Cross Contamination Within a Pharmaceutical Manufacturing Plant. Belinda Whalan Operations QC Laboratory Manager, Pfizer

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1 Cross Contamination Within a Pharmaceutical Manufacturing Plant Belinda Whalan Operations QC Laboratory Manager, Pfizer

2 Contamination The 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-contamination Contamination of a starting material, intermediate product or finished product with another starting material or product during production. WHO

3 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

4 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

5 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

6 Sources of Contamination Raw Materials Personnel Facilities & Environment Processes Equipment

7 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

8 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

9 Personnel Contamination from personnel include hair, microorganisms, 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

10 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

11 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.

12 Facilities & Environment The pressure cascade helps prevent crosscontamination 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

13 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

14 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

15 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

16 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

17 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

18 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

19 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

20 HPLC (High Performance Liquid Chromatography)

21 TLC (Thin Layer Chromatography)

22 FTIR (Fourier Transform Infra- Red) Spectroscopy

23 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