Developing specifications q3 q6
- 1. DEVELOPING SPECIFICATION PRESENTEDBY : NAMRATA BAWASKAR M PHARM(QA) SUBJECT : QUALTY CONTROL QUALITY ASSURANCE ALL INDIA SHRI SHIVAJI MEMORIAL SOCIETY’S COLLEGE OF PHARMACY ,PUNE
- 2. CONTENT • SPECIFICATION • TYPE OF SPECIFICATION • ICH Q6A GUIDELINE • ICH Q6B GUIDELINE • ICH Q3A(R2) GUIDELINE • ICH Q3C GUIDELINES 2
- 3. WHAT IS SPECIFICATION • A SPECIFICATION IS DEFINED AS A LIST OF TESTS, REFERENCE TO ANALYTICAL PROCEDURES , AND APPROPRIATE ACCEPTANCE CRITERIA WHICH ARE NUMERICAL LIMITS , RANGES, OR OTHER CRITERIA FOR THE TESTS DESCRIBED . 3
- 4. JUSTIFICATIONOF SPECIFICATIONS • Justification required for 1. Each procedure, 2. Each acceptance criterion included in the specification. • Justification should refer to: • Setting and justifying specifications by • Batches from: - 1) Primary stability 2)Scale-up, -3) Validation. 4 1. Relevant development data, 2. Pharmacopoeias standards, 3. Test data of batches used in toxicology and clinical studies 4. Results from accelerated and long term stability studies, 5. Reasonable range of expected analytical and manufacturing variability.
- 5. TYPE OF SPECIFICATION active and inactive starting material packaging materials for intermediate and bulk products 5
- 7. UNIVERSAL TEST/ CRITERIA NEW DRUG SUBSTANCE NEW DRUG PRODUCTS SPECIFIC TEST/ CRITERIA NEW DRUG SUBSTANCE NEW DRUG PRODUCTS 7
- 8. 1. Universal Tests / Criteria A. New Drug Substances The following tests and acceptance criteria are considered generally applicable to all new drug substances. a) Identification: e.g. IR , HPLC , HPTLC , GC ,GC/MS etc. b) Description: properties like colour , odour , state, etc. can be determined c) Assay: content uniformity d) Impurities : organic & inorganic impurities ,residual solvents B. New Drug Products . SAME 2. Specific Tests / Criteria A. New Drug Substances a) Physicochemical properties: pH of an aqueous solution, melting point / range, and refractive index 8
- 9. b) Particle size: solid or suspension drug products c) Polymorphic form : • Polymorphism may also include solvation or hydration products (also known as pseudo polymorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist. • Examples of these procedures are: • melting point (including hot-stage microscopy) • solid state IR, X-ray powder diffraction • thermal analysis procedures (like DSC, TGA and DTA) • Raman spectroscopy, optical microscopy, and solid state NMR. 9
- 10. d) Tests for chiral new drug substances: identity tests, impurity tests, and assays may be needed for both new drug substances and new drug products, according to the following concepts: Drug Substance :1. Impurities 2. Assay 3. Identity Drug Product:1. Degradation products 2. Assay 3. Identity e) Water content: This test is important in cases where the new drug substance is known to be hygroscopic or degraded by moisture. e.g., Karl Fischer titration 10
- 11. f) Inorganic impurities: • may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy. g) Microbial limits: • There may be a need to specify the total count of aerobic microorganism, the total count of yeasts and molds, and the absence of specific objectionable bacteria (e.g., Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be suitably determined using pharmacopoeia procedures. B. New Drug Products: The following tests are applicable to tablets (coated and uncoated) and hard capsules, oral liquids, and parenteral. One or more of these tests may also be applicable to soft capsules and granules. 11
- 12. SOLIDDOSAGEFORM • Dissolution • Disintegration • Hardness/friabili ty • Uniformity of dosage units • Water content • Microbial limits ORALLIQUID • Uniformity of dosage units • Ph • Microbial limits • Antimicrobial preservative content • Extractables • Alcohol content • Dissolution • Particle size distribution • Redispersibility • Rheological properties • Reconstitution time • Water content PARENTRAL • Uniformity of dosage units • Ph • Sterility • Endotoxins/Pyrogens • Particulate matter • Water content • Antimicrobial preservative content • Extractables • Antioxidant preservative content • Functionality testing of delivery systems • Osmolarity • Particle size distribution • Redispersibility • Reconstitution time 12
- 13. DISSOLUTION • Dissolution is considered product-specific. The method and limits should be appropriate for the proposed product. • Single-point measurements are normally considered to be suitable for immediate-release dosage forms. • For modified-release dosage forms, appropriate test conditions and sampling procedures should be established. - multiple time point sampling should be performed for extended-release dosage forms - two-stage testing (using different media in succession or in parallel, as appropriate) may be appropriate for delayed-release dosage forms. • For immediate-release drug products where changes in dissolution rate have been demonstrated to significantly affect bioavailability • Dissolution specs at release and shelf-life should be identical. It is useful to have the parameters (medium, apparatus, speed) in specs. 13
- 14. 14 • The limits should be expressed as “Q”, which also implies three stage testing as per harmonized texts. Ideally the stages are expressed in the specs (i.e. S1 all individual values Q+15%) There should be a discussion if the time is > 45 minutes. • For products containing water insoluble APIs, it is recommended to have a two tire dissolution limit.
- 15. 15Additional considerations are required when there is a BCS-based biowaiver: • BCS Class 1 (e.g. emtricitabine, stavudine, zidovudine, levofloxacin, ofloxacin): The test and comparator products must be at least rapidly dissolving. (NLT 85% in 30 minutes) • BCS Class 3 (e.g. abacavir sulphate, lamivudine, ethambutol, isoniazid, pyrazinamide): The test and comparator products must be very rapidly dissolving (NLT 85% in 15 minutes). • Dissolution limits must meet the biowaiver requirements.
- 16. 16• Setting of Dissolution Specifications • The Q value is recommended to be set on the basis of the bio-batch dissolution result (mean value of 12 units) minus 10%. • Usually the time points 15, 30 or 45 minutes would be sufficient, but other time points may be used if justified. Dissolution of the Biobatch Specification Setting ≥ 95% in 15min Q=85% in 15 minutes ≤ 95% and ≥ 85% in 15min Q=75%, 80% or 85% whichever is closer to Q=biobatch result -10% at 15 minutes ≥ 85% after 30min Q=75%, 80% or 85% whichever is closer to Q=biobatch result -10% at 30 minutes ≥ 85% after 45min Q=75%, 80% or 85% whichever is closer to Q=biobatch result -10% in 45 minutes ≤ 85% after 45min Q=75% in 45 minutes ≤ 75% after 45min Dissolution specification should be based on more than one time point
- 17. DISINTEGRATION For rapidly dissolving (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) products containing drugs which are highly soluble throughout the physiological range (dose/solubility volume < 250 mL from pH 1.2 to 6.8), disintegration may be substituted for dissolution. 17 Un coated tablet) NMT 15 min, in water with disc 37 °C ± 2°C Coated tablet NMT 30 min, in water with disc for film coated tab, and NMT 60 min, other than film coated tablet Enteric coated tab Intact for 1 hr in 0.1 N HCl & disintegrate within 2 hr in mixed 6.8 phosphate buffer. According to USP 1 hr in simulated gastric fluid, then in simulated intestinal fluid. Dispersible/soluble Within 3 min in water at 25°C ±1°C (IP) 15-25°C (BP) Orodispersible Within 1 min Effervescent tab 5 min in 250 ml water at 20 – 30 °C (IP) 5 min in 200 ml water at 15 – 25 °C (BP Buccal & sublingual Not applicable but dissolve within 15 – 30
- 18. HARDNESS/FRIABILITY • It is normally appropriate to perform hardness and/or friability testing as an in-process control. Under these circumstances, it is normally not necessary to include these attributes in the specification. • Chewable tablets: acceptance criteria should be included in the specification. • Friability limit is NMT 1 % 18 Water content • A test for water content should be included when appropriate. The acceptance criteria may be justified with data on the effects of hydration or water absorption on the drug product. • In some cases, a Loss on Drying procedure may be considered adequate; however, a detection procedure which is specific for water (e.g., Karl Fischer titration) is preferred.
- 19. WEIGHT VARIATION • This term includes both the mass of the dosage form and the content of the active substance in the dosage form • A pharmacopoeia procedure should be used. • In general, the specification should include one or the other but not both. • If appropriate, these tests may be performed in-process; • The acceptance criteria should be included in the specification. A test and limit for weight variation may be established in lieu of content uniformity testing; 19 IP/BP LIMIT USP 80 mg or less 10 % 130 mg or less 80 mg 80 mg-250 mg 7.5 % 130 mg -324 mg 250 mg or more 5 % 324 mg or more For tablet For capsule IP LIMIT Less than 100 mg 10 % 100 mg or more 7.5 %
- 20. ORAL LIQUID Uniformity of dosage units • Content uniformity • Mass uniformity pH :Acceptance criteria where applicable and proposed range justified. Microbial limits • TAMC, • TYMC, • Specified micro organism Antimicrobial preservative content • Acceptance criteria based on levels to maintain microbiological product quality throughout shelf life. • The lowest specified concentration should be controlled by antimicrobial preservative effectiveness test • Antimicrobial preservative effectiveness. should be demonstrated during development, scale-up, throughout the shelf life. 20
- 21. ANTIOXIDANT PRESERVATIVE CONTENT • Release testing should be performed • Shelf life testing may be unnecessary where justified by development and stability data. EXTRACTABLES Where development and stability data show no significant evidence of extractables elimination of this test may be proposed. • Where data demonstrate need acceptance criteria for oral solutions: - rubber stopper - cap liner - plastic bottle • Data should be collected as early in development process as possible. ALOCHOL CONTENT • Where it is declared quantitatively on the label in accordance with pertinent regulations, the alcohol content should be specified. It may be assayed or calculated. 21
- 22. 22Dissolution • It may be appropriate for insoluble drug substance • Single-point measurements - Immediate-release dosage forms • Multiple-point measurements - Modified-release dosage forms Particle size distribution • PSD may be appropriate for oral suspensions • Developmental data should be considered for either a dissolution procedure or a particle size distribution procedure for these formulations Particle size distribution • testing may also be proposed in place of dissolution testing, justification should be provided. • Mean, upper and/or lower particle size limits should be well defined.
- 23. Redispersibility • For oral suspensions which settle on storage (produce sediment), acceptance criteria for redispersibility may be appropriate. Shaking may be an appropriate procedure. Rheological properties • For relatively viscous solutions or suspensions, it may be appropriate to include rheological properties (viscosity/specific gravity) in the specification. Reconstitution time • should be provided for dry powder products which require reconstitution • The choice of diluent should be justified • Data generated during product development may be sufficient to justify skip lot testing, or elimination of this attribute from the specification may be proposed. 23
- 24. 24 Sterility: • This approach may be proposed for terminally sterilized drug products • Data generated during development and validation Endotoxins/Pyrogens: • Endotoxins-using a procedure such as the limulus amoebocyte lysate test (LAL test) • Pyrogenicity testing may be proposed as an alternative to endotoxin testing where justified Particulate matter: • Limits for visible particulates (foreign matter) and / or clarity of solution, as well as for sub-visible particulates as appropriate. PARENTRAL TEST
- 25. Water content: • For non-aqueous parenteral, and for parenteral products for reconstitution • Loss on drying is generally considered sufficient. • In certain cases a more specific procedure (e.g., Karl Fischer titration) may be preferable. Extractables: • More important for parenteral products than for oral liquids • where development and stability data show evidence that extractables are consistently below the levels that are demonstrated to be acceptable and safe, elimination of this test can normally be accepted. 25
- 26. 26Functionality testing of delivery systems: • For pre-filled syringes, autoinjector cartridges, or the equivalent • These may include control of syringability, pressure, and seal integrity (leakage), and/or parameters such as tip cap removal force, piston release force, piston travel force, and power injector function force. • Skip test applicable, if justified. Osmolarity: • When the tonicity of a product is declared in its labelling, appropriate control of its osmolarity should be performed. • Skip test applicable, if justified.
- 27. Q6 (B) GUIDELINES Objective This guidance document provides general principles on the setting and justification, to the extent possible, of a uniform set of international specifications for biotechnological and biological products to support new marketing applications. PRINCIPLES FOR CONSIDERATION IN SETTING SPECIFICATIONS 1. Characterization : a) Physicochemical properties b) Biological activity 27
- 28. Examples of procedures used to measure biological activity include: • Animal-based biological assays, which measure an organism's biological response to the product • Cell culture-based biological assays, which measure biochemical or physiological response at the cellular level • Biochemical assays, which measure biological activities such as enzymatic reaction rates or biological responses induced by immunological interactions. c) Immunochemical properties e.g., ELISA, Western-blot d) Purity, impurities and contaminants e) Quantity 28
- 29. 2. Analytical Considerations . • 1 Reference standards and reference materials 2 Validation of analytical procedures 3. Process Controls. 1. Process-related considerations: 2. Raw materials and excipient specifications : 3. In-process acceptance criteria and action limits: 4. Pharmacopoeial Specifications. 5. Release Limits vs. Shelf-life Limits : Statistical Concepts :. 29
- 30. 1.Drug Substance Specification Purity and impurities Potency Appearance and description Identity Quantity 1.Drug Product Specification Appearance and description Identity Purity and impurities Potency Quantity Additional testing for unique dosage forms General tests specification 30
- 31. Q3 GUIDELINES 31
- 32. OBJECTIVE • The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product. The control of impurities is currently a critical issue to the pharmaceutical industry. • Objective: To makes recommendation to applicant on reporting, identifying & qualifying information on impurities in new drug substance . 32
- 33. WHATIS IMPURITY…..? ICH defines impurities as substances in the API that are not the API itself. OR Any component of drug substance that is not the chemical entity Or for drug product that is not the drug substance or an excipient . • ICH Status: Q3A- Q3D Impurities • Q3A (R2) Impurities in New Drug Substances • Q3B (R2) – Impurities in New Drug Products • Q3C (R5) – Impurities : Guideline for Residual Solvents • Q3D – Impurities : Guideline for Elemental Impurities 33
- 34. DEFINATIONS 1. Impurity: Any component of the new drug product that is not the drug substance or an excipient in the drug product. 2. Impurity Profile: A description of the identified and unidentified impurities present in a drug product. 3. Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. 4. Degradation Product: An impurity resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system. 5. Degradation Profile: A description of the degradation products observed in the drug substance or drug product. 34
- 35. 6. Identified Degradation Product: A degradation product for which a structural characterisation has been achieved. 7. Unidentified Degradation Product: A degradation product for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time) 8. Qualification Threshold: A limit above (>) which a degradation product should be qualified. 9. Reporting Threshold: A limit above (>) which a degradation product should be reported. 10.Identification Threshold: A limit above (>) which a degradation product should be identified. 35
- 37. ORGANIC •Organic impurities mainly arise during the synthesis, purification(manufacturing process )and or storage of the drug substance •Organic impurities can be classified like... 1. Starting materials 2. Intermediate 3. Degradation products 4. Reagents, ligand and catalyst 37
- 38. INORGANIC Inorganic impurities derive from the manufacturing process and excipients. Generally, excipients contain high levels of heavy metals such as arsenic, bismuth, cadmium, chromium, copper, iron, lead, mercury, nickel and sodium. Sometimes they might present in the product during processing or they leached from packing material Heavy metals Inorganic salts Other material's like filter aids, charcoal 38
- 39. RESIDUAL SOLVENTS (ICH Q3 C GUIDELINE) • Residual solvents are potentially undesirable substances. • They either modify the properties of certain compounds or may be hazardous to human health. The residual solvents also affect physicochemical properties of the bulk drug substances such as crystallinity of bulk drug, which in turn may affect the dissolution properties, odour and colour changes in finished products • Residual solvents are those solvents which are used as vehicles for the preparation of solution / suspensions in the synthesis of a new drug substance 39
- 40. OBJECTIVE OF THIS GUIDELINE • The is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents • Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. 40
- 41. AS PER THE ICH GUIDELINES, THE SOLVENTS USED IN THE MANUFACTURING OF DRUG SUBSTANCES CLASSIFIED IN TO FOUR TYPES •Class 1 solvents: Solvents to be avoided •Class 2 solvents: Solvents to be limited •Class 3 solvents: Solvents with low toxic potential •Class 4 solvents: Solvents for which No Adequate Toxicological Data was Found 41
- 42. A) CLASS I SOLVENTS: • Solvents to Be Avoided Solvents in Class 1 should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table 1. 42
- 43. Residual solvent benzene Carbon tetra chloride 1,1 dichloro ethane 1,2 dichloro ethane 1,1,1 trichloro ethane Concentration limit ppm 2 (toxic) 4(toxic) 8(toxic) 5(toxic) 15000(environmental hazards) 43
- 44. Solvents to Be Limited Class II solvents usage should be limited in pharmaceutical products because of their inherent toxicity. Table 2 lists class II solvents with their daily permissible exposure. Class II solvents: 44
- 45. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 460 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870 Dichloromethane 6.0 600 Hexane 2.9 290 Cumene 1 0.7 70 45
- 46. CLASS III SOLVENTS: • Solvents with Low Toxic Potential These are less toxic and possess lower risk to human health than class I or class II • Long-term toxicity or carcinogenicity not reported, which is evident from the available data for the solvents under this category. • The use of class III solvents in pharmaceuticals does not have any serious health hazard. Some of the solvents are; Acetic acid, anisole, butanol, 2butanol, isopropyl acetate, methyl acetate, butyl acetate, ter-butyl methyl ether, pentene, cumene, Dimethyl sulfoxide, ethanol, ethyl acetate, formic acid, heptane, isobutyl ketone, tetrahydrofuran, 1-pentanol, 2propanol, methyl isobutyl ketone, propyl acetate, 3methyl- 1-butanol, methyl ethyl ketone. 46
- 47. CLASS IV SOLVENTS: • Class IV solvents, adequate toxicological data is not available. The manufacturers should justify the residual levels for these solvents in pharmaceutical products. • The solvents under class IV are 1, 1-diethoxy propane, 1-1-dimethoxy propane,2dimethoxy propane, methyl isopropyl ketone, isooctane, isopropyl ether, methyl tetrahydrofuran, petroleum ether, trichloro acetic acid. 47
- 48. REFERENCES: • GUIDELINE on Cgmp AND QUALITY OF PHARMACEUTICAL PRODUCTS By S. Iyer ,D.K.Publication pg. 203. • PHARMACEUTICAL QUALITY ASSURANCE BY Manohar A. Potdar, NIRALI PRAKASHAN , pg. 7.5-7.7. • Impurities evaluation of pharmaceuticals by satinder ahuja • ICH HARMONISED TRIPARTITE GUIDELINE ON : ICH Q6 A, Q6 B , Q3 A (R2). 48
- 49. THANK YOU 49