Small Molecules

Introduction

Small and large molecules are classes of molecules used as active substances. These molecules are often use by the pharmaceutical industry on finding the right approach for the best platform in terms of manufacturing. Small and large molecules differ not only in their applications but also on how they are being produce and process.

Small molecules are drug substances which are chemically-based with molecular weight of less than 900 daltons. These molecule form the bulk of traditional pharmaceutical medications on treating various indications from cancer to cardiac diseases, respiratory disease and other common ailments such as flu and headaches.

Production of small molecules depends on the type of final dosage form be it an oral or solid dosage form such as tablets and capsules or parenteral and injectable which are injected into the body.

Injectable is further divided into different types of pharmaceutical processing - from products that can be terminally sterilized to products that are manufactured via aseptic processing.

Products which are aseptically processed is utilize in ballpark cleanrooms with the use of various grades of Personnel Protective Equipment (PPE) and gowning leading towards Grade A (class 100) environment.

Small molecules are further divided into generics and New Chemical Entities (NCE) which contain patented novel compounds.

Esco Pharma provides various standard and custom containment solutions across the entire OEL/OEB range and across various dosage forms.

Discovery

Drug discovery of novel chemical entities often takes place within academic institutes, government research institutes or within pharmaceutical company.

Small molecules are often produced in either by the chemical interaction of organic to inorganic compounds or by high-throughput screening.

During the research phase, Esco Life Sciences provides an entire range of standard laboratory tools for the drug discovery process within chemistry labs, from Biological Safety Cabinets, Laminar Flow Cabinets, ovens, C02 Incubators, Ductless/Ducted Fume Cabinets.

The initial hits identified in a high-throughput screen rarely possess all the various properties that are required of a drug. Rather, a validated hit represents the departure point for an iterative process wherein the chemical structure of the hit is modified and the biological activities of new analogs are assessed. This process is by nature collaborative, requiring medicinal chemists to design and synthesize new analogs, and biologists to obtain activity (and/or structural) data that informs the next round of molecular design. The successful progression from initial HTS hit to cell-active and selective lead compound serves to effectively validate a target for subsequent lead-optimization studies. These later stages of the drug discovery process are highly resource intensive and are usually beyond the scope.

Hit to Lead Chemistry

The chemical optimization process begins with one or more validated hits from a high-throughput assay. Hit validation is an essential first step before chemistry resources can be allocated to an optimization effort. Validation studies involve confirmation of the chemical structures and biological activity of hits identified in the primary screen.

R&D in academic or industrial labs of potent powders and small molecules can be carried out in various powder coated isolators with BIBO filters (HPI G3, SCI-TE, CBI-T), Flowhoods, Cytotoxic Biological Safety Cabinets, Pharmflow Flowhoods or Powder handling cabinets / VBEs / Fume Cabinets depending on the scale, a typical r&D laboratory will also contain biological safety cabinets, laminar flow cabinets, CO2 incubators.

Primary or Secondary research facilities may often also contain Downflow Booths, Fume Cabinets, benchtop powder handling cabinets/VBEs.

Our sister division TaPestle Rx designed and built this secondary research facility in Singapore including 3 Downflow Booths, Laboratory Furniture and Fume Cabinet for a top 10 MNC.

Design Advantages:

  • Ergonomically designed oval gloveports are specified as standard, with Hypalon gloves.
  • Fully welded 7 gauge 316L stainless steel construction, with laminated safety glass, and 5/8 inch corner radiuses.
  • The PLC allows the Isolator to maintain a constant pressure within high and low set points, with a visual alarm back-up.
  • Cam-lock connections for inlet and outlet of gas sterilant.
  • Temperature control to maintain the Isolator at a constant temperature with high/low set points.
  • Negative pressure System with safe change supply & exhaust HEPA filtration.
  • Designed as a complete development laboratory containing the balance, magnetic stirrer, mixer, homogenizer, centrifuge and area for hand filling.
  • Automatic pressure control for ammonia leak testing.
  • Automatic oxygen and humidity control systems.

Reactors and glass-ware for chemical synthesis, in different sizes and configurations according R&D needs

  • Tray Dryer for material drying under controlled conditions
  • HPLC operations
  • Wet analysis on product
  • Dry analysis on product
  • In Process controls
  • Weighting
  • Equipment and final product discharging

Scaling Up/ Kilo Labs / Pilot Plants / Clinical Trials

Scaling up for early clinical trials or small batch production can be done in Glassware Hoods/Kilo Labs with integrated chemical reactors to produce kilograms of powders.

These are typically configured with an inward rush of air for operator protection only and can have additional extended uni-directional airflow air for secondary containment or for providing product protection. Extended plenums are either bolted onto the front of the glassware hoods or provided mounted flushed to the cleanroom ceiling grids as Ceiling Unidirectional Airflow Units (CUAFs/Clafs).

For clients that have budget constrains Esco Frontier Acela Floor Mounted Fume Cabinets featuring patented hot zone baffles can be provided instead of full st.st. cGMP Chemical reactor hoods.

Delivery (Commercial Production)

For potent OSDs <10kg with integrated 3rd party mixers, blenders, fluid bed dryers, granulators.

During small molecule production various other process considerations need to be taken into selecting the containment system depending on the OEL/OEB and at terms if powders handled need to be in an Atex Room or just an internal Atex Environment.

In pharmaceutical small molecule commercial manufacturing.

Weighing and dispensing of potent powder APIs and Excipients can be carried out in our Pharmacon Downflow Booths that can come integrated with Pharmaflow Flowhoods, 1D /2D

These can come in re-circulatory, single pass or combination systems (re-circulatory+single pass) and with or without added personnel, material airlocks and conveyor systems (use solidwork images).

Alternatively if the drums handled are small in size the operator can stand outside the clean area and operate in Pharmaflow Flowhoods with and without gloveports

Closed handling for weighing and dispensing of more potent powders can be carried out in our Weighing and Dispensing Containment Isolators WDCI. These are often integrated with multiple chambers, drum lifters , vertical drum lifters and other material handling devices to add in ergonomics.

In event, the potent powders prepared are to be injected into the body, it is becoming more typical for these powders to be weighed in Aseptic/Potent isolators with BIBO filters such as our Esco Aspetic Containment Isolator ACTI which are first bio-decontaminated with Hydrogen Peroxide before weighing as part of aseptic processing.

Esco Aseptic Containment Isolator ACTI with integrated Esco BioVap for an Oncology drug manufacturer with RTPs, CIP and integrated weighing scales, BIBO Filters.

Esco Pharma also provides CLAF or CUAF units over autoclaves and other aseptic processing areas that required product protection as part of the unit operation.

These small molecules can then after formulated in aseptic and/or potent formulation isolators are ready to be filled in various dosage forms that are either Ready-to-Use containers or in traditional filling lines.

As part of formulation of the mother vessel a stainless steel reactor or single use bag connected to a filter can be linked for final filtration of the bulk liquid product before final filtration and filling into a vial, syringe, cartridge or IV Bag.

Esco Pharma provides Filling line isolators, the passive or active Open Restricted Access Barrier System (oRABS) or closed Restricted Access Barrier System (cRABS) which are integrated with our without freeze/spray driers. Material handling of filling needles and other components, can be performed via laminar flow isolators to ensure transfer from Grade A to Aseptic Core (eg. From partial stoppering after filling in an oRabs or cRabs to freeze drier, or autoclave room to filling isolator)

If aseptic assemblies are to be connected within filling line isolators, isolators integrated with autoclaves can be provided for per-sterilizing re-useable filling needles. As an alternative single use filling needles connected to formulation bags in closed liquid transfer systems can be provided. Freeze driers come with manual or auto loading systems, auto stoppering of vials or manual stoppering outside the filling line.

For Personal and material handling utilizing the Cross-Contamination Facility Integrated Barrier (CCFIB) misting showers can be provided for operators who are dressed in powered air purifying respirators whilst operating in ballpark cleanrooms, Downflow Booths or potent handling isolators to prevent occupational exposure to potent powders during degowning procedures or during emergency situations.

Material pass-throughs utilizing either static or dynamic pass-throughs can be utilized, bringing in of pallets into the central dispensary or warehousing and dedusting of final finished goods can be carried out in dedusting hatches or large air showers to reduce particulates on surfaces of containers.

Quality Control/In-Process Quality Control (QC-IPQC)

Checking of tablets during IPQC /QC can be carried out within Flowhoods, Ventilated Balance Enclosure (VBEs) or for added containment in Esco Pharma powder coated standard Potent powder handling Isolators (CBI-T).

During small molecule manufacturing various QC/IPQC can be carried out from sterility testing utilizing sterility testing isolators (HPI-G3 / CBI-U / GPPI / ACTI) or Biological safety cabinets / Laminar flow Cabinets.

Stability testing of final products need to be carried out at the final packaging site hence Esco Pharma provides stability test chambers of either walk in or mounted within the QC/IPQC Lab *

Final storage of drugs or raw materials may need to be done in cold chain Esco Pharma provides walk in cold rooms. *

*For ASEAN countries only.

Pharmacy Compounding

Small molecules often need to be compounded within pharmacies depending on patients as such Esco offers Isolators / Cabinets and Laminar Flow Cabinets for cytotoxic drug reconstitution

As part of growing cGMP requirements within the Pharmacy Compounding and Radiopharmacy space, Esco Pharma was the first to introduce cGMP isolators into the USA market. Esco Pharma along consultation, design & build and validate division TaPestle Rx provides turnkey pharmacy compounding and radiopharmacy fit outs within Asean/Anz. This continues the legacy of Esco Group who was founded by 2 pharmacists and built the first cleanroom in the Far East for Siemens Components in 1978.

As small molecules evolve in requirements and dosage forms Esco Pharma is committed to providing from our core Pharmaceutical technologies a variety of ever growing products and services.

Recommended Products

Aseptic Containment Isolators

Ceiling Laminar Airflow Units

Cleanroom Air Showers

Containment Barrier Isolator

Dynamic Passboxes and Dynamic Floor Label Hatches

General Processing Platform Isolator (GPPI)

Infinity® Cleanroom Transfer Hatch

Laminar Flow Horizontal Trolley / Laminar Flow Vertical Trolley

Pharmacon™ Downflow Booths

Soft Capsule® Soft Wall Cleanroom

Ventilated Balance Enclosure

Weighing and Dispensing Containment Isolator (WDCI)