MICROBIOLOGICAL CONTROL FOR EXCIPIENTS, DRUG PRODUCT AND DRUG SUBSTANCE

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 useTAMC (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 suspension103102E.coli (1 g / 1 ml), Salmonella species (10 g/10 ml),
Used in preparation for Cutaneous/ topical use103102S. aureus, P.aeruginosa (1 g/1 ml)
Used in preparation for Rectal, vaginal/ urethral use103102Yeast 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 SubstanceTAMC cfu/gm or cfu/mlTYMC cfu/gm or cfu/ml
Use for the Non-sterile Preparation
Non-sterile drug substances103102
Use for the Sterile Preparation
Non-sterile drug substances102101

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 use103102E.coli (1 g or 1 ml)
Aqueous preparations for oral use102101E.coli (1 g or 1 ml)
Rectal use103102NA
Oromucosal use102101S.aureus,P.aeruginosa 1 g or 1 ml
Gingival use102101S.aureus,
Cutaneous use102101P.aeruginosa 1 g or 1 ml
Nasal use102101S.aureus,
Auricular use102101P.aeruginosa 1 g or 1 ml
Vaginal use102101S. aureus, P.aeruginosa, Candida albicans (1 g or1 ml)
Inhalation use102101S-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
OphthalmicComplete absence of viable microorganisms
Pulmonary drug deliveryComplete 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

About Pharmaceutical Guidanace

Ms. Abha Maurya is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 18 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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