves ga on product recalls cgmp viola ons consent decree criminal prosecu on 7 DRUG DEVELOPMENT PROCESS Excipients DRUG PRODUCT Drug Product Stability Excipient compatibility Formulation interaction API FORMULATION DEVELOPMENT PACKAGING SELECTION API Stability Process impurity FINAL PACKAGED PRODUCT Packaging interaction Storage conditions Storage configuration 8 4

5 Factors affecting Drug Stability Stability of the Active Pharmaceutical Ingredient (API) from storage Interaction between the API and excipient Formulation Development Selection of dosage form Manufacturing process of drug product Selection of container closure packaging system Effect of storage (temperature, humidity and light) Selection of marketing image Handling of the finished products 9 Issued in September 2012 CDER/OGD 5 pages 2 Cover pages Table of contents Introduction Background Discussion 10 5

6 11 International Conference on Harmonization (ICH) Purpose: To provide a forum for dialogue between Health Authorities and Industry on the disparities with respect to requirements of US, Europe and Japan (Zone 1 & 2 ) Goal: To develop guidelines that are acceptable for regulatory review by US, Europe and Japan ICH Steering Committee: 6 Parties PhRMa, FDA, EFPIA, EU, MHLW, JPMA and IFPMA (non voting member) Official Observers: Canada, WHO, EFTA Interested Parties: Pharmacopeia, IGPA, WSMI 12 6

7 Purpose of Stability Testing The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf lives. ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products [ICH Q1A] 13 Drug Degradation Physical Degradation Loss of water Absorb water Change in appearance Chemical Degradation Hydrolysis Oxidation Isomerization Polymerization Photo Decomposition 14 7

8 Storage Conditions Intended Storage Condition Stability Studies Study Condition Submission Requirement for NDA Long Term 25 ºC/60%RH 12 months Room Temperature Intermediate* 30 ºC/65%RH 6 months Accelerated 40 ºC/75%RH 6 months Refrigerated Long Term 5 ºC/ ambient 12 months Accelerated 25 ºC/60%RH 6 months Freezer Long Term - 20 ºC/ ambient 12 months * Significant change 15 Significant Change API Drug Product Significant change is defined as failure to meet the specification. 1. A 5 percent potency change from the initial assay value; 2. Any specified degradant exceeding its acceptance criteria 3. Failure to meet acceptance criteria for appearance and physical properties (e.g., color, phase separation, resuspendibility, delivery per actuation, caking, hardness); and as appropriate to the product type; 4. The ph exceeding its acceptance criteria; and 5. Dissolution exceeding the acceptance criteria for 12 dosage units. 16 8

9 Selection of batches API DRUG PRODUCT Selection of Batches Manufacturing Process Acceptance Criteria Container Closure Testing Frequency Stability Commitment 3 batches (pilot scale) 3 batches/strength (2 pilot + 1 lab scale) Representative of Commercial Production Similar to those used in pre-clinical and clinical studies Same to proposed commercial packaging Long Term: 0, 3, 6, 9, 12, 18, 24 mo and annually Intermediate: to 12 months, minimum 4 points Accelerated: to 6 months, at least 3 points Must commit to put up 3 production batches with same protocols 17 Key Factors of Q1A(R2) ICH condition contributing 80% of pharmaceutical market Outlines minimum stability data package for new drug application. It is not intended for INDs, ANDAs or sndas. Harmonizes stability requirement for marketing application in EU, Japan and US. Other countries adopt with some modifications. Must use Validated Stability-Indicating analytical methods Methods must cover physical, chemical, biological and microbiological attributes Studies evaluated under thermal and elevated humidity to cover storage, shipment and subsequent use Accelerated and intermediate used to evaluate impact of short-term excursions. Acceptance criteria should include individual and total upper limits for impurities and rights degradation reserved) products 18 9

10 Q1B: Photostability Requirements two types of studies, exposure is cumulative from the light sources: Forced degradation study to generate potential degradation products 2 X exposure to UV and fluorescent sources Confirmatory study to confirm product and package performance NLT 1.2 million lux hours watts/hrs per sq. meter Light Sources: Option 1 Dual output light sources, such as D65/ID65 Simulates artificial day light fluorescent lamp Use Xenon or Metal Halide Option 2 Tandem exposure to single light source types Cool white fluorescent lamp + near UV fluorescent lamp ( nm) Accumulate exposure under one, then the other 19 Q1D: Bracketing and Matrixing Bracketing: Used for packaging extremes Assume that the intermediates are represented by the extremes For a range of strengths, strengths must be identical or very closely related in composition Can be applied to different container sizes or fills of same packaging system Bracketing design is NOT appropriate if extremes are not demonstrated. Matrixing: Define full design and reduced design (with examples) Assume that the stability of each subset of samples tested represent the stability of all samples at a given time point Define what is needed for justification Covering different batches, different strengths, different sizes of the same container and closure, and, possibly, in some cases, different container/closure systems

11 Key Factors of Q1E Systematic approach in the presentation and evaluation of stability information An adequacy of mass balance should be assessed. Factors that can cause an apparent lack of mass balance should be considered Mechanism of degradation Stability indicating capability Inherent variability of the analytical procedures Each attributes should be assessed separately, and an overall assessment should be made. 21 Requirements of new ANDA Follow ICH Q1 A(R2), Q1B, Q1C, Q1D, and Q1E Three pilot scale batches (2 pilot and 1 small scale) 6-month accelerated and LT (intermediate as ICH) DP manufactured and stored in condition represent final process Must use multiple lots of DS Fully packaged primary exhibit batch 3 batches, if use Q1D Statistical analysis using Q1E Justify if there is any deviation from guidance 22 11

12 Questions and Answers: Issued in August 2013 General (10) DMF (2) DP Manufacturing and Packaging (22) Amendments to pending ANDA (1) Stability studies (7) Implemented by June Q/A General Scope: only apply to new ANDA, not for post-approval changes Move implementation date from 1-Jan-2014 to 20-Jun Need 6 month AC and LT data for all 3 batches. Intermediate Condition needed for all batches, if significant change is found in any of the batches. Recommend to start LT, IM and AC at the same time to avoid delay in review. Q1D allows bracketing and matrixing without prior approval, but cautions on specifics must be followed closely. Expiry can be 2 times the LT data 24 month expiry, if 12mo data submitted, and no significant change at AC

13 Q/A: General Small vs small scale batch: depending on the physical characteristics of the drug. For Solids, 2 batches pilot scale (10% of production) and a small scale (no less than 25% of the other two). Recommendation given for Inhalation, Cream/lotions/gels, transdermal, parenteral, solutions, suspensions, powders. Points out that stability should be calculated by months rather than weeks (1mo > 4 wks). At least 6mo data available at time of filing. Can t not submit 3mo data, and provide 6mo when they are available, even with an expiring patent. Submission batches are kept 1 year after ANDA approval. 25 Drug Master file 3 primary batches of API filed in DMF. Made under GMPs. Required 6 mo AC and LT for pilot scales submitted. LT data are supplemented as available through retest. DMF includes protocol, commitments and data to demonstrated studies started. Initial +1 for AC are sufficient to pass Completeness Assessment. OK to use 3 production scale batches

14 Manufacturing and Packaging Split filling one batch of bulk into different fill volumes are not discrete packaging. Blow-fill-seal packaged products must be packaged into secondary container. Packaging done with all 3 batches made. Stability should be generated using at least 2 API lots. Same lot of packaging can be use. Different lot to be considered when it could affect DP performance and delivery. No hand packaging. Same requirement for modified release products, orals, ophthalmic, solutions, suspension, transdermal, ointments, creams, granules, parenterals. 27 Manufacturing and Packaging All 3 batches are expected to: Have complete batch records and all CMC. Done under GMP (Technical grade is not acceptable. Same specs. Made in sterile facility, for sterile products. manufactured at the proposed production site. Requirements for ANDA containing multiple strengths. 3 separate immediate blends needed One blend used to make all strengths proposed The other 2 can be used to make lowest and highest strengths For multiple API sources, qualification using 3 batches of one source and one pilot scale using second proposed source (total 4) 28 14

15 Q/A Stability studies Amendments: All amendments after 20 Jun will not be held by this standard, unless there is a concern. Stability studies: 4 timepoints (instead of 0,3,6) Upright (vertical) and inverted (horizontal) storage orientation for solution, suspension and semi solid until full expiration date is verified and worst case is identified. Reconstitution and dilution done for all 3 batches Same definition for semipermeable containers as ICH Preservative: one batch at the EOS and done with all studies. L/E testing: one time studies. Additional studies for multiple types of containers. 29 It s Indeed A Global Market but 30 15

16 Global Climatic Zones Zone I: Temperate less than 20 o C e.g. Germany, Russia, Canada Zone II: Sub-tropical with possible high humidity averaging o C e.g. France, Peru, Australia, USA Zone III: hot and dry e.g. Botswana, Chad, Syria, Iraq Zone IV: hot and humid averaging more than 24 o C e.g. Taiwan, Singapore, India, parts of South America 31 Setting the stage. In general, drugs are developed for global market Goal is to have the same drug globally Manufacture and control to same quality levels? Acceptance of Global regulations such as ICH Expecting the same regulatory outcomes 32 16

17 Global Storage Conditions Long Term Intermediate Accelerated Zone I & II (ICH) 25 ºC/60%RH 30 ºC/65%RH 40 ºC/75%RH Zone III 30 ºC/40%RH 40 ºC/75%RH Zone IV a WHO (Nov 2003) Zone IV b ASEAN (June 2004) 30 ºC/65%RH 40 ºC/75%RH 30 ºC/75%RH 40 ºC/75%RH 33 Typical Stability Protocol TEMP HUMIDITY TZ 1 Mo 2 Mo 3 Mo 6 mo 9 Mo 12 Mo 18 Mo 24 mo 36 Mo 25 C 60%RH X X X X X X X X 30 C 65%RH X X X X (30 C 75%RH) X X X X X X X X 40 C 75%RH X (X) X X 50 C X 5 C H O L D Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh Ba (ed.), Springer, November 2008, Chapter

18 STABILITY TESTING Required by cgmp Regulations (21 CFR ) and global regulations (ICH Q1A(R2), WHO, ASEAN, etc.) FDA defined Stability is a Critical Quality Attribute (CQA) To establish a storage condition for labeling and an expiry for commercialization Stability characteristics of API and DP rely heavily on end Product Testing; therefore, Quality is measured instead of designed Understand regional versus global concerns to develop stability program FDA does not have a Stability Guidelines for DS & DP ANDA guidelines follow ICH Q1A (R2) Q/A addressed limited concerns Additional requirements for stability data at submission time for generics FDA ANDA Submissions Content and Format detailed requirements of of the CTD, especially the QOS. 35 Thank you! References: Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh Ba (ed.), Springer Publisher, Nov Pharmaceutical Stability Testing to support Global Markets, K. Huynh Ba (ed.), Springer Publisher, Jan Contact Information Kim.huynhba@pharmalytik.com 36 18