Why is a Separate Manufacturing Facility Required For Penicillin And Non-Penicillin Products

Why is a Separate Manufacturing Facility Required For Penicillin And Non-Penicillin Products

Why is a Separate Manufacturing Facility Required For Penicillin And Non-Penicillin Products

In this article, we will discuss the answer to a very common but confusing question regarding penicillin hypersensitivity & manufacturing facility of penicillin in the pharmaceutical industry. We will also discuss other beta-lactam ring antibiotics.

But before going into details of the manufacturing facility, first, have a brief look over penicillin and beta-lactam.

What Is Penicillin?

Penicillins are a group of natural or semisynthetic antibiotics containing beta-lactam rings with 6 APA or 6 aminopenicillins acid and are effective against bacteria.

Who Discovered Penicillin?

Penicillin was discovered by Alexander Fleming in 1928 from the fungus Penicillium. The discovery of penicillin brought huge changes in the field of medicine and it is also known as the "wonder drug" or queen of drugs.

Penicillin is a naturally occurring antibiotic produced by the mold Penicillium. It was discovered by Alexander Fleming in 1928 and is used to treat bacterial infections such as strep throat, pneumonia, skin infections, and ear infections.

When penicillin was first discovered, it was only effective against a few species of bacteria. However, over time researchers have developed new methods for producing penicillin that allows for greater quantities and more potency. This discovery has allowed doctors to use penicillin as a “wonder drug” for many types of bacterial infections.

In the last twenty years, scientists have discovered several antibiotics that are both more effective than penicillin and easier to produce. These include vancomycin, clindamycin, and linezolid. In addition to fighting bacterial infections, these new antibiotics can also be used against viruses such as HIV

 

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.

 

 

Note

  • As we discussed in the above section, the beta-lactam ring is not only present in penicillin but also present in other antibiotics as well so all these antibiotics containing beta-lactam ring are known as beta-lactam antibiotics.

Penicillins are antibiotics that belong to the group of beta-lactams, which have a beta-lactam ring in their structure that helps inhibit cell wall synthesis in bacteria. As a result, if the affected bacteria attempt to divide, their cell wall will collapse, killing them in the process!

Now, some bacteria have developed resistance to beta-lactam antibiotics through enzymes called beta-lactamases and penicillinases, which break down the beta-lactam ring within the antibiotic, making it ineffective. Penicillins can be classified into three main groups based on how vulnerable they are to beta-lactamases and penicillinases, as well as their spectrum of activity, which is how many different species of bacteria can they effectively treat.

Narrow spectrum penicillins include penicillin G and penicillin V, which are susceptible to penicillinases. These are the classics, still quite usable against common gram-positive bacteria like streptococcus pyogenes, as well as gram-negative bacteria like Neisseria meningitides. They are also effective against spirochetes - such as treponema pallidum (syphilis) or borrelia burgdorferi (Lyme disease).

Broad spectrum penicillins include amoxicillin and ampicillin, which are susceptible to beta-lactamases but can work well if combined with a beta-lactamase inhibitor, such as clavulanic acid. They’re effective against a wider variety of gram-negative bacteria like Haemophilus influenzae and Moraxella catarrhalis, helicobacter pylori, salmonella, shigella, and listeria. Other members of this group, sometimes called extended-spectrum penicillins, include piperacillin and ticarcillin. They have even more gram-negative coverage, such as Pseudomonas aeruginosa.

Finally, the newest ones are very narrow spectrum penicillins, which include methicillin, oxacillin, nafcillin, and cloxacillin. These are resistant to beta-lactamases and were created to fight bacteria like Staph aureus and Staph epidermidis which often had the beta-lactamase enzyme. They did work quite well until some Staph aureus developed the mutations and became MRSA (methicillin-resistant Staph aureus).

Name of Antibiotics Containing Beta-Lactam Ring

Some common classes of antibiotics that contain beta-lactam ring are as follows,

  • Penicillin
  • Cephalosporin
  • Penams
  • Carbapenem
  • Monobactams

What Is Common In All Beta Lactam?

The similarity between all the above-mentioned classes of beta-lactam antibiotic is that all contain 4 membered lactam ring having 3 carbon & 1 nitrogen cyclic amide.

How Does the Beta-lactam Antibiotic Class Differ?

The difference between the activity or reactivity of different classes of beta-lactam antibiotics is due to the difference in the attachment of the side chains or different groups’ attachment by a peptide bond.

Explanation

The difference is explained as,

Penicillins

  • Penicillins have 6 APA or 6 aminopenicillins acids.

Cephalosporins

  • Cephalosporins have 7 aminocephalosporanic acids.

Penams

  • In penams, the beta-lactam ring is fused to a saturated 5 membered ring which has 1 sulfur atom.

Carbapenem

  • Here carbon is substituted by sulfur.

Monobactams

  • Alone beta-lactam ring, not fused to another ring.

Hypersensitivity To Penicillin

Apart from giving many useful results in treating infections, penicillin is also harmful to those individuals who are allergic or sensitive to penicillin and produce minor skin rashes to life-taking anaphylactic shocks.

The hypersensitivity reactions of penicillin may include the following,

  • Skin Rashes
  • Hay Fever
  • Asthma
  • Hives
  • Itching Eyes
  • Swelling Of Tongue
  • Swelling of face
  • Difficulty in breathing
  • Runny nose
  • Fever
  • Anaphylaxis

Anaphylaxis is a life-threatening effect and it may contain many symptoms which are as follows,

  • Tightening of airways resulting in difficulty of breathing,
  • Nausea
  • Vomiting
  • Abdominal Cramps
  • Fainting
  • Fast or slow pulse rate
  • Reduction in B.P

Penicillin allergy is observed in patients sensitive to penicillin because the immune system recognizes the penicillin drug as a bacteria or virus and starts fighting against the drug.

 

Differences in 6 aminopenicillins acid side chains may cause allergic reactions.

 

Skin Test

The ratio of individuals who are allergic to penicillin is very small; only 10 out of 100 may be allergic to penicillin but as a preventive measure before using penicillin a skin test or sensitizing dose is used.

If the amount of IgE is increased after the skin test it indicates that the individual is sensitive to penicillin.

The individuals who are sensitive to penicillin may also be sensitive to other beta-lactam antibiotics so care should be done.

 

Why Does Penicillin Manufacturing Require a Separate Facility?

As we discussed in the above portion, penicillins are sensitizing agents and may trigger hypersensitivity reactions, although the ratio is very low at 10% US-FDA and other regulatory bodies demand to manufacture of these antibiotics in separate facilities to prevent cross-contamination.

 

So a common question is 

"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 other products.
  • Separate HVAC System
  • Separate Equipment
  • Separate Work Force
  • Separate Laundry
  • Separate Canteen
  • Separate Washrooms

 

Now let's explain why the above-mentioned precautions are done for penicillin manufacturing,

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.

Separate HVAC

The separate plant built for penicillin is installed with its heating, ventilation, and air conditioning system which has no connection with any other facility.

It is to prevent cross-contamination and as we know that air may also result in cross-contamination so a suitable distance is maintained between penicillin and other products manufacturing plants.

The common confusing question which is asked about distance is how much distance should we maintain between the penicillin manufacturing plant & other products plant?

A rough estimation is that a distance of 75 meters or more than 75 meters should be maintained between plant to plant.

Separate Equipment

In penicillin plants dedicated equipment and machines are used. Never shift or transfer any machine or part from the penicillin plant to another plant because any traces left may result in triggering the hypersensitive reactions.

Separate Work Force

All the staff including pharmacists,  workers, and engineering staff are separately hired for the penicillin plant.

Personnel movement from the penicillin plant to the non-penicillin beta-lactam plant is not allowed because it may result in cross-contamination.

One important point to remember is that top-level management like director production, director compliance, etc should also be separated to ensure strict control.

Separate Laundry,  Canteen & Washrooms

For washing uniforms, the laundry of penicillin is built separately.  For tea,  lunch & dinner the staff must have a separate canteen and in the same, we have a separate washroom facility.

Important Points

Like penicillin for all other sensitizing non-penicillin beta-lactam antibiotic classes, the FDA recommends separate manufacturing facilities and strict controls.

The penicillin sensitivity or hypersensitivity due to penicillin may be so severe that the invisible traces of penicillin on the documents like BMRs can start hypersensitivity reactions.

Sometimes it may be the case where a plant is not manufacturing the penicillin or other non-penicillin beta-lactam antibiotics but the adjacent or nearby plant is producing the above-mentioned.

So preventive measures will have to be taken by the plant of non-penicillin to prevent penicillin hypersensitivity.

Link to other Articles on this Topic  :

Separate Manufacturing Facility is Required for Manufacturing of Penicillin and Non-penicillin Products: Pharmaguideline

New FDA Guidance for Beta-Lactam Antibiotics facility (igmpiindia.org)

Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination (fda.gov)

Importance Of Separating Manufacturing Process For Penicillin And Non-Penicillin (lfatabletpresses.com)

Questions and Answers on Current Good Manufacturing Practices—Buildings and Facilities | FDA

 

 

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