SANITATION

PRA700 GMP PRESENTATIONS - GROUP 1

ANGELA CHOW, CHOWCIN KONKONA GOGOI, JANVIER NSANZIMANA, EMILI SAJI, AND ELVIRA AHMAD MOULEE
AGENDA

1. Overview
2. GUI-0001 (C.02.007 and C.02.008)
3. Contamination on Premises
4. Case I – Fresenius Kabi Violations
5. Case II –
6. Important Takeaways
OVERVIEW

 Contamination in the pharmaceutical industry can compromise patient/environmental

safety
 Important to identify/prevent possible contaminations
 GUI-0001
 Sanitation (C.02.007 & C.02.008)
 Applicable to fabricating and packaging/labelling
C.02.007

 Written sanitation program

o Cleaning procedures for premises/equipment
o Instructions for sanitary fabrication and packaging/labeling of drugs
o Handling of materials used
 Sanitation influences the quality of drugs and employee quality mindset
 Drug products must be fabricated and packed in areas free from contamination
 Design the sanitation program using quality risk management principles
C.02.008

 Health/hygienic behaviour and clothing of personnel adhere to standards

 The health, behaviour and clothing of employees can contribute to contamination
 No person can access the area where a drug is exposed if they are affected/carrier of a
communicable disease, or has an open lesion exposed on surface of body
 Poor hygiene offsets sanitation programs and can increase contamination risks
 Written hygiene program
CONTAMINATION ON PREMISES

 Contamination is one of the top Five reasons for FDA

recall.
 Source: Frieden, T. R. (2016). Evidence for Health Decision Making — Beyond Randomized, Controlled Trials. New England Journal of Medicine, 375(5), 401–404.
https://doi.org/10.1056/NEJMp1606193
WHAT DOES GMP CLEANING MEAN?

 Cleaning removes visible and

microscopic. contamination by
mechanical or physical means.
 visual inspection.
 take representative rinse or swab
samples for laboratory testing
WHAT IS SANITATION?

 Sanitation is the reduction of microbiological contamination.

 Sanitation can be achieved by

- Sanitizing Agent
- Heating
- Steaming
- Scrubbing
 Points to remember:

- For Sanitizing, the surface must be clean.

- Using the specified amount of sanitizing agent is very important.
- If using chemical Saniting agents, further cleaning of Sanitizer may be necessary.
WHAT IS SANITATION?

Several factors determine how effective sanitizing will be. These include:
– The number and types of microbes.
– The type of material containing the microbes.
– The concentration, temperature, and pH of the sanitizing agent
– The length of time you sanitize.
EXAMPLES:
1. After a production run, you clean and sanitize the equipment. After cleaning, you collect
rinse or swab samples from critical equipment surfaces and send those for laboratory
analysis to verify that residual levels are within acceptable limits. This process ensures that
remnants of previous formulations do not contaminate subsequent batches.
2. In tablet manufacturing, the compression tools are dismantled for detailed cleaning of
punches and dies. This prevents cross-contamination between different formulations
and tablet batches produced using the same compression machine.
3. Equipment surfaces are often treated with anti-static agents such as quaternary
ammonium salts to minimize the buildup of electrostatic charges, reducing the risk of
particle adhesion.
4. During environmental monitoring, agar plate samples are taken from the air, contact
surface, operator gloves, and gowning. The plates are then incubated to detect and count
microbial colonies. The alert and action limits indicate whether cleaning and sanitation
practices effectively reduce contamination.
EXAMPLES:

5. During the production of sterile products, Clean-in-place (CIP) systems are commonly
used to clean stainless steel tanks and piping between batches. This kills the bioburden loads
and minimizes the risk of contamination from harmful microbes.
6. Sporicidal disinfectants are used in the cleanroom environment to eliminate bacterial
spores on surfaces.
7. Sometimes, pharmaceutical manufacturers employ surface profilometry to assess the
roughness of stainless-steel equipment. Smoother surfaces are generally easier to clean and
less likely to harbor contaminants.
8. At the entrance of production areas, employees may step onto sanitizing mats that
dispense a disinfectant solution, reducing the likelihood of foot-borne contamination.
DIFFERENT TYPES OF CONTAMINANTS IN PHARMACEUTICALS

1. Chemical contamination
 When the product becomes contaminated with other foreign materials, products, or
residues.
 This can occur when-

- different products are processed in the same equipment or

- when materials such as cleaning agents and lubricants come into contact with
products or equipment surfaces.
 To avoid Chemical or Biological contamination

- Strictly following written GMP cleaning procedures.

- Validate the steps and conditions in the procedures to ensure they are effective
every time under different conditions.
DIFFERENT TYPES OF CONTAMINANTS IN PHARMACEUTICALS

2. Environmental contamination
 There is a higher risk of contamination in areas where the product is exposed to the
environment, such as the dispensary, formulation areas, and bottle-filling rooms.
 To reduce environmental contamination, you must take necessary measures to control the
air, typically using filters.
 Frequent facility cleaning and environmental monitoring are strongly recommended.
 In other areas, such as secondary packaging or material storage areas, the product isn’t
directly exposed to the environment, so there is a lower risk of contamination.
 In such areas, a lower level of environmental monitoring will be sufficient.
DIFFERENT TYPES OF CONTAMINANTS IN PHARMACEUTICALS

3. Biological Contamination
 Biological contamination refers to contamination by bacteria, yeasts, molds, viruses, or any
other microorganisms that may be present in the product.
 This also can include residues from dead micro-organisms or endotoxins, which can
contaminate injectable products.
 The origins of biological contamination vary but include the environment, personnel, raw
materials, contaminated water, and poorly cleaned or wet equipment.
 While cleaning reduces biological contamination, sanitizing agents are important in killing
microorganisms.
STERILE PRODUCTS

 Production of sterile products must be conducted in cleanrooms protected by High-

Efficiency Particulate Air (HEPA) filters.
 Cleanroom requirements are very strict
 Clean room utilizes positive room pressures (overpressure) to protect the areas from
external airborne contamination.
 Usually, 99.97% of all airborne particles above 0.5 microns are excluded by the HEPA
filters.
STERILIZATION VS. SANITATION

 Sterilization means the total elimination of any living organisms, while Sanitation only reduces the microbial load
(the bioburden).
1. Steam Sterilization
 Sterilization achieved by applying saturated steam under pressure.
 First choice of sterilization method for processing equipment, reactors, preparation tanks, solution delivery piping,
etc.
 The principles apply to sterilization-in-place (SIP) processes.
2. Sterilization by filtration
 This technique is used for products that cannot be sterilized due to their heat sensitivity.
3. Dry heat sterilization and depyrogenation
 This technique is commonly used to sterilize/depyrogenate containers (ampoules, vials, etc.), pharmaceutical raw
materials etc.
4. Radiation sterilization
 This is used to sterilize packaging equipment, consumables, garments, Medical device etc., that are difficult to
sterilize using steam or other methods.
GMP RULES FOR CLEANING AND SANITATION

1. GMP Cleaning process

 Cleaning procedures to be fully documented.
 These procedures are initially validated (shown to be effective) specifically for an item or equipment or an area.
 Once validated, the procedures are then published and used.
2. Cleaning validation
 All cleaning procedures should be validated (shown to be effective) under specific conditions of use.
 These conditions of use are specified in the written procedure.
 If employees alter the conditions of use, the cleaning methods may be “invalidated” and ineffective.
 For example, adding more sanitizer than the procedure requires would make cleaning faster or better, but this is
not always the case.
 Adding additional sanitizer may alter the pH of the cleaning agent and make it less effective.
 The relevant GMP rules are to only clean under validated conditions and strictly follow procedures.
GMP RULES FOR CLEANING AND SANITATION

3. Cleaning and sanitation conditions

 The written procedures describe the required conditions under which cleaning is optimal.
 These conditions may include a range of the following:
– Strength of the cleaning or sanitizing agent (e.g., 2.0% v/v)
– The type of water or solvent to be used
– The pH of the cleaning agent
– The temperature of the water to be used
– How much to dismantle equipment before cleaning commences
– The contact or residence time for the sanitizing agent on the surface
– What agents to use to clean off the sanitizing agent
– What standard of water to use in the final rinse (GMP, for example, requires purified water for injection as the final
rinse)
GMP RULES FOR CLEANING AND SANITATION

 4. Cleaning and sanitation records

 One essential GMP rule is the keeping of detailed cleaning records. Cleaning records prove
that cleaning took place and evidence of the cleaning outcomes.
 For example, the surfaces are visually clean or the results of rinse water tests.
 The records must also identify who did the cleaning and when and must be signed.
 For automatic cleaning procedures such as clean in place (CIP), the cycle conditions are
usually automatically monitored and the conditions recorded.
 Cycle conditions may include the temperature, flow rate, time, concentration of solvent, and
solvent agitation time. Often, CIP systems have alarms when something goes wrong.
 The completed and signed records should be attached to the records since they provide only
objective evidence that cleaning has occurred.
WHAT MUST BE CLEANED IN THE GMP FACILITY?

 The facility must be regularly cleaned. Particular emphasis is placed on areas or rooms where product is processed.
 Particular emphasis is placed on effectively cleaning all equipment in contact with the product, and it must be
cleaned according to validated and detailed procedures.
 All equipment in processing areas not in contact with the product needs regular cleaning to prevent dust and dirt
buildup.
 The inside of the factory should be regularly cleaned, but particular attention should be paid to the processing and
storage rooms. The floors, surfaces, benches, walls, and ceilings should undergo cleaning at defined intervals.
 Cleaning and sanitation also apply to any equipment in contact with the product during manufacture, such as
production and packaging equipment, transfer lines and tanks, and storage containers and drums.
CASE I : LEGACY PHARMACEUTICAL PACKAGING LLC

 Facility location: Earth City, Missouri, USA

 Inspection conducted by FDA revealed insanitary conditions
 From April 12, 2022 to April 27, 2022

Findings:
1. Inadequate Bioburden Control
2. Equipment and Facility Maintenance
CASE I : FRESENIUS KABI VIOLATIONS

I. Inadequate Bioburden Control

 Failure to investigate
 exceeding bacterial contamination
 insufficient testing
 inaccurate documentation
 insufficient written sanitation and investigation procedures
 repeat deficiency – 2010, 2012, 2013, 2021
CASE I : FRESENIUS KABI VIOLATIONS

2. Equipment and Facility Maintenance

 Failure to clean, maintain, and sanitize/sterilize equipment
 broken HEPA filter
 missing tubing connections
 brown residue on filling apparatus
 black residue on mixing tanks and growth on HEPA filters
CASE I : FRESENIUS KABI VIOLATIONS

2. Equipment and Facility Maintenance

 Failure to maintain buildings used in licensable activities in a good state of repair
 gaps and flaking paint on ceiling
 pooling of water in ceiling
 cracked floor and walls
 improper air filtration
CASE II : SUN PHARMACEUTICAL VIOLATIONS

• Inspection by USA FDA (2023, December 4-15) &

Warning Letter (2024, June 18)
• Violation of Current Good Manufacturing Practices
(cGMP)

Identified Issues:
Failing to clean and maintain equipment
Ineffective quality systems
FAILING TO CLEAN AND MAINTAIN EQUIPMENT

 Cases of microbial contamination & Cross contamination

 Batch recalls (June 2023- December 2023)
 USA FDA recommended CAPA: a proper cleaning program for
products and equipment.
o Evaluating residues
o Evaluating the scope of cross of contamination
o Independent consultant review of CAPA effectiveness and
improvement to cleaning and maintenance procedures
 INEFFECTIVE QUALITY SYSTEMS
Company’s structural deficiencies
Lack of management oversight in production and laboratory
operations
Quality unit lacking authority to enforce compliance.
Repeated Observations at the Facility: Repeated Violations at Multiple Sites:
· March 29, 2019: Cited for inadequate cleaning and Halo Site Warning Letters for Inadequate cleaning
maintenance of manufacturing equipment. practices
· April 13, 2017: Issues with laboratory-contaminated December 15, 2022 & October 16, 2023.
glassware.

Management Response and Remediation:

·Sun Pharmaceutical Industries Limited decided to replace key senior leaders.

·The company modified corporate structure to enhance quality oversight and

ensure compliance with regulatory requirements.

TAKEAWAYS
REFERENCES