Developing Specification (ICH Q6 and Q3), Purchase specifications and maintenance of stores for raw materials

Purchase specifications are detailed guidelines that define the operational, physical, and chemical characteristics of items to be acquired, ensuring they meet quality and quantity requirements. They include essential information such as the name, description, composition, production method, packaging, delivery method, and labeling of raw materials and ingredients. Specifications serve as a standard for purchasing, informing suppliers and aiding in quality control and assurance processes.
ICH Q6 provides guidelines for establishing specifications for new drug substances and products, focusing on universal and specific tests and criteria to ensure quality and safety. It aims to create a uniform set of international specifications for biotechnological and biological products to support marketing applications.

ICH Q3 addresses impurities in pharmaceuticals, categorizing them into four guidelines (Q3A, Q3B, Q3C, and Q3D) that outline the identification, reporting, and control of unwanted chemicals in active pharmaceutical ingredients and formulations, emphasizing their impact on product efficacy and safety.

1. QUALITY CONTROL AND QUALITY ASSURANCE Presented By: MOHD SAMEER M.Pharm 1 st Sem Pharmaceutical Quality Assurance SPER, Jamia Hamdard New Delhi-110062 “Developing Specification (ICH Q6 and Q3), Purchase specifications and maintenance of stores for raw materials” Presented to: Prof. ( Dr. ) Zeenat Iqbal Department of Pharmaceutics SPER, Jamia Hamdard New Delhi-110062

2. Developing Specification (ICH Q6 and Q3) 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. JUSTIFICATION OF SPECIFICATIONS Justification required for Each procedure, Each acceptance criterion included in the specification. Justification should refer to: Relevant development data, Pharmacopoeias standards, Test data of batches used in toxicology and clinical studies, Results from accelerated and long-term stability studies, Reasonable range of expected analytical and manufacturing variability. Setting and justifying specifications by Batches from: Primary stability Scale-up Validation

4. Type of specification Active and Inactive Starting material Packaging Materials For Intermediate and Bulk Products

5. Q6A Guidelines Universal Test/ Criteria New Drug Substance New Drug Products 2. Specific Test/ Criteria New Drug Substance New Drug Products

6. Universal Tests / Criteria New Drug Substances The following tests and acceptance criteria are considered generally applicable to all new drug substances. Identification: e.g. IR, HPLC, HPTLC, GC,GC/MS etc. Description: properties like colour, odour, state, etc. can be determined Assay: content uniformity Impurities: organic & inorganic impurities, residual solvents B. New Drug Products . SAME

7. 2. Specific Tests / Criteria New Drug Substances Physicochemical properties: pH of an aqueous solution, melting point / range, and refractive index 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.

8.   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

9. 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 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 microorganisms, 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.

10. 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. Dissolution Disintegration hardness/ friability Uniformity of dosage units Water content Microbial limit 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 Uniformity of dosage units Ph Microbial limits Antimicrobial preservative content Dissolution Particle size distribution Redispersibility Rheological Properties Reconstitution time Water content Solid Dosage Form Parenteral Oral Liquid

12. 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

13. Dissolution specs at release and shelf-life should be identical. It is useful to have the parameters (medium, apparatus, speed) in specs. 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+5%). There should be a discussion if the time is > 45 minutes. For products containing water insoluble APIs, it is recommended to have a two tier dissolution limit. Image source :https://pharmaceuticalupdates.com/

14. Additional 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.

15. 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.

16. 2. 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. Figure source: http://unitedpharmatek.com

17. 3. 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 % Image source: https://torontech.com/

18. 4. 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. 5. 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. For Tablet For Capsule

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.

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.

22. Dissolution • 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.

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.

26. Functionality 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.

28. Principles for Consideration in Setting Specifications Characterization: Physicochemical properties Biological activity 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

29. 2. Analytical Considerations. Reference standards and reference materials Validation of analytical procedures 3. Process Controls. Process-related considerations: Raw materials and excipient specifications: In-process acceptance criteria and action limits: Pharmacopeial Specifications. Release Limits vs. Shelf-life Limits: Statistical Concepts .

30. Q3 GUIDELINES 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.

31. WHAT IS 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

32. 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. Type Of Impurities ORGANIC INORGANIC RESIDUAL SOLVENTS

34. Organic Organic impurities mainly arise during the synthesis, purification (manufacturing process) and/or storage of the drug substance. Organic impurities can be classified like... Starting materials Intermediate Degradation products Reagents, ligand and catalyst

35. 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

36. 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.

37. Objective Of This Guideline This 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.

38. As per the ICH guidelines, the solvents used in the manufacturing of drug substances classified in to 4 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

39. Class 1 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 unless otherwise justified.

40. Class 2 Solvents Solvents to be limited Solvents in class 2 should be limited in pharmaceutical products because of their inherent toxicity. Examples of class 2 solvent in the below table.

41. Class 3 Solvents (Solvents with low toxic potential) Solvents in Class 3 may be regarded as lower risk to human health. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3. These solvents are considered of no human health hazard Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and GMP.

42. Class 4 Solvents ( Solvents for which No Adequate Toxicological Data was Found) The following solvents may also be of interest to manufacturers of excipients, drug substances, or drug products. However, no adequate toxicological data on which to base a PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products. Examples: 1,1-Diethoxypropane Methylisopropyl ketone 1,1-Dimethoxymethane 2,2-Dimethoxypropane Trifluoroacetic acid

43. Purchase specifications and maintenance of stores for raw materials

44. WHAT ARE RAW MATERIALS: All materials that are used in the manufacturing of the finished bulk and which are consumed by Person using it are called as raw materials. Raw materials can be either active drug or inactive substances. Eg.Hard Gelatin Capsules

45. INTRODUCTION: Raw materials, including ingredients, processing aids, and packaging, are the foundation of finished food products. As such, they must meet not only specifications, but also regulatory requirements. As such, they must meet regulatory requirements (safe and legal for intended use) and specifications

46. Purchase Specification Written Guidelines That Precisely Define The Operational, Physical, And/or Chemical Characteristics, As Well As The Quality And Quantity Of A Particular Item To Be Acquired.

47. Mode of Purchasing: By Inspection By Sample By Description Of Brand By Grading Purchase Specifications Should Be Used Whenever Possible In Purchasing. It is concise Description of the Quality, Size and Weight required for a particular item.

48. Reasons for Preparing Specifications: It establishes a buying standard of a commodity. It informs the supplier in writing precisely what is required. It Provides detail information of the goods to the receiving clerk and storekeeper.

49. Steps involved in purchase procedure Purchase requisition Selection of supplies Inviting Quotation Placing the order Receiving the material Checking of invoice or bill Recording of bills in books Releasing the payment to the supplier Steps involved in purchase procedure:

50. Raw Material Selection R&D selects the appropriate raw materials based on functionality. Functionality can holds multiple areas, such as providing identified characteristics of the finished product (binders, thickeners, type of resin for plastic packaging, etc.), Organoleptic characteristics (flavor, color, aroma, texture), product safety characteristics (to lower the pH or water activity), and preservatives (extension of shelf life, color, or flavor retention, etc.).

51. Specifications for raw materials and content of ingredients Specifications for raw materials and ingredients should contain the following information: Name of the material A description of the material, including biological, chemical and physical characteristics Composition of the material, including additives and processing aids Method of production Packaging format or unit of measure Delivery method A description of the labeling, lot ID

52. 8. Storage conditions and shelf life 9. Preparation and/or handling before use 10. Acceptance and rejection criteria 11. Special requirements such as allergen information, organic status, GMO status, fair-trade and ethical sourcing policies 12. Information about compliance with statutory and regulatory requirements, where relevant 13. A requirement for suppliers to notify of any authenticity issues with the product 14. A requirement for suppliers to notify of any changes to the product 15. Formal agreement between the supplier and purchaser 16. Document control features, such as author, date and page numbers.

53. Maintenance of Stores – Location of stores The stores should be located adjacent to the manufacturing area. The location depends upon the nature and value of items to be stored and the frequency with which items are received and issued. Objectives of store location: Minimum wastage of space Maximum ease of operations Minimum handling costs Minimum other operating costs.

54. 2. Storage Area Specifications:- Sufficient Capacity Clean, Dry and Maintained within acceptable temp. limit Designed and equipped reception area Ensuring of quarantine status Separate sampling area Segregation for storage of rejected, recalled or returned material Safe and secure area for narcotics and highly active, dangerous and risky material First in First out rule (FIFO) First expiring First Out (FEFO)

55. 3. Facilities Inspection Centre Space For Storing Retained Samples For Quality Control Centralized Weighing Room Wash Room Quarantine Room

56. 4. Storage Conditions Room temperature should be 30°C. Low Temperature storage 2-8°C. Light sensitive material in amber color container. 5. Labeling Of Material In Storage Area Designated name of product and internal code reference Batch no given by supplier Status of content expiry date or date beyond which retesting is necessary.

57. GUIDELINE on Cgmp AND QUALITY OF PHARMACEUTICAL PRODUCTS By S. Iyer, D.K.Publication pg. 203. PHARMACEUTICAL QUALITY ASSURANCE BY Manohar A. Potdar . Impurities evaluation of pharmaceuticals by Satinder Ahuja ICH HARMONISED TRIPARTITE GUIDELINE ON: ICH Q6 A, Q6 B, Q3 A (R2). https://www.pharmasop.in/sop-for-raw-material-storage-procedure/ https://www.ar-racking.com/en/blog/raw-material-warehouse-organisation-and-keys/ https://www.pharmaguideline.com/2010/03/sop-for-handling-and-storage-of-raw.html https://www.finaleinventory.com/inventory-management/effective-strategies-for-raw-material-storage https://ask.pharmaguideline.com/t/storage-condition-of-incoming-raw-materials/7593 REFERENCES