Scopeia

• Objective:
  • To define the stability data requirements for a drug product that is sufficient for a registration application.
  • To evaluate a drug product under storage conditions, to test its thermal stability and if applicable its sensitivity to moisture.
  • To provide evidence on how the quality of a drug product varies with time under the influence of a variety of environmental factors such as temperature and humidity, and enable recommended storage conditions, and shelf lives to be established.
  • To check that the storage conditions and the length of studies chosen are sufficient to cover storage, shipment, and subsequent use.
  • To demonstrate that the specifications present at the time of release can be expected to be present when the drug product is administered at any time throughout the shelf life. It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.
  • To describe arrangement of work and results’ registration in stability studies of pharmaceutical dosage forms.

 

• Climatic zone :

  • The design of the stability testing program must take into consideration the climatic conditions of the area in which the drug product will be used.
  • The concept of dividing the world into five zones (according to recent WHO recommendations)

Climatic zone	Definition	Long term condition
I	Temperate climate	21 ºC /45 %RH
II	Subtropical and Mediterranean climate	25 ºC /60%RH
III	Hot and dry	30 ºC /35 %RH
IV A	Hot and humid climate	30 ºC /65 %RH
IV B	Hot and very humid climate	30 ºC /75 %RH

 

• Definitions:
  • Long term study:

Stability studies program under the recommended storage condition (temperature 30 ºC ± 2 ºC and relative humidity 65 % ± 5 %).

• On-going study:

Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labelling which are carried out for only one annual production batch to follow up the drug product during its shelf life.

• Accelerated study :

is a stability study program for product at stress storage conditions, temperature 40 ºC ± 2 ºC and relative humidity 75 % ± 5 %,these studies designed to increase the rate of chemical degradation or physical change of pharmaceutical product by using exaggerated storage conditions as part of the formal stability studies.

• Stress Testing (pharmaceutical product):

Studies undertaken to assess the effect of severe conditions on the pharmaceutical product such studies include photo stability testing and specific testing on certain products.

• Storage conditions:

  • General storage conditions:

Study Storage Conditions Storage Period Long term (Shelf life) 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH According to the predetermined shelf life (0,3,6,9,12,18,24 and 36) Accelerated 40 0C ± 2 0C , 75% RH ± 5% RH 0,3 and 6 months

5.3.1.1       Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30

°C ±2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the  climatic  condition under which the API is intended to be stored. Testing at a more severe long-term condition can be an alternative to testing condition, e.g. 25 °C/60% RH or 30 °C/65% RH.

If 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is the long-term condition there is no intermediate condition.

• Drug substances intended for storage in a refrigerator:

Study	Storage conditions	Minimum time period covered by data at submission
Long term	5°C ± 3°C	12 Months
Accelerated	25°C ± 2°C/65% RH ± 5% RH	6 Months

 

• Drug products packaged in impermeable containers:

Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

• Container closure system:

  • The stability studies should be conducted on the API packaged in a container closure system that is the same as, or simulates, the packaging proposed for storage and distribution.

 

• Stability Protocol :

  • The design of stability studies for the drug product should be based on the knowledge of properties and stability characteristics of drug substance(s).
  • A written stability protocol for stability determination should be developed and implemented to include elements such as:
    • A complete description of the study.
    • Provisions of special storage conditions.

 

• • Stability report.

    • A written stability protocol for stability determination should be developed and implemented to include elements such as:
      • A summary of all data generated, including the conclusions of the study in tabular form

 

• • • Numbering of stability Protocol and Report.
      • Stability protocol number consists of ten characters.

(P/R)-ST-XX-YY001

       Where

• P/R donates for protocol or report.
• ST donates for Stability.
• X X donates for RD: Research & Development batch.

PI: Pilot batch

FI: Finished product batch (production batches)

• YY donates for year
• 001 donates for serial

 

• • Control of product:  Products must be defined in writing:
    • Dosage forms.
    • Product name.
    • Batch No.
    • Storage condition.

 

• • Batches for stability study:

    • For registration purposes test samples are taken from one pilot /or research and development batch.
    • After registration and upon production, the first three batches are followed throughout their shelf life.
    • For re-registration three production batches are followed throughout their shelf life (long term stability study).
    • For major change control (e.g. change in manufacturing process, change in composition of pharmaceutical product “According to SUPAC guidelines”, change of the packaging type, and change in the API suppliers), three production batches are followed by accelerated conditions and throughout their shelf life.
    • Stability Studies should be performed on each individual strength & container size of the drug product unless bracketing or matrixing is applied.

 

• • Stability tests: (according to the protocol):

    • The testing should cover those attributes susceptible to change during storage and likely to influence quality, safety and/or efficacy.
    • Moreover, it should cover as appropriate the physical, chemical & microbiological attributes and preservative content (antioxidant, antimicrobial preservative)
    • The assay methods should be fully validated and designed to be stability indicating.
    • All product characteristics likely to be affected by storage include assay value, or potency, content of products of decomposition and physicochemical properties such as hardness, moisture content, disintegration, dissolution, pH, etc. should be carried out as appropriate for the dosage form under stability study.
    • Test method to prove the efficacy of additives, such as anti-microbial agents and antioxidants, should be foreseen to see if they remain effective and unchanged throughout the shelf life. Any difference between the release and shelf life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation intended for marketing.
    • Stability testing of the drug product after constitution or dilution e.g. (a powder for injection or a concentrate for oral suspension) should be conducted to provide information for labelling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or the diluted product at initial and final time points of the study. In general this testing need not be repeated on commitment batches.

 

• • Sampling requirements:

    • Representative samples for the required product and correct sample size for each interval.
    • Sampling requirements should include provision for extra samples (10%), which may be required for retesting or intensified testing during stability studies.

 

• • Testing frequency:

    • Stability testing for Long term (Shelf life) studies generally should be performed at three-month intervals during the first year, six-month intervals during the second year, and yearly thereafter (e.g. 0,3,6,9,12,18,24 and/or 36 months).
    • For the accelerated storage conditions, a minimum of three points including the initial and final time points (e.g. 0, 3, 6 months). Increased testing can be conducted at other time points (e.g. 0, 1, 2, 3 and 6 months) as a requirement of registration of the product or where an expectation (based on development experience) exists that results from accelerated testing are likely to approach significant change criteria. Increased testing should be conducted either by adding samples at the final time point or by including a 4^th time point in the study design.

 

• • Analytical Data:

    • The release result of the batch should be used as zero time stability data.
    • The analytical method followed at zero time should be the same throughout the stability study of the product in order to ensure valid conclusion. Changing the analytical method at any time should be verified by validation of the new method to ensure its applicability.
    • Specifications to be applied to stability study should be registered according to their relevant SOP’s where each product has its own specification.

 

• • Retest and intensifying testing:

    • Retest is required when there is a questionable result, after investigation of all steps, utensils and instruments used according to OOS.
    • Retest should be done at least in duplicate.
    • Increased frequency testing may be advisable when expectation based on development experience exists that results are likely to approach significant change criteria “refer to definition”.

 

• • Monitoring of temperature and relative humidity for stability chamber:

    • Follow up of the humidity and temperature is done by the cabinet recorder printout which are signed daily
    • Data logger printout are signed weekly, where checks for predetermined temperature and humidity are done for each cabinet.
    • All stability chamber connected with Uninterruptible power supply (UPS)
    • If any deviation in temperature and Humidity occurs; the alarm system -attached to each cabinet displays where appropriate actions should be taken according to the cause of the alarm.
    • If the deviation cannot be fixed within 24 hours according to ICH, all the contents are transferred at once to another cabinet with the same storage conditions (temperature and Humidity).

 

• • Important notes:
    • All microbiological worksheet of analysis are attached at zero time and final intervals
    • In major deviations (complete breakdown of cabinets, complete shutdown of electricity), a risk assessment should be held to identify appropriate actions.
    • In case of OOS in drug product inserted in the accelerated condition, then we rely on the results from long term (shelf) study. However, in case of OOS in drug product inserted in shelf condition, then we make NCR to be raised to QA department and the product will undergo redevelopment.
    • Significant change for a drug product (As appropriate for the dosage form) according to ICH guidelines:
    • More than a (5 %) change in assay from its initial value, or failure to meet the acceptance

 

Criteria for potency when using biological or immunological procedures.

• Any degradation product’s exceeding its acceptance criterion.
• Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, caking, hardness, dose delivery per actuation). However, some changes in physical attributes (e.g. softening of suppositories, melting of creams) may be expected under accelerated conditions.
• Failure to meet the acceptance criteria for pH.
• Failure to meet the acceptance criteria for dissolution for 12 dosage.