PHARMACEUTICAL REFERENCE STANDARDS

Transcription

1 PHARMACEUTICAL REFERENCE STANDARDS 11 th International Symposium organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe 3-4 September 2012, Strasbourg, France Session 3 Presentations (Part 1) Material Management / Technology Changes

2 September 2012, Symposium Pharmaceutical Reference Standards Managing Third Parties for the Preparation and Maintenance of Reference Standards Mr. Vaughn R. Stultz Dr. Matthew Borer Ms. Kimberley Dancheck Mr. Michael Julius Mr. David Lytle Ms. Margaret McInerney Deciding What to Outsource Self-contained processes done together at one vendor Missing or unique technical capabilities Operations that have minimal oversight requirements Well defined processes with minimal associated difficulty Processes that are performed infrequently or require expensive equipment Always keeping in mind cost and quality Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 2 1

3 Expertise and Customer Service Find vendors who perform the operations as a core part of their business and deliver services with the customer s needs in mind Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 3 Examples of Outsourced Operations with Respect to Reference Standards Prepackaging and labeling of bulk material Special synthesis of small molecules IT Support Disaster recovery storage Physicochemical characterization tests (where site certification is not required) Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 4 2

4 Examples of Outsourced Operations with Respect to Reference Standards Processing and dispensing of routine customer orders Vial lyophilization Shipping dock services Remote distribution centers Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 5 The level of third party oversight required is determined by: Complexity Expertise Level of business integration Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 6 3

5 High Level Oversight Considerations Routine joint management team meetings In-depth and higher frequency audits Detailed master service agreement Detailed performance metrics monitored Man in plant for key operations Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 7 The key to a successful third party relationship is based on the mutual understanding of expectations. Specifically, the third party should understand the difference between Reference Standard and Drug Substance / Drug Product manufacturing and testing Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 8 4

6 High Level Differences Reference Standard Intended use laboratory control Limited regulatory requirements Limited registration commitment Closed system of users Infrequent manufacturing Overprotective packaging Overprotective storage Sterility typically unimportant Documentation is critical! Drug Substance or Drug Product Intended use human dosing Extensive regulatory requirements Extensive registration commitment Open system of patients Routine manufacturing Packaging optimized for cost Storage optimized for convenience Sterility typically vital Documentation is critical! Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 9 Lessons Learned Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 10 5

7 Real Examples: Problems when Outsourcing Instructions are too complex or there is insufficient communication of expectations During preparation of a degraded suitability mixture, the caustic solution was quenched prior to a sufficient extent of reaction, resulting in a material incompatible with its intended use Critical raw material requirements not identified Changing a water source led to observation of extra peaks during the analysis of the reference standard, causing the batch to be rejected Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 11 Real Examples: Problems when Outsourcing Inconsistent communication model A sample submission process that is in constant flux causing the submission of materials for testing to be consistently incorrect Low/incorrect prioritization given to assignments, leading to missed deadlines Quality and Expertise Significant issues with reported analytical characterization data Simple, routine assignments required excessive guidance and oversight Assumption that the third party understood more than they did, leading to aggregation issues in the solubilization of a simple protein Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 12 6

8 Real Examples: Benefits when Outsourcing Avoidance of Capital Spending Outsourcing of small-scale vial-lyophilized reference standards Self-Contained Work Outsourcing of general characterization and monograph testing like IR, UV, and thermal analysis, allowing focus internally on core activities Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 13 Real Examples: Benefits when Outsourcing Staffing Flexibility and Expense There when you need them, no expense when you don t Vendor Expertise with Minimal Oversight Developed a more efficient and cost-effective synthesis route for an isolated impurity Development and pre-packaging of solution reference standards Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 14 7

9 Other Considerations Successful outsourcing relationships require oversight Cannot initiate and then ignore May change depending on loss of key talent Selecting the low cost third party may not be beneficial in the long run if high employee turnover is an issue Understand the contract Sales staff that gain the business may have a different understanding than the technical staff who design and implement their products/services Include all required deliverables Internal (in-sourcing) vs. external (outsourcing) Allows for direct oversight of contracted activities but internalizes infrastructure costs Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 15 Thank You Stultz, et. al.- Managing Third Parties for the Preparation and Maintenance of Reference Standards September 2012 Copyright 2012 Eli Lilly and Company 16 8

10 9/4/2012 Selection of Source Material for Reference Standard Anu Bansal, Associate Director Heather Runes, Sr. Technical Manager MMTech, Pharma Technical Quality Genentech, A Member of Roche Group 1 Introduction What is a reference standard? Reference standard (RS) is a material used to determine presence or absence of strength, identity, purity and/or potency of the target product. How to choose a RS? Target product attribute(s) and testing purpose determine the reference standard choice Desired RS should be sensitive and specific to ensure test method and/or product undesired performance and/or attribute can be detected and analyzed with high confidence Is there only one single RS per sample/product? Use of a single RS is ideal but more than one RS may be necessary to determine presence or absence of target product attributes 2 Confidential 1

11 9/4/2012 Types of QC Reference standards 3 Purpose of Reference Standard in Pharmaceutical QC For method development and validation and equipment calibration Critical for determining strength, identity, purity, and potency of each product lot Critical for: product comparability after process changes technology transfer method monitoring (if used for system suitability) training and troubleshooting The link throughout the product lifecycle - from the early stage clinical trials to the commercial product To qualify future primary and working reference standards 4 Confidential 2

12 9/4/2012 Use of reference standards in analytical methods For identity confirmation For direct quantitative test sample result determination, e.g. relative purity and potency To generate a test sample response through the qualitative comparison of a quality attribute e.g. purity by SDS-PAGE or test method requiring result to be conforms to standard As a component of system suitability and/or assay acceptance criteria to demonstrate assay precision, efficiency, recovery and resolution that is similar to historical performance Method performance trending/monitoring programs To directly detect a known or stability indicating impurity 5 What is required in a Reference Standard for analytical methods? 6 Confidential 3

13 9/4/2012 Reference standard requirement At all stages, the reference standard should be representative of production and clinical materials (ICH Q6B). The quality attributes of the standard should represent the desired product characteristics A reference standard should not demonstrate substantially different profile than the product lots it is intended to support release and stability testing For a potency bioassay, the reference standard must have a biological activity that is identical to the biological activity of the target sample (i.e. shows parallelism) RS should be free from assay interfering substances The reference standard must be homogeneous and stable 7 Sourcing of Reference standard Primary consideration for selecting material to be used as reference standard is its intended use Reference standards may be obtained from pharmacopeias (e.g. USP and Ph. Eur.), other authorities (e.g. WHO), or commercial suppliers (e.g. NIST, NIBSC), as available and appropriate An in-house primary and/or secondary reference standard is typically manufactured using a drug substance lot(s) representative of the existing manufacturing process. It may be additionally purified, if necessary Specialized excipients utilized in pharmaceutical manufacturing may be obtained from the supplier and/or manufacturer of the material. 8 Confidential 4

14 9/4/2012 Attributes desired in a Primary and working RS Identity - positive Purity representative of the product expected purity at release and stability Additional purification may be necessary for chemical purity or impurity characterization Composition specified major, minor or trace forms, e.g. excipients, stabilizers, solvents Special physico-chemical properties concentration, viscosity, moisture etc. Homogeneity and stability Generally, biological reference standards cannot be fully characterized by physicochemical tests alone, and require the use of specific bioassay to establish their specific activity 9 Reference Standard requirement (Chemical vs. Biologics) RS attribute compared to Target Chemical Biologics Purity Similar or better Similar Identity Positive Positive Stability Better Better Strength Similar or better Similar Matrix Can be different Similar or Different Activity Not necessary Similar (parallel) Product related impurities Similar Similar Process related impurities Similar Similar Same process as Product manufacturing process Desired but not necessary* Yes Linkage to Ph III material Not necessary* Necessary * Depends on the molecule and process, e.g. synthetic peptide vs. small molecule 10 Confidential 5

15 9/4/2012 Sourcing: Drug Substance or Drug Product? For small molecules, API is used for RS. Drug substance may be suitable for a reference standard: 1. Some drug products may not be stable enough to serve as a long term reference standard in the final formulation 2. The formulation and/or concentration of drug substance may lend greater stability to the molecule, such that it may be used for an extended period of time as a reference standard 3. Drug substance may be better suited to illustrate the presence of impurities if final product goes through additional processing steps 4. Further formulation, processing and different ratio of major and minor forms in final drug product may not provide appropriate sensitivity needed for testing However, there may be the need to have both DS and DP reference standards depending on how they are used in assays. 11 Sourcing consideration for chemical reference standard A primary reference substance exhibits the highest degree of purity which is reasonably achievable Primary reference standard (API) is generally manufactured according to a special synthetic process or directly from a production API batch. It may undergo additional purification to yield a very pure form. Impurity reference substances (relevant synthetic precursors and by-products, potential impurities and degradation products) are usually obtained by selective synthesis or isolation. RS obtained from further purification shall be characterized carefully as this may impact physico-chemical and/or stability properties of the RS, e.g. X tal properties, mass balance etc. 12 Confidential 6

16 9/4/2012 Purity profile for an example chemical compound Characterization lot Reference lot Sourcing consideration for Biological RS A primary reference standard is a material, which is the key (gold) standard, that links commercial product to the material utilized in pivotal clinical trials. RS represents the desired characteristics of the production lots. Generally, biological reference standards cannot be fully characterized by physicochemical tests alone, and require the use of specific quantitative bioassay (e.g. cellular, immuno, or enzymatic) to establish their specific activity Product potency ( through bioassay) is established relative to RS. Therefore, it is necessary that the dose response characteristics of the standard are the same as those of tests samples (parallelism) It is critical that the RS manufacturing process be the same/comparable as that of the production lots 14 Confidential 7

17 9/4/2012 Biological RS Sourcing contd. Bioassays are multifactorial making it difficult to quantitatively correlate biological response to a single bio-analyte source of RS can impact bioassay response RS used in quantitative assay validation is critical for method s specificity and product specification. Hence, link to the RS used during pivotal clinical trial must be maintained throughout production to prevent product drift First primary reference standard is generally established early or late Phase III from commercial scale material Meeting specifications (both the test and limits) alone is often not enough to ensure the reference standard fully represents the product - additional characterization tests are usually employed for the primary reference standard 15 Biological RS Sourcing contd. It is desired that primary standard is maintained for long-term and reserved for future reference standard lot qualification: as 1-2, 1-3, 1-4 and not , to ensure there is no drift Because quantitative attributes (potency and content) are determined by direct comparison to the reference standard, these parameters must be precisely determined during new reference standard qualification Biomolecules have variable purity profile due to posttranslational modification and/or process related impurities extensive characterization of RS is necessary to support product comparability, investigation etc. Qualification tests generally include some or all of the following: potency, concentration (strength), mass, primary, secondary and tertiary structure, disulfide structure, carbohydrate structure and impurity profile 16 Confidential 8

18 9/4/2012 Biological RS Sourcing contd. Bioproducts are temperature sensitive and are prone to degradation over long-term storage. Therefore, for long term stability it may be necessary to have RS formulation and presentation different than that of the test article, as long as it does not adversely affect the test method, e.g. lyophilized RS vs. liquid product Microbial, protein aggregation and particulate controls be maintained during RS manufacturing to ensure long term stability To maintain long-term supply of the primary reference standard it is desirable to manufacture secondary/working reference standard lot for routine use. Secondary RS must be qualified against the primary standard and quantitative results must be precisely determined to prevent drifts. 17 Effect of Process Change on profile Lot A Lot B 18 Confidential 9

19 9/4/2012 Effect of process change on Profile Lot A Lot B 19 Source of RS Innovator production process or third party manufacturer? Depends on the RS intended purpose A new lot of RS must always be fully characterized RS used for non-quantitative testing can be sourced from material obtained from processes similar to innovator - as long as impact of difference from original RS have been established to be non-critical. Additionally, the product released using such sourced RS do not affect product quality and safety requirements. RS quality and characteristics are highly critical for methods requiring reference standard for quantitative output. In this case, impact of differently sourced RS must be evaluated against specific method s performance as well as impact to the product specification. 20 Confidential 10

20 9/4/2012 Source of RS contd. It is usually not desirable to use biological primary reference standard obtained from a different process for product release than the reference standard used during pivotal clinical studies, due to biological molecules complexity and impact to biological activity (unless equivalency for potency has been established) If a different sourced material is used to generate a new biological RS lot, it is recommended: to be qualified against the original primary reference standard used in pivotal clinical studies quantitative limits be established using the same or comparable methods used during original primary reference standard qualification extensive characterization is performed to ensure the critical quality attributes and overall quality profile is maintained 21 Summary RS Sourcing consideration Intended purpose of RS attributes to be measured, methods to be utilized and analytical specification Selection of material appropriateness Manufacturing process utilized comparable to the commercial manufacturing process Qualification and characterization of RS methods used and their validity, attributes characterized through high precision for quantitative assays, comparability to the desired product characteristic and homogeneity Stability on storage and distribution Documentation and traceability Environmental and handling control (e.g. sterility, volatility, hygroscopic, sensitivity to temperature, air or light etc) 22 Confidential 11

21 9/4/2012 Acknowledgements Heather Runes Dieter Schmalzing Susan Janes Hansjoerg Beckh Nessie Tam Nik Chetwyn Michael Dong EDQM Organizing Committee 23 Confidential 12

22 Compendial Reference Standards Manufacturing Li Bo, Ph.D. National Institutes for Food and Drug Control, China 4 September 2012 Outline RS evaluation RS manufacturing 1

23 Management procedures of RS Create RS development plan Candidates sourcing Qualified Subpackage Test(including collaborating test) Approval Approved Package Storage Supply Center National reference standard quality management system protocol develop (1) Fist lot approval candidates sourcing and test filling evaluation stability testing approval packaging and store distribution market feedback (1) API screening (2)API testing (1)filling environment (2)guidelines for filling (1) sampling (2)testing insturments (3)protocol (4)analysis report (1) time interval (1) approval procedures (2)approval (1) packing (2)storage (1) supply (2)supply chain (1) feedback information collect (2)correction actions 2

24 RS management system The system consists of four parts : 1 Preparation management 2 Sub-package and package Management 3 4 Storeroom management Supply management RS management system (Cont.) 1 3

25 RS management system (Cont.) Application form for RS candidates: RS management system (Cont.) Initial forms for sub-package and package: 4

26 RS management system (Cont.) Database information of RS: Procurement Goal: To source high quality candidates that can be used in reference standards development Accomplished by: donations customer syntheses purchases 5

27 Purity requirements: Procurement 1. Assay RS: not less than 99.5% or one batch API with appropriate quality 2. Limit testing RS: not less than 90%(TLC)or 95% (LC, etc) 3. System suitability RS: not less than 99.5% or one batch API with appropriate quality 4. Identification RS: One batch API with appropriate quality Classification 1. Quantitative use Assay standard and limit test standard, value assignment by Mass balance Microbial assay or bioassay 2. Qualitative use Identification standard (e.g., IR) System suitability (e.g., HPLC resolution or peak identifier) No purity value assigned on package label 6

28 Characterized Structures elucidation of Chemical RS: The first batch : UV IR NMR MS Element analysis X-ray Function group analysis Characterized (Cont.) Purity test of Chemical RS: HPLC (DAD) GC TLC CE DSC Compatibility degree method UV, IR, NMR Titration Optical activity Water, residual solvent, loss on drying 7

29 Collaborating study 1. Protocol prepared by NIFDC laboratory. 2. Protocol and samples sent to participants. 3. Participants test and feedback results. 4. Results evaluated by NIFDC. 5. Report with proposed assigned value. 6. Approval from expert committee. 7. Adoption by the commission. Collaborating study (Cont.) Selection of collaborating test lab from: 1. Local drug control institutes 2. Manufactures 3. NIFDC 8

30 04/09/2012 Chemical RS value assign Mass balance (majority of the small molecules, some biologics): X % = water/solvent residual on ignition x chromatograic purity/100 Production technologies Powder filling Liquid Filling Freeze drying 9

31 Production conditions 1. Highly toxic / highly potent substances: glove box under negative pressure for containment and protection of the operators 2. Hygroscopic substances: controlled humidity 3. Substances sensitive to oxidation: under inert gas Label Institute emblem Bar code Only one number Continuation 10

32 RS value: Label (Cont.) No labeling value, account for 100.0%, or Have labeling value, base on below using instruction: Do not dry before using, take the labeling value. Need dry before using, the labeling value is after drying value. Determine the water content before using, the labeling value should be subtract by the water content. There are no labeling value for RS intended for identification and impurities testing. Label (Cont.) RS value: 1. Assay RS: XX.X% 100.0% 2. Limit testing RS: If purity is higher than 95.0%, account for 100%;If lower than 95.0%,account for labeling value 3. System suitability RS: No labeling value 4. Identification RS: No labeling value 11

33 04/09/2012 Package Supply chain 1. Supply principals on-demand supply 2. Supply mode two level supply chain The first level NIFDC The second level local drug control institutes 3. Supply management Dynamic management The second level is audited and assessed by NIFDC every year 12

34 04/09/2012 Supply chain (Cont.) NIFDC provides RS to the second level unit. Both the two level units can directly supply local drug control institutes, drug manufacturers and related research institutes and other end-user of RS. Supply chain (Cont.) Self pick up and mailing. For large amount, the second level unit must check in NIFDC. Regard with toxic, narcotic, psychotropic, radioactive, and pathogenic microorganisms RS, self pick is mandatory with the official documents. 13

35 Monitoring programme Once established, the RS is underwent periodic testing to ensure its suitability for continue use. Testing interval and extent depends on the usage of the RS and its stability information available. In general the major concern is focusing on the properties that may change during the life cycle of a RS. No expiry date is provided. Question? 14

36 Storage and Distribution of Pharmaceutical Reference Standards INTERNATIONAL SYMPOSIUM PHARMACEUTICAL REFERENCE STANDARDS 3 4 SEPTEMBER 2012, STRASBOURG, FRANCE Robert L. Watters, Jr Associate Director for Measurement Services Mark Cronise Supervisory Physical Science Technician Ilse Bercik Physical Scientist Andrea Iwanik Director, Reference Standards Production Sarah Koegel Manager, Reference Standards Production National Institute of Standards and Technology United States Pharmacopeia Three Challenges 2 1

37 Reference Materials NIST SRMs and RMs A CRM that meets additional NIST-specific certification criteria Certificate reports the results of characterizations (value assignments and uncertainties) Uses to help develop accurate methods of analysis to calibrate measurement instruments to ensure the long-term adequacy and integrity of measurement quality assurance programs USP RSs A highly characterized specimen of a drug substance, excipient, major impurity, degradation product, food ingredient, or performance calibrator Uses in compendial methods to assure that products are of the appropriate identity, strength, quality, and purity as a convenience to industry 3 Reference Materials (2) NIST RMs and SRMs 1209 SRMs 86 RMs 32K units/yr. Categories Environmental Industrial Health & Clinical Engineering High-Purity Physical Properties Food & Agricultural Radioactivity USP RSs and CRMs 4 CRMs 2929 RSs 500K units/yr. Categories Health and Clinical 4 2

38 Global Reach NIST SRMs USP RSs 5 Global Reach Consequences (1) Shipping/Carrier complications Carrier policies Can change monthly Customer preferences Government procurement barriers (NIST problem) Carrier capabilities Advertised vs. our experience 6 3

39 Global Reach Consequences (2) Customs issues Harmonized Commodity Description and Coding System (HS) established a tariff code for CRMs Free Varying interpretations resulting in costs to customers Lack of required storage facilities Local customs that increase costs to customers 7 Global Reach Consequences (3) Other country specific issues Manufacturer s declaration Health certificate for human or animal derived materials Customized labelling USP shipping system Shipping name UN number Hazard class Handling, packaging & labelling instructions 8 4

40 04/09/2012 Cold Storage NIST units in units in stock (7 %) USP ~1.2 M units (56 %) 9 Cold Storage Facilities NIST new warehouse 2167 m2 125 m3 at 4 C 200 m3 at 20 C 200 m3 at 75 C USP 17 refrigerators 7 freezers 833 m3 total 10 5

41 Hazard Assessment Safety Data Sheet (SDS) Labelling Work process flow OSHA GHS Hazard Communication Safety Data Sheet (SDS) 16 Sections Section 2: has changed to incorporate pictograms and Hazard or Precautionary Statements; it requires calculations and specific information such as ph and toxicity to be able to classify pure chemicals and mixtures Section 9: Minimum required information for Physical/Chemical properties Section 12: Ecological information non mandatory in the US Labels Labels are required to include Material warnings, Measurement pictograms, Laboratory hazard/precautionary statements 12 6

42 Calculations Needed Health Hazard Acute Toxicity Skin Corrosion/irritation Serious Eye Damage/Eye Irritation Respiratory or Skin Sensitization Germ Cell Mutagenicity Carcinogenicity Reproductive Toxicology Target Organ- Single Exposure Target Organ-Repeated Exposure Aspiration Toxicity Environmental Hazard Hazardous to the Aquatic Environment Acute/Chronic Bioaccumulation Degradability Physical Hazard Explosives Flammables Oxidizing Self Reactive Pyrophoric Solids/Liquids Self-Heating Material Organic Measurement Peroxides Laboratory Corrosive to Metals 13 Challenges of Mixture Classification: Acute Toxicity Example 100 or % Exposure route Category 1 Category 2 Category 3 Category 4 Oral (mg/kg bodyweight) 5 >5 and 50 >50 and 300 >300 and 2000 Dermal (mg/kg bodyweight) 5 >50and 200 >200 and 1000 >1000 and 2000 Inhalation - Gases (ppm) 100 >100 and 500 >500 and 2500 >2500 and Material Measurement Laboratory Inhalation - Vapors (mg/l) 0.5 >0.5 and 2.0 >2.0 and 10.0 >10.0 and 20.0 Inhalation Dusts and Mists (mg/l) 0.05 >0.05 and 0.5 >0.5 and 1.0 >1.0 and

43 OSHA new GHS SDS Material Measurement Laboratory 15 OSHA: New GHS Label Information on Label and SDS Match Material Measurement Laboratory 16 8

44 Section 9: OSHA Required Information Appearance (physical state, color, etc) Odor Odor threshold ph Melting point/freezing point Initial boiling point and boiling range Flash point Evaporation Rate Flammability (solid, gas) Upper/lower flammability or Explosive limits Vapor pressure Vapor density Relative density Solubility (ies) Partition coefficient: n-octanol/water Auto-ignition temperature Decomposition Material Temperature Measurement Laboratory Viscosity All items are required; if not applicable or not available: it has to be indicated 17 Information Needed Safety Data Sheet, Label, and Department of Transportation 8 properties are needed for classification Most Needed Appearance (physical state, color, etc.) Upper/lower flammability or explosive limits ph Initial boiling point and boiling range Flash point Flammability (solid, gas) Material Measurement Laboratory Auto ignition temperature Melting point/freezing point 18 9

45 Safety Data Sheet and Label Classification Figure A.1.1: Tiered approach to classification of mixtures for acute toxicity Test data on the mixture as a whole No Yes Sufficient data available on similar mixtures to estimate classification hazards Yes Apply bridging principles in A CLASSIFY No Available data for all ingredients Yes Apply formula in A CLASSIFY No Other data available to estimate conversion values for classification Yes Apply formula in A CLASSIFY No Convey hazards of the known ingredients Apply formula in A (unknown ingredients 10%) or Apply formula in A (unknown ingredients > 10%) CLASSIFY 19 OSHA 2012 HazCom Effective Dates Effective Completion Date Requirement(s) Who December 1, 2013 Train employees on the new label elements and safety data sheet (SDS) format. Employers June 1, 2015* December 1, 2015 Compliance with all modified provisions of this final rule, except: The Distributor shall not ship containers labeled by the chemical manufacturer or importer unless it is a GHS label Chemical manufacturers, importers, distributors and employers June 1, 2016 Update alternative workplace labeling and hazard communication program as necessary, and provide additional employee training for newly identified physical or health hazards. Employers Transition Period to the effective completion dates noted above May comply with either 29 CFR (the final standard), or the current standard, or both Chemical manufacturers, importers, distributors, and employers * This date coincides with the European Union implementation date for classification of mixtures

46 Current Process Material received Processing/packaging Characterization Statistical analysis Technical reports Hazard assessment Certificate, labels, & SDS 21 New Process Material received HA, SDS & label Processing/packaging Characterization Statistical analysis Technical reports Certificate & labeling 22 11

47 Receiving Candidate Material from a Supplier Concerns about having a non compliant label Special Concerns with SRMs that need to be frozen and having to do relabeling Material Measurement Laboratory 23 12