Finished Product Specifications & Validation

Specification of Finished Product (FPP)

• Specification refers to qualitative and/or quantitative characteristics, test procedures, and acceptance limits that a product must comply with.
• Specifications of the Finished Product (At Release) is a monograph defining characteristics, test procedures, and acceptance limits with which the product must comply at its release.
• Specifications of the Finished Product (Up to the End of Shelf life) refers to a monograph ensuring a medicinal product complies with qualitative and quantitative characteristics, test procedures, and acceptance limits throughout its shelf life on the market.

Validation & Testing

• Validation of Manufacturing Process involves proving that any procedure, process, equipment, material, activity, or system leads to the expected results, according to Good Manufacturing Practice principles.
• Routine tests are carried out on each industrial batch of the intermediate product, the bulk product, or the finished product.
• Periodic tests are special tests, carried according to a defined periodicity, and mentioned separately.

FPP Specifications

• FPP specifications are quality standards.
• Specifications establish criteria a substance should conform to for the manufacture of medicinal products.
• A substance conforms to specifications when it meets acceptance criteria after testing with listed analytical procedures.
• Specifications are provided by Pharmacopoeias in each region, like the United States Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), and European Pharmacopoeia (EP).
• Specifications are based on Compendial monographs.
• Specifications include standards for the type of dosage form, I.D of colorants, microbial limits, and I.D and assay of preservatives.

FPP specifications Typical parameters

• Appearance
• Identification includes APIs, Colorants (testing might be skipped), and Preservatives
• Physical tests such as LOD, friability, and hardness for tablets.
• Uniformity such mass/content of dosage units
• Pharmaceutical tests, such as dissolution and tests for each API in Fixed Dose Combination (FDC) products.
• Purity tests for degradation products, API-API degradation products, and residual solvents.
• Microbial count / sterility / bacterial endotoxins testing
• Content of APIs in FPP (assay), with limits of 95.0% – 105.0%, unless justified.
• Content of preservatives, with Limits 90.0% – 110.0%, generally acceptable.

FPP Specifications for Uncoated Tablets

• Attribute: Appearance; Release Limits: Full description; Stability Limits: Same as release
• Attribute: Identification; Release Limits: At least 1 method
• Attribute: Dimensions; Release Limits: Diameter, etc; Stability Limits: Not required for stability studies
• Attribute: Average mass; Release Limits: theoretical
• Attribute: Mass uniformity; Release Limits: Ph.Eur/USP/Int.Ph
• Attribute: Tablet hardness*; Release Limits: product specific; Stability Limits: Same as release
• Attribute: Friability*; Release Limits: ≤ 1% (normally); Stability Limits: Same as release
• Attribute: Dissolution Release; Limits: Set per product; Stability Limits: Same as release
• Attribute: Disintegration; Release Limits: Not required if dissolution is done
• Attribute: Related substances (degradants); Release Limits: Only if formed during production; Stability Limits: Required, Limit to one/two decimals.
• Attribute: Assay (content); Release Limits: 95.0-105.0%, unless justified; Stability Limits: May be 90.0-105.0, if justified
• Attribute: Microbial limits; Release Limits: Skip-testing; Stability Limits: End of shelf
• • Tests not necessary at release if done in-process

Analytical Procedures

• Analytical procedures should be presented with enough detail to be repeated by another laboratory.
• If a test is based on a Pharmacopieal monograph, a copy of the monograph and methods referenced must be submitted.
• Details of any additional specifications and test methods to those in the pharmacopoeia must be submitted.

Reference Standards

• If a primary reference standard is available, it should be used.
• If a primary reference standard is unavailable, a reference standard should be developed and qualified.
• Secondary working standards' content should be assayed relative to the primary standard using the same assay method

Verifying Specifications

• Individual tests carried out for the release of the finished product are done routinely on each batch of finished product.
• Acceptance limits are for specifications of the different quality characteristics like the activity and safety. -For pharmaco-technical specifications, the European Pharmacopoeia or national pharmacopoeias of the Member States describe test procedures, standards, or maximal limits.

Acceptance limits for excipients

• Excipients affecting the bioavailability of an active substance must undergo quantitative determination in each batch.
• For preservatives, content limits of 90-110% at release should be acceptable without justification, except in special cases.
• On expiry, the lower limit of antimicrobial preservatives may be reduced based on satisfactory preservative efficacy testing.
• For chemical preservatives (antioxidants), the lower limit may be considerably lower than 90% during the shelf life because of preferential degradation.

Test Procedures

• Test procedures must be described sufficiently to enable any official laboratory to verify compliance up to the end of shelf life.
• Analytical Procedures must include a description of the test procedure, reference substance, including its specifications, and calculation formula/example if needed.

ICH Guidelines for FPP Specifications Q6A

• ICH guideline is good for both FPP and generics.
• Tests Procedures and Acceptance Criteria for New Drug Substances and Drug Products
• Tests for Chemical Substances
  • Impurities in new drug products is coverd in ICH Q3B (R2)
  • Impurities – Guidelines for Residual Solvents is coverd in ICH Q3C (R3)
  • Pharmaceutical development is coverd in ICH Q8 (2)
  • Pharmaceutical quality system covered in ICH Q10

Specification Setting for Drugs

• Drugs must conform to certain limits through their shelf life.
• Manufacturing processes should be robust and in control.
• Measurement systems should be in control and traceable.
• Storage conditions should be controlled.
• Practical implications should involve a statistical process using control limits, release limits, shelf life limits and in-use limits.

IPQC for Liquid Dosage Forms

• Purified vehicle (water) should be filtered and purified to remove any microorganisms. The water should be tested frequently to ensure that it is clean and pure before the preparation.
• Volume in container testing to ensure the final pack contains the desired volume.
• Testing of organoleptic properties (appearance) testing includes the color with a Light Transmittance Meter for syrup, clarity, odor, and taste.
• Specific gravity (for suspension & syrup) density decrease indicates entrapped air. It is determined using a density bottle or Hydrometer.
• Rheological studies assess viscosity using Brookfield or Cone and plate Viscometers.
• pH determination should be carried out with a pH meter.
• The uniformity of dosage unit is tested in suspension, emulsion in single unit container or capsule for systemic use, solution in single unit container or capsule for systemic use, and solution for inhalation through nebulizer.
• Zeta potential (for suspension & emulsion) is tested for long term system stability containing dispersed particles.
  • from 0 to ±5 gives Rapid coagulation or flocculation
  • from ±10 to ±30 gives Incipient instability
  • from ±30 to ±40 gives Moderate stability
  • from ±40 to ±60 gives Good stability
  • more than ±61 gives Excellent stability
• Seal integrity of the product is verified Using E-scan HVLD (high voltage leak detection) by scanning the product to detect small pinholes, micro cracks and defective seals.

Special Tests for Syrup

• Sucrose concentration (66.7%, BP) testing to ensure no favor for microbial growth based on concentration. HPLC and UV-spectroscopy is used
• Physical stability is tested for appearance (no crystallization and microbial growth), color, odor and taste (palatable), and Solid material completely miscible in liquid.

Special Tests for Elixir

• Determination of alcohol concentration determination by use of Alcoholmeter. Elixir usually contains 5 to 40% alcohol.

Special Tests for Suspensions

-Sedimentation Volume (F) testing is the ratio of the ultimate volume (Vu) of the sediment to the original volume (Vo) of the suspension. F = Vu / Vo

• Redispersibility describes the ease of redispersion of the formed sediment by shaking to yield a homogeneous system, and is done by Simple agitation of the suspension in the container or with mechanical device that simulates arm motion during the shaking process.
• Particle size changes testing uses freeze-thaw cycling. Particle size changes and crystal growth can measured with microscope, coulter counter device or Laser diffraction device.

Special Tests for Emulsions

• Dilution test used to identify the emulsion type.
  • Water distributed uniformly in the emulsion when mixed with 2 - 3 drops of water in a test tube means the emulsion is o/w type
  • Water separates out as a layer when mixed with 2 - 3 drops of water in a test tube means the emulsion is w/o type
• Creaming, sedimentation and coalescence can be initiated by centrifugation at 2000-3000 rpm at room temperature.
  • Creaming is temporary phase, the globules moves upward and can be re-distributed by mild shaking/stirring
  • Coalescence is serious. The dispersed globules coalesce together with two separate layers, which is difficult to redisperse.
• freeze-thaw cycling done for accelerated stability testing, and examined for any creaming, sedimentation or coalescence.

IPQC Tests for sterile products

• Parenteral Products
• Ophthalmic Products
• Volume in containers (solutions) is confirmed
• Sterility testing is carried out by the Direct Incubation Technique. A volume of the tested product is transferred aseptically to culture tubes containing a suitable culture medium, plugged with sterilized cotton wool, and incubated for 7 days at 30 to 35°C. Turbidity indicates microbial growth, thus clear tubes indicate sterile product.
• Pyrogen testing verifies pyrogens which are the metabolic products of cell wall of microorganisms.
  • Dangerous pyrogens are those produced by Gm -ve bacilli, and cause fever, anaphylactic shock and may lead to death in large doses.
  • Pyrogens withstand heat, survive pH change, and pass through many filters.
• Pyrogen test (rabbit method) USP,BP should be performed in group of three rabbits by injecting the tested solution in the ear vein (0.5 mL/kg-10 mL/kg body mass). The body temperature is recorded at least 90 min before injection and continuing 3 h after. Rise in temperature of >0.6°C indicates pyrogenic product.
• Clarity testing identifies particulate matter. Particulate matter in ophthalmic preparations are irritating to the eye, and in parentral preparations they can block blood vessels with serious results (embolism).
• Clarity testing follows USP & BP limits; Light obscuration method and the Microscopic method.

USP & BP Limits

• Light obscuration method : Small-Volume Injections > 6000 >10µm or 600 >25µm per container and Large-Volume Injections > 25 >10µm or 3 >25µm per mL
• Microscopic method : Small-Volume Injections > 3000 >10µm or 300 >25µm per container and Large-Volume Injections > 12 >10µm or 2 >25µm per mL