FDA’s Inspection Approach - Sterile Drug Process Inspections

 

FDA’s Inspection Approach   (Sterile Drug Process Inspections)

 

Will be updated soon.

Sterile Dosage Forms - Aseptic Processing And Terminal Sterilization

STERILE DOSAGE FORMS   ASEPTIC PROCESSING AND TERMINAL  STERILIZATION

 

A dosage form is said to be sterile when it is free from:

v Microorganisms

v Spores

v Pyrogens

v Pathogens

Sterile dosage forms are prepared and stored under aseptic conditions. The dosage form is made sterile by using different methods of Sterilization:

Dosage forms that require to be sterile are:

v Ophthalmics

v Pulmonary drug delivery

v Parenterals:

·       Injectables

·       Infusions

·       Implants

 

TYPES OF STERILIZATION

There are two broad methods to produce a sterile drug product:  1. Terminal Sterilization  2. Aseptic Processing of sterilized unit components. There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization. Terminal sterilization should be utilized when the product and container/closure system are able to withstand the terminal sterilization process.

A.TERMINAL STERILZATION

The terminal sterilization process usually involves filling and sealing product containers under high quality environmental conditions designed to minimize microbial and particulate contamination of the product. This minimization of upstream bioburden reduces the challenge to the subsequent sterilization process. In most cases, the product, container, and closure have low bioburden, but are not sterile at the time of filling. The product is then subjected to a sterilization process in its final container. There are various methods of terminal sterilization including: 1. Moist Heat Sterilization 2. Irradiation 3. Ethylene Oxide (typically for assembled components/kits) Types of sterilization cycles include:

1.    Overkill method:

·       Generally used for heat stable materials.

·        Designed to provide a significant level of sterility assurance regardless of the number and resistance of the actual bioburden organisms in the load.

·       Results in greater heat/exposure input to the product or items being sterilized.

2.  Bioburden Based cycle:

·       Requires studies to determine the number and resistance of the microorganisms found in the product and the bioburden load of the incoming components and containers/closures.

·       Cycle development to destroy the microbial load, but not degrade the product.

·       Routine bioburden monitoring of batches and ongoing knowledge of the heat/exposure resistance of organisms found in product bioburden, container/closure bioburden and environmental monitoring samples.

B. ASEPTIC PROCESSING 

 Aseptic processing presents a higher risk of microbial contamination of the product than terminal sterilization. In an aseptic filling process, the drug product, containers and closures are sterilized separately and then brought together under an extremely high quality environmental condition designed to reduce the possibility of a non-sterile unit. Aseptic processing involves more variables than terminal sterilization. Any manual or mechanical manipulation of the sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of microbial contamination.

Some types of aseptic processing involve manual manipulations of sterile components, containers, and closures in addition to routine operator interventions in the critical area. Humans are a significant source of contamination in traditional aseptic processing, especially in production lines that require operators to routinely enter critical areas (Class 100, ISO 5, or Grade A) of the filling line. Aseptic processing systems based on more advanced control-based technologies, such as Restricted Access Barrier Systems (RABS) and Blow-Fill-Seal systems, are designed to reduce human interventions in the critical areas of the fill line while an isolator system completely separates the aseptic filling line from the external environment and minimizes employee interaction with the critical area.

Difference between Purified water and Water For Injections

 

Difference between Purified water and Water For Injections

 

Specification*	Purified Water	WFI
Conductivity	<1.3 µ S/cm at 250c	<1.3 µ S/cm at 250c
Total Organic Carbon (TOC)	< 500 ppm	< 500 ppm
Microbial (Recommended action limit)	100cfu/ml	10cfu/100ml
Endotoxin	NA	< 0.25 EU/ml
pH	5 - 7	5 -  7
Production Method	Not Specified	Distillation is the preferred technique

 *As per USP Standards

 

IP,BP & USP - Effective Dates (2020) (Information on Pharmacopoeia, Issuance Authority, Update Frequencies and Latest Editions)

Pharmacopoeia is a vital reference tool for all individuals and organisations involved in pharmaceutical.

Pharmatreasures data base on Pharmacopoeial names, Issuance authority, Update frequencies and details on Latest editions is updated on constant basis. This post is last updated on (last updated on 22^nd March 2020) to catch up latest information.

In a border sense, Pharmacopoeia is an official standard (these standards are legally binding) for the quality control of medicines, it includes general chapters, specification and procedures for analysis for active pharmaceutical ingredients (APIs), Excipients and Finished products. The existence of such specifications and requirements is necessary for patient safety and for the proper functioning or regulatory control of medicines.

Details on Pharmacopoeia, Issuance Authority, Update Frequencies and Latest Editions updated in the below table

*Note: USP–NF is a combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF). Monographs for drug substances, dosage forms, and compounded preparations are featured in the USP. Monographs for dietary supplements and ingredients appear in a separate section of the USP. Excipient monographs are in the NF.

Key Words USP 43 and NF 37 effective date, Indian Pharmacopoeia 2018,IP addendum,Pharmacopoeia issuing authority, update frequency and latest edition

Is Orange Book and Orange Guide are same?

 

Orange book VS  Orange Guide

 

Orange Book	Orange Guide
“Orange book” is published by the FDA's Centre for Drug Evaluation and Research (CDER).	“Orange guide” is published by MHRA.
“The Orange Book" is actually the U.S. Food and Drug Administration's (FDA) official listing of Approved Drug Products with Therapeutic Equivalences.	“Orange guide” contains the requirements of Good Manufacturing Practice (It contains EU guidance on good manufacturing and good distribution practice along with relevant information on EU and UK legislation).
“The Orange Book” lists drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act.	“Orange Guide”, provide guidance for those who involved in the manufacture and distribution of medicines in Europe.

 

How non condensable gases (NCGs) impact on steam sterilization process?

 

 

Effect of non condensable gases (NCGs) on steam sterilization process

 Steam Sterilization process is defined as the action of exposing dry, saturated steam on the product to be sterilized for a specified time period under high pressure. This kills off all living microorganisms. In medical and pharmaceutical fields, the steam is produced from purified water which has to comply with the limit values of the EP/USP. 

Non condensable gases (NCGs), have a low boiling point and as the name implies, are not able to condense out of a process at non-cryogenic temperatures (examples of non condensable gases are nitrogen, carbon dioxide, etc.).NCGs can have a serious impact on sterilization process, energy efficiency and lifetime of an autoclave.

In steam sterilization process steam is considered as a condensable gas (water vapor) and anything else that cannot be turned into a liquid using cooling water is considered non-condensable. In steam sterilization process non condensable gas can blanket (insulate) the items to be sterilized, which could inhibit heat penetration to the surface of the object.This may leads to improper sterilization.

Sources of non condensable gases in an autoclave

1. Inadequate air removal from the sterilisation chamber before steam entry. 

2. Leaks: Leaks in door seals, valves or screw fittings, allow air to enter. 

3. The main source of NCGs is the feed water which used to generate steam. These NCGs are formed during   steam generation because of: 

–Dissolved air in the water that is expelled when the water is heated.  

– Hydrogen carbonate salts dissolved in the feed water which when heated disintegrate in to carbonate salts (lime scale) and give off carbon dioxide (CO2) as a NCG. 

Therefore feed water processing is of paramount importance in steam generation. The water should be demineralised and degassed before being fed into the steam generator.

 

Non condensable gases impact sterilization process in two ways

• Insufficient energy delivered to the load to sterilize. Gases do not deliver the same latent heat energy as steam.
• Pockets of gas can form that provide “islands” of un sterility. Unless the indicator is in such an island, their presence will go undetected.

What is Biowaiver ?

BIOWAIVER = WAIVER (EXEMPTION) OF IN VIVO BIOAVAILABILITY & BIO EQUIVALENCE STUDIES

 

The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is approved based on evidence of equivalence other than in vivo bioequivalence studies.

 

Air Flow Visualization (smoke test) and contamination control - FDA's inspectional observations (483's)

SMOKE TEST   AIR FLOW VISUALIZATION STUDIES IN CLEAN ROOMS

 

“Air flow visualization studies are intended to demonstrate visual evidence of air flow direction. The test helps to identify stagnant areas within a clean room; these areas can further act as a channel or reservoir of contaminants. The test can also be used to demonstrate the effects on airflow caused by equipment”.

 

The predominant sources of contaminants within a clean room are people and machinery. Air flow patterns in the clean zones can be easily disturbed by the factors such as machine guarding, equipment design, inappropriate component specifications or necessary interventions. These factors can altogether contributes to a higher potential risk of air borne contamination.

 

FDA and regulatory agencies in the EU ask for documented studies about air flows in critical zones under dynamic conditions. Turbulence and stagnant air can act as a channel or reservoir for the accumulation of air borne contaminants.

 

Smoke studies provides visual evidence of air flow direction. If a particle or air born contaminant  enters a clean room, the smoke test will demonstrate where the particle will likely move. 

Desired airflow characteristics in clean room are 

1.Air flow move toward potential sources of contamination and away from the product path. Ex:HEPA  filtered air should not flow over clean room personnel and then over the product path.

2.Air should be flowing smoothly in one direction with no turbulence or eddies.

3. For movement within the air stream, such as a person manipulating materials or product, air disruption should recover quickly to regain unidirectional flow.

 

CLEAN ROOM AIRFLOW VISUALIZATION AND REGULATORY REQUIREMENTS

WHO GMP For Sterile Pharmaceutical Products Working document QAS/09.295 Rev.1

“Grade A: The uniformity and effectiveness of the unidirectional flow shall be demonstrated by undertaking airflow visualization tests”

 

EU GMP Annex 1

“It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle generating person, operation or machine to a zone of higher product risk”.

Pharmaceutical Inspection Convention (PIC/S)GMP Annex 1 Revision 2008 Interpretation Of Most Important Changes For The Manufacture Of Sterile Medicinal Products -Recommendation January 2010

“Non-viable particles should be measured and are expected to meet grade A requirements. Smoke studies should be performed.”

 

FDA Guidance  Document” Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice” (September 2004)

Proper design and control prevents turbulence and stagnant air in the critical area. Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area). In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment design. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. It is important to note that even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.

Airflow patterns are highly sensitive and easily altered by everyday occurrences; this disruption can compromise product quality. Since unidirectional air flow in a clean room plays a major role in contamination control, the FDA inspectors pays more attention to the videotaped air flow visualization studies. The number of 483’s issued to pharmaceutical manufacturers in recent years strongly supports this statement.

FDA’s Inspectional Observations (483’s) on  Air Flow Pattern Visualization   1.Smoke studies in ISO 5 hoods were not conducted under dynamic conditions.   2. There has been no air flow pattern (i.e smoke study) evaluation study performed to determine the acceptability of the horizontal air flow, that is, the air flow is not compromised (i.e air turbulence/air eddies) during the aseptic operations that are performed in the ISO-5 area.   3. There has been no air flow pattern evaluation to determine that the personnel activities and manual transfer of materials between the ISO-8 and ISO-7 areas negatively affect the air movement and air cascade.   4. Smoke studies  have not been properly documented for the air flow patterns of the ISO 6 class rooms or  ISO 5  laminar air flow hoods used in the processing of injectable products.   5. The air flow pattern video does not present data to adequately assess the requested “downward sweeping air flow pattern” for the ISO 5 aseptic fill zone. The firm failed to evaluate the potential product impact of the turbulence, air eddies observed in the middle of the ISO 5 hoods  during dynamic operations.   6.Smoke study did not include an evaluation of the personnel activities performed in the  adjacent ISO 5 hoods to determine that the personnel activities do not negatively affect air flow patterns within ISO 5 hoods.   7. The smoke study does not demonstrate critical aseptic connections performed during the assembly of ISO 5 hoods used to fill sterile pharmaceuticals.

 

In any environment where human operators are involved ,microbial contamination is inevitable .Carefully designed ventilating  system and operating  practices  can protect the product from contamination risks to some extent. Airflow visualization helps to diagnose problems such as excess contamination build up in clean room.

 

BCS (Bio pharmaceutics Classification System) & ANDA approvals

 

 

 

 

 

 

 

BCS (Bio pharmaceutics Classification System) & ANDA approvals   BCS avoid expensive and time consuming clinical bioequivalence studies with in vitro solubility, permeability, and dissolution data.