Cross Contamination Within a Pharmaceutical Manufacturing Plant

Belinda WhalanOperations QC Laboratory Manager, Pfizer

ContaminationThe undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackaging, storage or transport.

Cross-contaminationContamination of a starting material, intermediate product or finished product with another starting material or product during production.

WHO

Consequences of Contamination

• Patient Safety

– Adverse reactions, allergies and anaphylactic reactions, illness, efficacy of the product

• Company Reputation and Cost

– Recalls, litigation, criminal prosecution, shareholder value decline, plant /company closure

Top 5 Reasons for Class I Product

Recalls in the Last 3 Years –inpharm.com

1. Super or sub-potent formulations

2. Particulate contamination

3. Contamination of APIs

4. Sterility failure in injectable products

5. Contamination with TBA

Contamination Cases

• Well-known cases of contamination:� Penicillin based products - Aidapak Services had a voluntary recall of a large number of repackaged drug products due to potential cross contamination of non-penicillin with penicillin drug products repackaged in the same facility.� Diethylene Glycol in Cough Syrup –Diethylene Glycol labelled as Glycerin and used in cough syrups: tens of thousands have died� Melamine in Wheat Gluten – melamine added to raw milk (effected milk-based products, baby formula) and pet feed

Sources of Contamination

• Raw Materials

• Personnel

• Facilities & Environment

• Processes

• Equipment

Raw Materials

• From approved manufacturer’s and suppliers; avoid counterfeits, and audited facilities and processes

• Identification and chemical testing to required specifications (e.g. BP, USP)

• Inspection for foreign matter

• Microbiological testing for those susceptible to micro contamination, as well as BSE/TSE declarations

• Testing of materials includes purified water generated on-site

Raw Materials

• Inspection for damage, and seals intact • Cleaning of outside of containers • Cleaning and sterilisation of sampling equipment, or

use of disposable tools• Sampling and dispensing performed in clean area,

one material at a time and cleaned in between materials

• Gowning and Hygiene procedures of personnel sampling and dispensing

• Containers re-sealed after opening• Segregation and proper storage of materials

Personnel

• Contamination from personnel include hair, micro-organisms, illness, jewellery, fake nails or nail polish, contact lenses, street clothing, shoes, stationary, food or drink, personal medications

• Gowning procedures to reduce contamination include: –Hair nets, beard covers, gloves, masks, lint-free overcoats, plant dedicated uniforms and shoes, shoe covers

• Clean gowning to be stored to prevent contamination• Correct gowning & PPE to be worn in designated

areas

Personnel

• Gowning to be replaced when required • Check shoes and gowning for trapped product,

tablets etc. Rolling up of sleeves and pockets are not allowed too for the same reason

• Policies on people with product contact who are sick or injured; no jewellery & make up policy; no paperclips, pens with lids etc; no eating, drinking or smoking in GMP areas; personal medications not kept in GMP areas

Facilities & Environment

• The facilities are designed in a way to reduce introduction, generation and retention of contaminants in the area

• The Core Area concept effectively separates manufacturing areas from the warehousing/shipping areas, as well as other support areas

• Exposed product area is segregated (physically separated through wall and doors) from the rest of the operation

• Entry into the areas is through – Airlocks; or– Double Doors which are Interlocked

• The Separation of the Different Zones/Modules is Maintained through a Pressure Cascade when the Doors are opened.

Facilities & Environment

• The pressure cascade helps prevent cross-contamination between adjacent areas, prevent build-up of contaminants from outside and used to enhance separation between areas of different cleanliness

• Keeping the doors to rooms closed maintains air balance, pressure differential, prevents back flow and contamination and keeps the manufacturing rooms clean

• The aisle ways must remain clean and free from dirty equipment, as air flow is from manufacturing aisle ways into rooms

Facilities & Environment

• The environment in GMP areas are temperature and humidity controlled

• Air handling system, including the use of a HEPA (High-Efficiency Particulate Air) filter

• Walls and surfaces are made of smooth and easy to clean material

• Inspection of rooms for cleanliness before using

• Environmental monitoring of the air and surfaces in the GMP facility for micro-organisms

• Cleaning and prevention of cross contamination applies throughout the whole facility in which personnel transit through

Facilities & Environment

• Facilities are to be kept in good repair• Good housekeeping minimises errors and prevents

contamination, protecting the materials, products and equipment

• Identified locations for storing equipment, tools, clean and dirty

• In manufacturing area use lint free cloth, no wooden pallets and no cardboard

• Pest Control Program

Processes

• Cover materials, products and equipment, only removing covering immediately before use

• Equipment and materials not needed in the process being performed should not be in the rooms

• Double plastic lining of containers for product, and kept closed until needed

• Sieving of materials before or during charging to detect contamination

• Metal detectors, bottle blowers

• Use in-line, enclosed or covered systems where possible

Processes

• Labelling of all materials and equipment for identification and status

• Labelling of materials on the container not the lid

• Second verification for dispensing and addition of materials to prevent mix-ups

• Preventative maintenance program and inspections for deterioration of parts

• Schedule for replacing consumable parts e.g. seals, lubricants

Equipment

• Cleaning prevents cross contamination• Ineffective cleaning of equipment is a common

source of cross-contamination, so the use of validated effective cleaning and decontamination procedures is needed

• Effective and validated cleaning processes are essential to maintaining a GMP compliant facility

• Gloves to be worn to prevent microbial contamination, and extra cleaning precautions should be taken if exposed skin contact with surfaces

• Where possible, have product dedicated equipment • Cleaning status labels on equipment is essential

Equipment

• Segregation of dirty and clean equipment• Equipment not in use to be stored clean, dry and

covered• Assess need to re-clean equipment if idle for set

period of time• Inspection of all equipment before use for cleanliness

and integrity• Inspection of equipment after use, to determine

integrity of parts • Cover equipment and tools when not in use• Pallet jacks etc to be dedicated to the manufacturing

area and cleaning program in place

Equipment

• Cleaning tools not stored in manufacturing rooms, and inspected prior to use for cleanliness and damage

• Cleaning validation methods to ensure no product residue, detergent residue or microbial contamination

• Cleaning validation performed on difficult to clean surface areas

• Cleaning determined on campaign length• Equipment and line inspections between

products/batches, to ensure no trapped products• Inspection and testing of semi-finished and finished

products manufactured

HPLC (High Performance

Liquid Chromatography)

TLC (Thin Layer

Chromatography)

FTIR (Fourier Transform Infra-

Red) Spectroscopy

Summary

In Summary;

• Prevention of contamination is critical for the safety of the consumer and the continuity of the business

• Contamination of products can occur through a multitude of sources

• Every activity carried out in manufacturing must be assessed as to the risk of product contamination

• Trained personnel, strict procedures and controls are needed to minimise the potential for contamination

• Methods to detect contamination if present