Why is it Necessary to Manufacture Penicillin and Non-Penicillin Products in Separate Facilities?

What Is Penicillin?
Penicillins are a class of organic or semi-organic antibiotics that work well against bacteria because they include beta-lactam rings with 6 APA or 6 amino penicillanic acids. In 1928, Alexander Fleming isolated penicillin from the fungus Penicillium notatum.

What is Beta Lactam?
Antibiotics featuring a beta-lactam ring in their structures are known as beta-lactam antibiotics. They have beta-carbon molecules with nitrogen molecules connected. They are broad-spectrum antibiotics like cephalosporins, monobactams, carbapenems, and derivatives of penicillin. These antibiotics prevent the manufacture of bacterial cell walls, killing any bacterial infections that may be present.

When compared to other antibiotics, their usage is high. Nevertheless, microorganisms have become resistant to these beta-lactam medicines. They have developed many resistances to beta-lactam antibiotics due to the enzyme beta-lactamase. As a result, physicians use beta-lactamase inhibitors with beta-lactam antibiotics to address this issue. Antibiotics in the beta-lactam class are more effective against gram-positive bacteria. However, gram-negative bacteria can also be treated with beta-lactam medicines.

What is a Beta-Lactam Ring?
Beta-lactam is a 4 membered lactam & lactam is an amide in the form of cyclic amide. This lactam is called beta-lactam because nitrogen is attached to the beta-carbon. Beta-lactam is part of many important antibiotics and these antibiotics work by inhibiting the synthesis of the cell wall of bacteria. The antibiotics those contain beta-lactam rings are known as beta-lactam antibiotics.

The most often given class of medications is the beta-lactam antibiotics, which all share a certain structural element of the beta-lactam ring. One of the first and most often used antibiotics among them is penicillin. Penicillin is also thought to be among the safest and most effective antibacterial medications.

Facts Relating to Penicillin Allergy
The main issue with the usage of penicillin is allergic reactions. Anaphylaxis is thought to occur 1–5 times per 10,000 instances of penicillin treatment, making true penicillin allergy rare. Its most significant side effect, however, is hypersensitivity, which can cause nausea, vomiting, pruritus, urticaria, asthma, laryngeal edema, and finally cardiovascular collapse. Antibiotic use is improved and the expansion of several drug-resistant bacteria is slowed by the identification of people who mistakenly possess ß-lactam allergies. Penicillin and second- and third-generation cephalosporin cross-reactivity is negligible and may even be lower than penicillin's cross-reactivity with unrelated medicines.

Hypersensitivity To Penicillin
Penicillin has a lot of positive effects in the treatment of infections, but it may also be hazardous to those who are sensitive to it or allergic to it, causing mild skin rashes and even life-threatening anaphylactic shocks. The following are examples of penicillin hypersensitivity reactions:
  • Swelling of Tongue
  • Swelling of face
  • Difficulty in breathing
  • Runny nose
  • Fever
  • Anaphylaxis
  • Skin Rashes
  • Hay Fever
  • Asthma
  • Hives
  • Itching Eyes

Penicillin Skin Tests and Challenge Doses
Based on the patient's history and physical exam, additional tests may be needed to confirm a penicillin allergy. Penicillin skin testing and challenge doses are reliable and useful methods for evaluating IgE-mediated penicillin allergy.

Penicillin Skin Testing
A positive result means the patient is likely to have a penicillin allergy. If negative, the skin test is usually followed by an oral penicillin class challenge (e.g., with amoxicillin) to safely rule out an IgE-mediated penicillin allergy.
  • The current standard of care is to perform a skin test with the major determinant penicilloyl polylysine and commercially-available penicillin G.
  • To rule out penicillin allergy, an oral challenge dose can be done after skin testing. The negative predictive value of skin testing with the major and minor determinants is more than 95%, but approaches 100% when followed by a challenge dose.

A direct oral challenge without prior skin testing may also be performed in selected patients and can rule out penicillin allergy. 

What is Non Beta Lactam?
Non-beta lactam antibiotics are medicines or antibacterial agents whose molecules do not include the beta-lactam ring. These drugs are less effective than beta-lactam drugs. Their usage has led to subpar therapeutic results. This, according to scientists, is a result of the non-beta lactam group having a greater rate of incorrect empiric treatment. One kind of non-beta lactam antibiotic with a highly complicated molecular structure is vancomycin. Another two non-beta lactam antibiotics include fosfomycin and bacitracin. Another non-beta lactam antibiotic that is a lipopeptide is daptomycin. The bacteriostatic antibiotic chloramphenicol is a non-beta lactam.

Cross Contamination
The US Food and Drug Administration (FDA) now has regulations in place that oversee the manufacturing procedures that pharmaceutical businesses must adhere to, Separate production facilities should be developed for each product in order to prevent cross-contamination between beta-lactam and non-beta-lactam goods.

This entails separating the individuals working with beta-lactam and non-beta-lactam goods as well as the buildings, machinery, and utilities. A certain distance should be maintained between facilities, and each should have its own heating, ventilation, and air conditioning (HVAC) system due to the possibility of contamination through the air. Additionally, it is necessary to maintain separation between the active pharmaceutical substances employed in the production of beta-lactam and non-beta-lactam ingredients.

Why Does the Production of Penicillin Need a Separate Facility?
Penicillins are sensitizing agents and can cause hypersensitivity responses, as we stated previously. Despite the ratio being as low as 10%, the US-FDA and other regulatory agencies mandate that these antibiotics be manufactured in different facilities to avoid cross-contamination.

Cross-contamination between beta-lactam and non-beta-lactam goods, as well as between penicillin beta-lactam and non-penicillin beta-lactam, should be avoided, according to FDA current good manufacturing practices.

Penicillin beta-lactam and non-penicillin beta-lactam medicines should be produced in different facilities. A distinct manufacturing facility entails a separate structure, air handling unit, machinery, electrical system, and even people.

Even when using air, cross-contamination should be completely prevented. Therefore, there needs to be enough space between two industrial plants. Cephalosporin is one example of a non-penicillin beta-lactam product for which a separate production facility is not required.

Separate manufacturing for final goods using beta-lactam API and those containing non-beta-lactam API is also advised by the US Food and Drug Administration. These production facilities must each have their own HVAC and air handling systems. According to the FDA, only medications belonging to the cephalosporin family are exempt from the need for a separate facility and air handling system and may instead be produced using the same machinery after a thorough cleaning. It is important to validate the equipment cleaning process.

According to cGMP rules, non-penicillin items that might potentially be contaminated with penicillin must be tested for the presence of penicillin and cannot be marketed if there is proof of its presence at a detectable level.

What FDA Guideline Says:
Because of the potential health risks associated with the cross-reactivity (cross-sensitivity) of beta-lactams, manufacturers should assess and establish stringent controls (including appropriate facility design provisions assuring separation) to prevent cross-contamination. Just as FDA considers the separation of production facilities for penicillins to be current good manufacturing practice, FDA expects manufacturers to treat sensitizing non-penicillin beta-lactam-based products similarly. Specifically, FDA recommends that manufacturers establish appropriate separation and control systems designed to prevent two types of contamination: 
  1. the contamination of a non-penicillin beta-lactam by any other non-penicillin beta-lactam, and 
  2. the contamination of any other type of product by a non-penicillin beta-lactam. Accordingly, FDA recommends that the area in which any class of sensitizing beta-lactam is manufactured be separated from areas in which any other products are manufactured, and have an independent air handling system.

As with penicillin, the section of a facility dedicated to manufacturing a sensitizing non-penicillin beta-lactam should be isolated (i.e., completely and comprehensively separated) from areas in the facility in which other products are manufactured. This control applies to each of the five classes of sensitizing beta-lactams; the area in which any class of sensitizing beta-lactam is manufactured should be separated from areas in which any other products are manufactured, including any other class of sensitizing beta-lactam. Manufacturing that is restricted to a specific class of beta-lactam compound (e.g., the cephalosporin family of products) generally would not mandate separate facilities and air handling systems and could permit production campaigning and cleaning as sufficient control.

Finally, as discussed above, beta-lactam intermediates and derivatives may induce allergic reactions and therefore pose risks of cross-contamination. Accordingly, firms that manufacture beta-lactam intermediates or receive them for further processing, as well as firms whose manufacturing processes result in beta-lactam derivatives, should evaluate their manufacturing operations for the possibility of cross-contamination and implement appropriate controls to reduce or mitigate the potential for cross-contamination. As with penicillin and non-penicillin beta-lactam drugs, such controls could include, but are not limited to, isolation and separation of intermediate and derivative materials, facilities, equipment, and personnel.

Beta lactam and non-beta lactam products
Non-penicillin beta-lactams and other non-penicillin beta-lactams (cross-reactivity risk)

For the manufacture of a specific class of non-penicillin beta-lactams (e.g. the cephalosporin family), separate facilities and air handling systems are not mandatory. According to the FDA, production campaigning and cleaning may be sufficient.

As long as the equipment is kept in good working order and is kept clean, manufacturing cephalosporin medications doesn't need its own building or air handling system. As long as there is no chance of contamination with beta-lactam goods, a separate facility for non-beta-lactam products is also not necessary. In order to minimize cross-contamination, cleaning, and maintenance must adhere to all rules and directions.

FDA guidelines state that there is always a chance of cross-contamination, however remote. Therefore, before being sold, all non-beta lactam items should be checked for contamination. If contamination is found, the product should not be sold.

What does a separate manufacturing facility mean?
The answer is very simple:
A separate manufacturing facility is a design that has, Separate manufacturing area from the main plant for manufacturing of other products.
  1. Separate HVAC System
  2. Separate Equipment
  3. Separate WorkForce
  4. Separate Laundry
  5. Separate Canteen
  6. Separate Washrooms

1. Separate Manufacturing Area
To prevent cross-contamination of penicillin with non-penicillin beta-lactam antibiotics or with other general products the manufacturing plant of penicillin antibiotics is dedicated and built separately where only penicillin beta-lactam antibiotics are manufactured.

2. Separate HVAC
The distinct penicillin factory was constructed with its own heating, ventilation, and air conditioning system that is installed and has no link to any other facility. As air may also cause cross-contamination, it is important to have an appropriate distance between the factories that make penicillin and other goods. This is done to prevent cross-contamination.

How much space should be maintained between the manufacturing facility for penicillin and other plants is a sometimes perplexing subject concerning distance.

According to a basic calculation, a space of at least 75 meters should be kept between each plant.

3. Separate Equipment
Penicillin manufacturing facilities need specialized machinery and equipment. Never move or transport a machine or component from the penicillin factory to a different plant since any traces might induce hypersensitivity responses to occur.

4. Independent Workforce
For the penicillin factory, every employee, including pharmacists, employees, and engineering personnel, is hired independently. Cross-contamination may occur if employees moved from the penicillin factory to the non-penicillin beta-lactam plant.

One thing to keep in mind is that in order to achieve strong control, top-level management functions like director production, director compliance, etc. should also be segregated.

5. Separate restrooms, a canteen, and laundry
The laundry of penicillin is constructed specially for washing uniforms. The employees is required to have a separate cafeteria for tea, lunch, and supper, and at the same location, we have a separate bathroom facility.

Significant Points
  1. Similar to penicillin, the FDA advises distinct production facilities and stringent controls for all other sensitizing non-penicillin beta-lactam antibiotic families.
  2. Penicillin hypersensitivity or sensitivity may be so extreme that responses to invisible traces of penicillin on records like BMRs might cause hypersensitivity.
  3. Sometimes a facility may not produce penicillin or other non-penicillin beta-lactam antibiotics, but the next-door or nearby plant may be making the aforementioned medications.
  4. Therefore, the non-penicillin plant will need to take precautions to avoid penicillin hypersensitivity.

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