29 April 2016, AS1 Control of Drug Product Institute of Biological Products (IBP), DMSc, Ministry of Public Health, Thailand Apichai Supasansatorn

29 April 2016, AS2 Outline: P5 Control of Drug Product ACTD: P5 Control of Finished Product 5.1 ข้อกำหนดมาตรฐาน (Specification) และหนังสือรับรอง การวิเคราะห์ (Certificate of Analysis) 5.2 วิธีการวิเคราะห์ (Analytical Procedures) 5.3 การตรวจสอบความถูกต้องของวิธีการวิเคราะห์ (Validation of Analytical Procedures) 5.4 การวิเคราะห์รุ่นการผลิต (Batch analysis) 5.5 การตรวจลักษณะเฉพาะของสารเจือปน (Characterization of Impurities) 5.6 การชี้แจงเหตุผลของข้อกำหนดมาตรฐาน (Justification of Specification)

29 April 2016, AS3 Drug Product The drug product is the finished dosage form of the product. The drug product contains the drug substance (s) formulated with other ingredients in the finished dosage form ready for marketing. Other ingredients, active or inactive, may include adjuvants, preservatives, stabilizers, and/or excipients. For vaccine formulation, the drug substance (s) may be diluted, adsorbed, mixed with adjuvants or additives, and/or lyophilized to become the drug product (USFDA).

29 April 2016, AS4 Final Bulk Vaccine (ACTD: P 3.3 Control of Critical Steps and Intermediates) Material that has undergone all the steps of production except for the final filling. It consists of one or monovalent pooled harvests, from cultures of one or more species or types of microorganism, after clarification, dilution or addition of an adjuvant or other auxiliary substance. It is treated to ensure its homogeneity and is used for filling the containers of one or more final lots (batches)

29 April 2016, AS5 Finished pharmaceutical product (FPP) A product that has undergone all stages of production, including packaging in its final container and labeling. An FPP may contain one or more APIs. Other name: Final Product, Final Lot Finished Product

29 April 2016, AS6 5.1 Specification and Certificate of Analysis Specification: The rationale used to establish the acceptance criteria should be described. Based on data obtained: Relevant development data Lots used in preclinical, clinical studies Lots used for demonstration of manufacturing consistency Stability studies

29 April 2016, AS7 5.1 Specification and Certificate of Analysis Specification: The requirements that used as references are enclosed. (How to choose the requirement?) Thai Pharmacopoeia The United State Pharmacopoeia European Pharmacopoeia British Pharmacopoeia International Requirement (WHO)

29 April 2016, AS8 Drug product: a Toxoided Vaccine (WHO) Final Bulk Filling Final Product Sterility Specific Toxicity Potency Preservative Adjuvant Residual detoxifying agent pH Inspection Identity Sterility Innocuity Adjuvant pH, filling volume

29 April 2016, AS9 Drug product: a Live Bacterial Vaccine (WHO) Final Bulk Final Product Identity Sterility Test for absence of virulent mycobacteria Total bacterial count Viability test Oxygen uptake test Identity Sterility Test for absence of virulent mycobacteria Skin reactivity test in guinea pigs Total bacterial count Viability test Oxygen uptake test Filling, Freeze-drying

29 April 2016, AS10 Drug product: a Inactivated Bacterial Vaccine (WHO) Final Bulk Filling Final Product Inspection Identity Sterility Innocuity Adjuvant pH, filling volume Agglutinogens Preservative Adjuvant Sterility Potency Specific toxicity pH

29 April 2016, AS11 Drug product: a Live Attenuated Viral Vaccine (WHO) Final Bulk Final Product Residual serum proteins Sterility Filling/freeze drying Inspection Identity Sterility Virus titration Thermostability General safety Residual moisture

29 April 2016, AS12 Drug product: a Inactivated Viral Vaccine (WHO) Final Bulk Final Product Sterility Antigenicity Residual Inactivant Filling Sterility Potency Identity Innocuity Pyrogen

29 April 2016, AS13 Drug product: a Polysaccharide Vaccine (WHO) Final Bulk Final Product Filling, Lyophilization Identity (group specific Ag) Heterologous polysaccharide Conc of polysaccharide Phosphorous/gm polysacch. Sterility Abnormal toxicity Pyrogens Molecular size Moisture Sterility Serological specificity Identity

29 April 2016, AS14 Drug product: a conjugated polysaccharide vaccine (WHO) Final Bulk Final Product Sterility Filling, Lyophilization Identity (specific for the PRP) Potency Conc of Hib polysaccharide Preservative Sterility Abnormal toxicity (innocuity) Pyrogens Moisture

29 April 2016, AS Specification and Certificate of Analysis Specification Ex. diphtheria and Tetanus vaccine (Final Bulk) No.Tests (including method used and reference) Specifications 1.Description (Inspection)Whitish turbid liquid 2.SterilityNo evidence of contamination 3.pH6.0–7.0 4.Thiomersal content0.085–0.115% 5.Aluminum contentNMT 1.25 mg per single dose 6.Free formaldehydeNMT 0.02% w/v (0.2 g/L)

29 April 2016, AS Specification and Certificate of Analysis Specification Ex. diphtheria and Tetanus vaccine (Final bulk) No.Tests (including method used and reference) Specifications 7.Specific Toxicity test for D&T None of the animals shows any symptoms of Diphtheria or tetanus toxemia or dies from Diphtheria with 42 days, from tetanus 21 days 8.Potency for Diphtheria component LCL of estimated potency ≥ 2 and ≤ 30 IU/SHD 9.Potency for Tetanus component LCL of estimated potency ≥ 40 IU/SHD 10.Adsorption of DiphtheriaFor information 11.Adsorption of TetanusFor information

29 April 2016, AS Specification and Certificate of Analysis Specification Ex. diphtheria and Tetanus vaccine (Final Lot) No.Tests (including method used and reference) Specifications 1.Description (Inspection)Whitish turbid liquid 2.Identity for TetanusIdentical 3.Identity for DiphtheriaIdentical 4.SterilityNo evidence of contamination 5.pH6.0–7.0

29 April 2016, AS Specification and Certificate of Analysis Specification Ex. Diphtheria and tetanus vaccine (Final Lot) No.Tests (including method used and reference) Specifications 6.Thiomersal content0.085–0.115% 7.Aluminum contentNMT 1.25 mg per single dose 8.Abnormal toxicity (Innocuity) the animals survive for at least seven days without showing significant signs of toxicity. 9.Extractable volume (Filling volume) Not less than nominal volume.

29 April 2016, AS Specification and Certificate of Analysis Ex. Rabies vaccine (Final Bulk) No.Tests (including method used and reference) Specifications 1.Preservatives and Substances added -Adjuvant -Preservative -Human albumin -beta-propiolactone - 2.Antigen content- 3.SterilityNo evidence of contamination

29 April 2016, AS Specification and Certificate of Analysis Ex. Rabies vaccine (Final Lot) No.Tests (including method used and reference) Specifications 1.IdentityIdentical 2.SterilityNo evidence of contamination 3.Abnormal toxicity (Innocuity) the animals survive for at least seven days without showing significant signs of toxicity. 4.PotencyNLT 2.5 IU/SHD 5.Stability test at 37C for 7 weeks NLT 2.5 IU/SHD 6.Residual moistureNMT 1%

29 April 2016, AS Specification and Certificate of Analysis Ex. Rabies vaccine (Final Lot) No.TestsSpecifications 7.Volume≥ 1 ml 8.Sodium chloride0.85–0.95 %

29 April 2016, AS Specification and Certificate of Analysis Ex. Diluent's for rabies vaccine No.TestsSpecifications 1.AppearanceClear, colorless solution 2.SterilityNo evidence of contamination 3.Particulate matter ≥ 10 µm, max 3000 particles/container ≥ 25 µm, max 300 particles/container 4.Bacterial endotoxins≤ 0.25 EU/ml 5.pH5.0–7.0 6.Chloride≤ 0.5 mg/ml

29 April 2016, AS Specification and Certificate of Analysis Ex. Diluent's for rabies vaccine No.TestsSpecifications 7.SulfateNo turbidity is produced 8.Ammonia≤ 0.6 mg/ml 9.CalciumNo turbidity is produced 10.Carbon dioxideMixture remain clear 11.Oxidizable SubstancePink color dose not completely disappear

29 April 2016, AS Specification and Certificate of Analysis Certificate of analysis: -A batch-specific document that is used to list test methods and results, including applicable specifications, acceptance criteria, and a final batch disposition. -(USP) A list of the analytical tests, acceptance criteria, and results obtained on a particular article.

29 April 2016, AS Specification and Certificate of Analysis Certificate of analysis: 1. Analytical tests and test procedure Ex. Sterility test (Analytical method) Direct inoculation or Membrane filtration (test procedure) 2. Specification, acceptance criteria 3. Results

29 April 2016, AS Specification and Certificate of Analysis Certificate of analysis each batch Name of Product:__________ Batch Size:____________ Batch Number:_________ Mfd:_________ Exp:________ No.Tests (including method used and reference) SpecificationsResult 1.Description (Visual Inspection) Whitish turbid liquid 2.Identity for Tetanus (Flocculation) Identical with TATPositive 3.Identity for Diphtheria (Flocculation) Identical with DATPositive 4.Sterility (Direct inoculation) No evidence of contamination No contamination found in 14 days 5.………

29 April 2016, AS ทั้งที่เป็น Compendia method และ In-House method ประกอบด้วย แสดงวิธีการทดสอบอย่างละเอียด หลักการทดสอบ สารสำคัญที่ใช้ เครื่องมือสำคัญของการทดสอบ เอกสารอ้างอิงที่ใช้ในการทดสอบ สถิติที่ใช้ในการคำนวณผลการทดสอบและตัวอย่างการ คำนวณผล 5.2 Analytical Procedures

29 April 2016, AS Analytical Procedures No.TestsAnalytical Method/ Test Procedure 1.Description (Inspection)SOP no. 1 -Testing Description for vaccines. 2.Identity for TetanusSOP no. 2 -Testing Identity for Tetanus component in combined vaccines. 3.Identity for DiphtheriaSOP no. 3 -Testing Identity for diphtheria component in combined vaccines. 4.SterilitySOP no. 4 -Sterile Testing by Direct Inoculation method. 5.……

29 April 2016, AS Non compendia or In-house method Validation Protocol Validation Report Compendia method Verification protocol Verification report Reference Ex. ICH Q2 (R1) 5.3 Validation of Analytical Procedures

29 April 2016, AS Validation of Analytical Procedures No.Tests ValidatedParameters for Validation 1.Validation of Identity test of Tetanus component in combined vaccines Specification, Precision (Repeatability, Intermediate precision) 2.Validation of Identity test of Diphtheria component in combined vaccines Specification, Precision (Repeatability, Intermediate precision) 3.Verification of pH measurementPrecision 4.Determination of Aluminium contentLinearity, Range, Precision, Accuracy, Specificity and Robustness 5.Determination of Thiomersal contentLinearity, Range, Precision, Accuracy and Specificity

29 April 2016, AS 5.4 Batch analysis ประกอบด้วย Batch description (มีการวิเคราะห์วิจารณ์เหมือน หรือต่างจาก clinical ถ้าต่างทำอะไรต่อ) จำนวนสามรุ่นการผลิต แสดงในรูป Summary table มี Summary Production Protocol (SPP) ประกอบในแต่ละรุ่นการผลิต

29 April 2016, AS Batch analysis No.TestsSpecificationsBatch No.1Batch No.2Batch No.3 1.Description ( Visual Inspection) Whitish turbid liquid 2.Identity for Tetanus (Flocculation) IdenticalPositive 3.Identity for Diphtheria (Flocculation) IdenticalPositive 4.Sterility (Direct inoculation) No evidence of contamination No contamination found in 14 days 5.……………

29 April 2016, AS Characterization of Impurities Impurity: A foreign agent or material either introduced as part of processing (such as buffers or salts added during chromatography) or intrinsic to the nature of bioprocessing (such as product variants and cellular debris).

29 April 2016, AS Characterization of Impurities Impurity Profile: (ICH Q3B (R2)) A description of the identified and unidentified impurities present in a drug product.

29 April 2016, AS Characterization of Impurities Impurity Profile: A description of the identified and unidentified impurities present in a typical batch of API (Active Pharmaceutical Ingredient) produced by a specific controlled production process. It includes the identity or some qualitative analytical designation (e.g. retention time), the range of each impurity observed, and type of each identified impurity. For each API there should be an impurity profile describing the identified and unidentified impurities present in a typical batch. The impurity profile is normally dependent upon the process or origin of the API.

29 April 2016, AS Characterization of Impurities The impurities are derived from 1. Process-related impurities and contaminates: -Cell substrates ( e.g., host cell protein, host cell DNA) -Cell culture (e.g., inducers, antibiotics, Serum, media component) -Downstream ( e.g., enzymes, chemical and biochemical processing reagents )

29 April 2016, AS Characterization of Impurities The impurities are derived from 2. Product-related impurities including degradation products: -Truncated forms: Hydrolytic enzymes or chemicals may catalyse the cleavge peptide bonds. -Other modified forms: Deamidated, isomerised, mismatched S-S linked, oxidiesd -Aggregates: includes dimers and higher multiples of the desired product.

29 April 2016, AS Characterization of Impurities การตรวจลักษณะสารเจือปน Physiochemical characterizations 1. Structural characterization and confirmation -Amino acid and Terminal Amino acid sequence -Amino acid composition -Peptide map -Sulfhydryl group (s) and disulfide bridges -Carbohydrate structure

29 April 2016, AS Characterization of Impurities 2. Physicochemical properties -Molecular weight or size -Isoform pattern -Electrophoretic pattern -Liquid chromatographic pattern -Spectroscopic profiles

29 April 2016, AS Characterization of Impurities Technique used: -SDS-PAGE -HPLC -Western-blot -Mass spectroscopy -Capillary electrophoresis -Size exclusion chromatography, etc.

29 April 2016, AS Justification of Specification The setting of specifications for drug substance and drug product is part of an overall control strategy which includes control of raw materials and excipients, in- process testing, process evaluation or validation, adherence to Good Manufacturing Practices, stability testing, and testing for consistency of lots. When combined in total, these elements provide assurance that the appropriate quality of the product will be maintained. Since specifications are chosen to confirm the quality rather than to characterize the product, the manufacturer should provide the rationale and justification for including and/or excluding testing for specific quality attributes. The following points should be taken into consideration when establish in scientifically justifiable specifications. (ICH Q 6 B )

29 April 2016, AS Justification of Specification Based on data from Linked to a manufacturing process. Account for the stability of drug substance and drug product. Linked to preclinical and clinical studies. Linked to analytical procedures

29 April 2016, AS43 Reference คู่มือ/หลักเกณฑ์การขึ้นทะเบียนตำรับยาสามัญใหม่ (New Generic Drugs) แบบ ASEAN HARMONIZATION, กันยายน 2556 WHO TRS No. 980, 2014 (D, T) WHO TRS No. 941, 2007 (Rabies) ICH Q 6 B PHARMACEUTICAL AND VACCINE QUALITY ILLUSTRATED, ÜMİT H. KARTOĞLU,

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