CONTAMINATION- CROSS-CONTAMINATION

current GMP

what regulation recognizes that Contamination and Cross Contamination of pharmaceutical products must not occur?

contamination

is one of the major challenges that pharmaceutical industries face today. Identifying the source of contamination and maintaining high standards of hygiene can help manufacture safe and quality products.

contaminants

▪ an impurity or any substance or material that causes contamination or spoilage

contaminants

matter in either solid, liquid and gas states that can cause harm

contaminants

airborne or surface particles

contaminants

static charges

contaminants

microorganisms

contaminants

endotoxins (degraded microorganisms)

contamination

the undesired introduction of impurities (of a physical, chemical, or microbiological nature) or of foreign matter into or onto a starting material or intermediate

• production

• sampling

• packaging or repackaging

• storage or transport

contamination occurs during

contamination

anything that can corrupt a process or render a product impure by either touching or mixing with i

• direct contamination

• cross contamination

what are the mode of contamination?

direct contamination

 involves the transfer of contaminants directly from its source

direct contamination

direct exposure or contact

cross- contamination

indirect transfer, contact or exposure to contaminants from a material/item to another material/item

cross- contamination

in pharmaceutical industry, this is a contamination of a starting material, intermediate product, finished product with another starting material or a product particularly during production

contamination

• contaminant from environment operators

• contaminant from equipment

cross- contamination

• product from environment operator

• product from equipment

1. physical

2. pyrogenic

3. chemical

4. biological

Common Types of Pharmaceutical Contamination

physical contamination

include chips, particles and fibre materials that may enter the manufacturing or packaging process and contaminate the Physical entire batch.

pyrogenic contamination

substances or micro-organisms that cause fever. Presence of these contaminants in sterile pharmaceutical products may potentially inject fever into the user’s bloodstream.

chemical contamination

moisture, gases, vapor or molecules may also contaminate sterile pharmaceutical products and cause major safety issues

biological contamination

microorganisms such as virus, bacteria, or fungus, molds, spores, yeast that can cause diseases and must not be found in pharmaceutical products.

• equipment

• airflow extraction/ issues

• manufacturing equipment

• cleaning

• personnel

• facility design

sources of contamination

1. Lack of training

2. Inappropriate segregation

3. Space limitation

4. Proper labeling not done

5. Lack of attention

sources of cross contamination

• uneven, rough, and presence of pits of surfaces

• reactive contact surfaces (absorption and corrosion)

• cleaning aids and tools such as bristles, brushes, shedding clothes, etc... that can raise or bring dust or generate contamination

• leaving difficult-to-clean equipment improperly cleaned

• residuals from cleaning agents left sticking on the surfaces of the equipment

how can equipment can cause contamination?

• poor design and inadequate space that can lead to cross-contamination and mix-ups 

• improper ventilation, lighting, and air filtration system 

• inadequate cleanliness and sanitization practices 

• pests and insect infestation inside the premise 

• facilities and equipment are not properly located or arranged based on their purpose of use

• entry of unauthorized personnel inside the premises, especially in the production area 

• presence of cracks, open joints, crevices, shedding paints or particulate matter on internal surfaces such as walls, ceilings, and floors

how can facility and design of the building can cause contamination?

personnel

People who are performing or supervising pharmaceutical manufacturing and packaging processes can be a strong source of contamination.

• lack of training 

• inadequate cleanliness and hygiene standards ( hair, skin flakes, oil, perspiration, clothing debris) 

• direct contact with the materials and products 

• lack of personnel protective equipment

• malpractices like eating or drinking in the manufacturing or storage areas 

• entry or use of critical manufacturing units by unauthorized personnel

how can personnel can cause contamination?

• lack of dedicated production facility for each product

• absence of statutory-compliant hygiene and cleanliness standards

• lack of proper zoning, resulting in mix-up or cross-contamination

• no/insufficient cleaning and maintenance status labeling on materials and equipment used in the manufacturing process

how can manufacturing can cause contamination?

cleaning and sanitation procedures

Having inappropriate or ineffective cleaning procedures could invariably cause cross-contamination between batches and/or campaigns.

• cleaning and housekeeping of all areas within a facility not routinely done 

• no SOP labeled on each piece of equipment on how to clean it 

• use of corrosive and reactive cleaning agents 

• abrasive cleaning materials or aids such as bristles and brushes and shedding of cloth used in wiping & cleaning equipment

• no regular and routine disposal of waste or trash

• left-over and spills not immediately cleaned

• lack of waste management

how can cleaning and sanitation procedures cause contamination?

air extraction/HVAC system

External contaminants should be removed by effective filtration of the supply air, to retain the required cleanroom classification.

• poorly designed air handling systems and dust extraction systems

• poorly operated and maintained air handling systems and dust extraction systems

• ineffective air ventilation, filtration, and air conditioning

How can air extraction/ HVAC system can cause contamination?

Heating Ventilation and Air Conditioning (HVAC) System

HVAC stands for

• Contamination of a batch with a previous batch of the same product

• Contamination with a different product through a carryover or proximity of production lines

• Contamination by a foreign starting material usually of the dispensary or in the store

Other Sources of Cr0ss-Contamination

• surfaces of equipment must be even, and the absence of pits

• must have inert (non-reactive contact surfaces ( to avoid additive or absorptive reaction)

• avoid using cleaning aids and tools such as bristles, brushes, shedding clothes, etc., that can raise or bring dust or generate contamination

• if the equipment is difficult to clean, then consider using it for a dedicated purpose

• avoid using cleaning agents that are sticky in nature since this can leave residue

preventive measures in in terms of equipment

• be of suitable size, construction, and location to facilitate 

• suitable cleaning, maintenance, and appropriate operation 

• have adequate space for placement of equipment as well as production and packaging materials

• consider the sequence of operation during the design phase, paying particular attention to the location of equipment and removal of unnecessary traffic

• have adequate internal temperature, ventilation, and lighting;

• have smooth surfaces (no cracks, crevices, or shedding) on walls, floors and ceilings that are easily cleaned; 

• Ventilation and light points should be designed to avoid the creation of recesses that are difficult to clean. \

• have adequate segregation of materials, products, and components to further reduce the risk of cross-contamination.

• Eliminate the risk of the entry of insects and pests inside the manufacturing area by designing facilities and services that are equipped with maximum protection.

• entry of unauthorized persons should be prevented in production, packing, and quality control areas. Persons who do not work in these areas should not use them as a passageway

preventive measure for facility and design of the building

•  all personnel, prior to and during employment as appropriate, should undergo a health examination 

• personnel should wear clean body coverings appropriate to the duties they perform or minimize exposure to body surfaces 

• all personnel must be trained; this is the key to instill good practices 

• prior to and during employment, all personnel should undergo the relevant GMP and cleaning training and be periodically assessed for competency

• Avoid direct contact between the operator and starting materials, primary packing materials, and intermediate and finished products.

• only authorized personnel have access to enter the premises

• wearing of Personnel Protective Equipment (PPE) should be used whenever applicable, ESPECIALLY for beta-lactam antibiotics, cytotoxic hormones, and drugs manufactured using live microorganisms.

• Strict discipline must be maintained regarding not eating or drinking within the production unit, properly washing hands after toilet use, or routine washing of hands

prevention methods for personnel

0. wet hands with water

1. apply enough soap to cover all hand surfaces

2. rub hands palm to palm

3. right pal over left dorsum with interlaced fingers and vice versa

4. pal to palm with fingers interlaces

5. back of fingers to opposing pals with fingers interlocked

6. rotational rubbing of left thumb clasped in right palm and vice versa

7. rotational rubbing, backwards and forwards with clasped fingers or right hand in left palm and vice versa

8. rinse hands with water

9. dry thoroughly with a single use towel

10. use towel to turn off faucet

11. … and your hands are safe

steps in handwashing

• over clothing and gloves

• beard masks, hair nets, and shoe covers

basic GMP gowning

• safety goggles and mask

• gloves

• hood

• one piece suit

• gators

cleanroom gowning

• Clothes should not get contaminated by cleaning agents and should be capable of repeated wear and laundering without deterioration.

• Opt for linen, as this is a non-shredding type of material

• Wear clothing that lessens or minimizes the exposure of body parts.

• the operator should ensure that clothes are changed and are clean during the product change-over process

• personal footwear should not be allowed inside the manufacturing area. The company should provide appropriate footwear to the personnel functioning in particular areas. The procedure for cleaning footwear should be in practice.

• Street clothing and shoes must not be worn within GMP areas

• Strict discipline must be maintained regarding not eating or drinking within the production unit, properly washing hands after toilet use, or routinely washing hands.

preventive methods/ measures for clothing

• Dedicate the facility to the manufacture of a single formulation of the product 

• Manufacture products in a campaign, with the appropriately qualified cleaning processes and checks performed in between batches to minimize the number of product changeovers 

• Utilize a closed manufacturing system. This is where the product is not exposed to the immediate room environment (and vice versa)

• Perform an area line clearance according to approved procedures following each 

• cleaning process and between each batch/campaign

• Zone the facility 

• Use Cleaning Status labeling on all equipment and materials used within the manufacturing facility

preventive methods/ measures for manufacturing