Choosing Containment Equipment in the Pharmaceutical Industry

 

Snakes can be venomous! Venom is a highly potent substance, refined by years of natural selection, to make a lethal brew of Peptides and proteins with Cytotoxic (cell damaging) properties.  Evolved to immobilize or kill prey. A few micro mills of venom injected into your body will immediately cause pain swelling and digestion of your tissues because snakes like a pre digested meal. Unless antivenom is administered promptly. Venom will be carried round your body affecting your brain, heart liver and other vital organs within the bite area cells die off by swelling up until they burst, leading to secondary infection resulting in limb amputation or death.

Active pharmaceutical Ingredients (API) are becoming more potent. Very small quantities of active have a big impact on the body, like snake venom.  Cancer therapies are in development which include targeted drugs, potent chemotherapies, and highly potent cell-killing cytotoxic agents conjugated to delivery molecules.  Which use monoclonal antibodies to selectively deliver High Potent Active pharmaceutical Ingredients (HPAPI) to specific cancer tumors. These cancer killing agents can be targeted onto the tumor cells reducing chemotherapy side effects on healthy fast growing cells in the body, like hair follicles.

 

Cancer malignant tumor treatment (Oncology) is already one of the largest drug product sectors which is growing. That’s why custom chemical suppliers that can manufacture potent compounds for drug industry customers occupy an attractive niche. Those with conjugation expertise sit in an even more appealing niche within the high-potency area.  Given these prospects, more and more contract chemistry firms are advertising high-potency manufacturing Cytotoxic, Peptides and protein active ingredients.

 

Development has been industry led, much of what’s been done to define and handle these biologically potent materials has been undertaken by the API industry. At present, Food & Drug Administration guidelines only address cross-contamination as it relates to product quality and safety. Worker safety falls under occupational health regulators.

In Europe, however, drug regulators do consider worker and environmental concerns when they inspect a facility. Regulatory moves are afoot internationally to require dedicated facilities for certain classes of compounds, such as cytotoxics and reproductive hormones.

In response, pharmaceutical industry groups are promoting the use of risk-based assessments to determine what manufacturing strategies, and physical and procedural controls, adequately allow for multi product, rather than dedicated, facilities. An example is the International Society for Pharmaceutical Engineering ISPE Risk-based Manufacturing of Pharmaceutical Products (Risk-MaPP) program.

 

Containment Definition

Contain: to keep within limits, hold back, or hold down, keep inside.

Exposure: being subjected to an action or influence.

Operator Exposure Limit OEL , refers to the exposure to airborne concentration of substances that will not result in adverse effects to most healthy workers, exposed for 8 hours/day, 40 hours/week.

 

The potency of pharmaceutical chemicals is often characterized by OELs in μg/m3 the lower the value, the more potent the chemical and the greater the level of containment that is required.

 

Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs well below 10 μg/m3. These processes require specialized containment to ensure that employees and their environment are protected from exposure

 

Hazard: anything with potential to cause harm.

 

Risk: the combination of likelihood  and severity of being harmed.

N.B. You can’t have no risk. Risk must be managed and mitigated by engineering.

 

Containment engineering: responds to the Hazard of Exposure to a Potent substance by engineering controls to reduce the risk to an acceptable level (i.e. maintain exposure within the OEL for the substance).

Material Characteristics

Operator exposure limit (OEL) and Occupational exposure band (OEB)

There are many different classification systems for  IChemE containment system guides give a practical design guides for the handling of toxic solids or liquids -specifically the containment of dust during materials handling operations

The IChemE endorses the use of an occupational exposure band (OEB) method for categorizing materials hazard. Safe Bridge also have a similar system.

 

Occupational Exposure Band

A table developed by the UK HSE provides a template for assessing the OEB form worst case substance OEL:-

Occupational exposure band :-Dust concentration range in air μg/m³ Hazard
Occupational exposure band A –10,000μg/m³-1,000 μg/m³ Least Hazardous

Most Hazardous

Occupational exposure band B –1,000μg/m³-100 μg/m³
Occupational exposure band C –100μg/m³-10 μg/m³
Occupational exposure band D –10μg/m³-1 μg/m³
Occupational exposure band E –1μg/m³-0.001μg/m³
Occupational exposure band F -<0.001μg/m³

 

Process Operation

Equipment is selected using a combination of OEB and consideration of a number of interrelated factors to give the most applicable containment device.

  • Scale of operation
  • Material form (dust potential)
  • Task duration

Exposure Potential Matrix

Scale of Operation Material Form (Dust Potential) Duration of Task
Low Medium High
Small

gm to kg

EP1 EP1 EP2 Short < 30mins
EP1 EP2 EP3 Long > 30mins
Medium

10-100kg

EP1 EP2 EP3 Short < 30mins
EP2 EP3 EP3-4 Long > 30mins
Large

100kg+

EP2 EP3 EP3 Short < 30min
EP3 EP4 EP4 Long > 30mins

 

Equipment Selection Matrix

Exposure Potential (EP) and Occupational Exposure Band (OEB) are combined in the Equipment Selection Matrix to determine the equipment containment strategy or level.

Occupational Exposure Band EP1 EP2 EP3 EP4
Band A –10,000μg/m³-1,000 μg/m³ 1 1 1 2
Band B –1,000μg/m³-100 μg/m³ 1 2 2 3
Band C –100μg/m³-10 μg/m³ 2 3 3 4
Band D –10μg/m³-1 μg/m³ 3 3 4 4
Band E –1μg/m³-0.001μg/m³ 4 4 4 4
Band F -<0.001μg/m³ 5 5 5 5

The equipment selection matrix contains the following containment strategies or levels defined by the IChemE as:

Level 1 -Controlled general ventilation

Level 2 -Local exhaust ventilation

Level 3 -Barrier isolation systems

Level 4 -Closed handling within isolator

Level 5 -Robotic handling, totally contained barrier isolation system

 

Level 1 – Controlled General (Dilution) Ventilation

Area Air Changes are sufficient to maintain the atmosphere below the OEL

Controls Atmospheres by Ventilation Diluting to a Safe Level

Air Supplied to or Exhausted from the General Area

Must Have:-

  • Small Quantity of Contaminants released at a Uniform Rate
  • Sufficient Distance between the Person and Source
  • No Need to Collect or Filter the Contaminant Before Release
  • Not affect outside area of discharge in other detrimental way

(e.g. Foul Odors)

Level 2 – Local Exhaust Ventilation

Directional Airflow Systems

Hoods

Charge Ports and drum fillers

Localized exhausts and makeup air

Downflow Booths

Laminar Airflow Systems

Material, Equipment or process Enclosed as much as possible with extraction hood close to the point of release.

Air Extracted at Rate Sufficient to Ensure air flow is always into the Fume Hood.

Area Air Changes are sufficient to maintain the atmosphere below the OEL

 

Level 3 – Barrier Isolation Systems

Closed Restricted Access Barrier (RABS)

Positive Pressure Enclosed Nature Provides protection for Operator and Product usually in Grade C/D Clean Room. (No Air Gap of Traditional RABS which is not a containment device)

 

Level 4 – Closed Handling Within Isolator

 

Examples of Level 4 Equipment

Level 5 – Robotic handling, Totally contained barrier isolation

Negative Pressure Glove Box Isolator with total Containment Robotic Handling

 

Equipment Selection Process 11 Step Summary

  1. Know your Process
  2. Know the Material Characteristics
  3. OEL used to determine the compound Occupational Exposure Band (OEB)
  4. Determine the product material form, how dusty –how much fugitive dust?
  5. Define the Process Operations
  6. Define the operator interface and duration.
  7. Quantify the batch size.
  8. Evaluate the Exposure Potential Matrix
  9. Establish the Exposure Potential.
  10. Identify the appropriate Containment Level
  11. Use the Equipment Selection Matrix to select the equipment

The development and manufacture of high-potency active pharmaceutical ingredients (HPAPIs) requires significant planning, extensive employee training, proper equipment, and facility design as well as implementation of the necessary procedures to safely handle the compounds. The capital investments are significant, and the knowledge gained through experience is invaluable. Robust systems must be employed in all aspects of the HPAPI-handling program, from initial project evaluation through equipment cleaning, to disposal of process wastes.

As the number of potent compounds in pharmaceutical development continues to increase, so will the opportunities for HPAPI manufacturers, especially for companies with capabilities in growing niche areas such as HPAPI–antibody conjugation.

 

Final thought Venomous snakes are often said to be poisonous, although this is not the correct term, as venoms and poisons are different. Poisons can be absorbed by the body, such as through the skin or digestive system, while venoms must first be introduced directly into tissues or the blood stream (envenomated) through mechanical means. It is,  with a few exceptions, harmless to drink snake venom as long as there are no lacerations inside the mouth or digestive tract. .. I don’t recommend you  try this!

 

Remember all information in this article and information sources is for engineers information only. You must check the facts when applying it in the context of your own projects.  

 

Thanks for reading, any comments? Please write below.

 

Sources used for this article and further reading

 

Institute of Chemical Engineers http://www.icheme.org/

Safe Bridge http://www.safebridge.com/

World Health Organisation WHO http://www.who.int/en/

International Society for Pharmaceutical Engineering ISPE http://www.ispe.org/

Food and Drug A FDA http://www.fda.gov/

MHRA https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency/services-information

Extract Technology http://extract-technology.com/

PSL http://www.powdersystems.com/containment.html

Hosokawa Containment http://www.hosokawa.co.uk/sectors/technologies-and-applications/containment/

Health and Safety Executive HSE (UK) http://www.hse.gov.uk/

Control of Substances Hazardous to health COSHH http://www.hse.gov.uk/coshh/

Occupational Safety and Health Administration OSHA

https://www.osha.gov/

https://osha.europa.eu/en

 

Wikipedia

http://en.wikipedia.org/wiki/Venom http://en.wikipedia.org/wiki/Poison

http://en.wikipedia.org/wiki/Envenomation

http://en.wikipedia.org/wiki/Cytotoxicity

 

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