MICROBIOLOGICAL CONTROL FOR EXCIPIENTS, DRUG PRODUCT AND DRUG SUBSTANCE
PURPOSE:
To describe microbiological test controls to be applied for outsourced and in house drug substances, drug products and excipients.
SCOPE:
This SOP is applicable to drug substances, drug product, sterile drug product and excipients tested for microbiological quality.
RESPONSIBILITY:
Microbiologist shall be responsible for carrying out microbiological analysis for drug substance, drug product, sterile drug product and excipients as per SOP.
DEFINITIONS:
Drug Substance
Any substance or mixture of substances intended to be used in the manufacture of a drug, (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.
Such substances that are intended to furnish pharmacological activity.
Drug Product
Drug product means a finished dosage form, e.g. tablet, capsule, solution, etc. that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients.
Sterile Drug Product
Drug product means a finished dosage form, e.g. Ophthalmic, Pulmonary drug delivery, Parenteral. Dosage form is said to be sterile when it is free from Microorganisms Spores, Pathogens. The sterile dosage form has to pass test for sterility. These products are prepared and stored under aseptic conditions. The dosage form is made sterile by using different methods of Sterilization.
Excipient
Excipients are inactive ingredients that are intentionally added to therapeutic products which may act to improve product delivery (e.g., enhance absorption or control release of the drug substance) include fillers, extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavours, absorption enhancers, sustained-release matrices, and colouring agents.
Active Pharmaceutical Ingredient
An active ingredient (Al) is the ingredient in a pharmaceutical drug that is biologically active. The similar terms active pharmaceutical ingredient (API) and bulk active are also used in medicine, and the term active substance may be used for natural products.
PROCEDURE:
Based on the nature of the product, its ability to support the growth, use of product, and route of administration, the excipients, APl’s, drug substances and drug product shall be tested for microbiological quality.
Microbiological controls for raw materials (excipients):
The microbiological tests for excipient depend on the origin of material (natural) and its ability to proliferate growth.
For natural origin materials from plant, animal and minerals sources, test for total aerobic microbial count, total combined yeast and mould count and absence of specified organisms shall be performed.
The non Pharmacopoeia excipients shall be tested based on origin and use of material as indicated in below table:
| Material Origin and use | TAMC (cfu/g or cfu/ml) | TYMC (cfu/g or cfu/ml) | Absence of Specified Microorganisms |
| Material of Natural Origin (Plant, Animal or Mineral) | |||
| Used in preparation for oral solutions and suspension | 103 | 102 | E.coli (1 g / 1 ml), Salmonella species (10 g/10 ml), |
| Used in preparation for Cutaneous/ topical use | 103 | 102 | S. aureus, P.aeruginosa (1 g/1 ml) |
| Used in preparation for Rectal, vaginal/ urethral use | 103 | 102 | Yeast and Mold (C. albicans, A brasiliensis 1 g /1 ml) |
Excipients intended for injectable ophthalmic preparation should be evaluated for bio-burden (total aerobic microbial count and test for total combined yeast and mould count).
Microbiological controls for Drug Substance
The microbiological tests applied for non-sterile drug substances, nonsterile APl’s /Excipient shall depend on its intended use (e.g. injections, ophthalmic, solid orals, metered dose inhalers etc.) and its ability to proliferate growth.
The acceptance criteria for microbiological test in drug substances shall be applied as indicated below:
| Drug Substance | TAMC cfu/gm or cfu/ml | TYMC cfu/gm or cfu/ml |
| Use for the Non-sterile Preparation | ||
| Non-sterile drug substances | 103 | 102 |
| Use for the Sterile Preparation | ||
| Non-sterile drug substances | 102 | 101 |
Based on the vendor/Supplier testing criteria /customer specific requirements and, in-house assessment for the Material further intended to be used in the product preparation, tests for specified microorganisms (S.aureus, P. aeruginosa, E.coli, Salmonella species) may also be carried out for drug substances .
Microbiological controls for Drug Product:
The microbiological test for non-sterile drug products, non-sterile bulk drug, depend on its intended use (e.g. solid orals, metered dose inhalers etc.) route of administration and its ability to proliferate growth.
The drug products shall be evaluated for microbiological test as per Pharmacopoeia Monograph (if available).
Based on the route of administration following acceptance criteria shall be applied for non-sterile dosage forms:
| Route of administration | TAMC (cfu/g or cfu/ml) | TYMC (cfu/g or cfu/ml) | Absence of specified microorganism(s) |
| Non-aqueous preparations for oral use | 103 | 102 | E.coli (1 g or 1 ml) |
| Aqueous preparations for oral use | 102 | 101 | E.coli (1 g or 1 ml) |
| Rectal use | 103 | 102 | NA |
| Oromucosal use | 102 | 101 | S.aureus,P.aeruginosa 1 g or 1 ml |
| Gingival use | 102 | 101 | S.aureus, |
| Cutaneous use | 102 | 101 | P.aeruginosa 1 g or 1 ml |
| Nasal use | 102 | 101 | S.aureus, |
| Auricular use | 102 | 101 | P.aeruginosa 1 g or 1 ml |
| Vaginal use | 102 | 101 | S. aureus, P.aeruginosa, Candida albicans (1 g or1 ml) |
| Inhalation use | 102 | 101 | S-aureus, P.aeruginosa,Bile tolerant Gram negative bacteria(1 g or 1 ml) |
On customer specific requirements, test for additional specified microorganisms (S.aureus, P.aeruginosa, E.coli, Salmonella species) may also be carried out for drug products.
The microbiological test should be performed at a suitable frequency for drug products which are not included in Pharmacopoeia. The frequency should be scientifically justified.
Microbiological controls for Sterile Drug Product:
The microbiological test for sterile drug products depend on its intended use (e.g. Ophthalmic, Pulmonary drug delivery, Parenteral. Dosage form etc.) route of administration and its ability to proliferate growth.
The sterile drug products shall be evaluated for microbiological test as per Pharmacopoeia! monograph (if available).
Based on the route of administration following acceptance criteria shall be applied for sterile dosage forms:
| Absence of microorganism(s) | Absence of microorganism(s) |
| Parenteral (Injectable,: Implants) | Complete absence of viable microorganisms |
| Ophthalmic | Complete absence of viable microorganisms |
| Pulmonary drug delivery | Complete absence of viable microorganisms |
Failure Investigation:
The failure investigation shall be carried out in following conditions as per respective failure investigation but is not limited to.
If product (excipient, drug substance, and drug product) exceeds the acceptance limit for Total Aerobic Microbial Count, Total Yeast and Moulds Count.
If product does not comply with specified organism test (If applicable).
If product does not comply in sterility test.
If growth is observed in negative control.
If no growth is observed in positive control.
If microbial growth is observed in negative control, or no microbial growth is observed in positive control the test shall be considered as invalid.
ABBREVIATIONS:
- SOP: Standard Operating Procedure
- QC: Quality Control
- CFU: Colony Forming Unit
- TAMC: Total Aerobic Microbial Count
- TYMC: Total Yeast and Mould Count
- g: Gram
- ml: Millilitre
- API: Active Pharmaceutical ingredient.
REFERENCES:
USP <1111> Microbiological examination of non-sterile products: Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use.
Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use.
IP 2010 2.2.9 Acceptance Criteria for Microbiological Quality of Non- Sterile Pharmaceutical Substances and Non-Sterile Doses Forms