PHARMACEUTICALS AND BIOCHEMICALSAPPLICATION NOTE 6.01.00 PHARMACEUTICAL PROCESSING

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ACTIVE PHARMACEUTICAL INGREDIENTS (API’S), RAW MATERIAL Typical end products Active pharmaceutical ingredients, excipients, intermediates and raw material for pharmaceutical drugs

Introduction

The regulatory authority of the Food and Drug Administration (FDA) is fundamental to the development and production of pharmaceuticals. Furthermore, those involved must comply with the Good Manufacturing Practices (GMPs), a set of regulations requiring disciplined standard operating procedures, with comprehensive documentation covering every step in the manufacturing process.

The K-Patents Process Refractometers are ideal real-time instruments perfectly suited for the fulfilment of these requirements. The ability to measure and control parameters such as Refractive Index nD contributes significantly to the development of effective drugs and their efficient manufacturing.

Typical applications

• PHARMACEUTICAL CHEMICALS

• ACTIVE PHARMACEUTICAL INGREDIENTS: Actives, Excipients, Intermediates.

• ANTIBIOTICS: Penicillin, Sreptomycin, Tetracyclines, Antifungals.

• BLOOD PRODUCTS: Blood, Plasma, Serum, Infusion liquids, Sodium chloride, Glucose.

• PROTEINS: Proteins and Protein buffer solutions.

• SYNTHETIC DRUGS

• VITAMINS: Ascorbic acid, Ca-Arabonate, Riboflavin, Vitamin-B, Vitamin-C, Sodium pantonate.

• SYNTHETIC HORMONES

• SYRUPS: Concentrated aqueous solutions of sucrose.

• DRUGS OF VEGETABLE ORIGIN: Drugs and Herbal extracts.

• VACCINES

• SURGICAL SUTURES AND DRESSINGS: Glue for human tissues.

• SOLVENTS, ACIDS AND BASES

PHARMACEUTICALS AND BIOCHEMICALS APPLICATION NOTE 6.01.00 PHARMACEUTICAL PROCESSING

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FDA Regulations and Validation

FDA regulations require everything to be thoroughly tested to make sure that the produced drugs meet set standards. This is called validation. The short textbook definition of validation is: "Proof of specified performance". An important part of the validation process is determining and proving the suitability of the process instrumentation for its designated function, and appropriate use by the purchaser.

Therefore, any new instrumentation needs thorough testing at the laboratory and at pilot plant stages. After initial lab testing, the K-Patents refractometer can be subjected to a pilot plant trial, which may involve a skid manufacturer. Fulfilment of all the test phases and their careful documentation facilitates the refractometer installation into the full scale production process.

Pharmaceutical Process Design Utilizing PAT

Process design is the conversion of information on product formulation and requirements into manufacturing knowledge. Products and manufacturing processes should be designed using science- and risk-based design strategies to manage variation. To achieve this, integration of Process Analytical Technology (PAT) principles and tools during process design is recommended. This will enhance opportunities to build, maintain and expand process understanding throughout the product lifecycle. The product lifecycle includes a period in production as well as in development. Process understanding is the foundation in establishing manufacturing (process selection, methodology, implementation and practice), process control (real-time control on the basis of measured critical quality attributes), effective risk mitigation and product release concepts.

The K-Patents Process Refractometer is the ideal process control tool in accordance with the PAT framework. The drug manufacturer can both reduce development time and improve product reliability through thorough process analysis. This is possible using the same refractometer during pilot and production phases.

FDA Title 21 CFR Part 11 and Data-logging via Ethernet

Title 21 CFR Part 11 of the Code of Federal Regulations deals with the Food and Drug Administration (FDA) guidelines on electronic records and signatures in the United States. Part 11 defines

the criteria under which electronic records and signatures are considered to be trustworthy, and equivalent to paper records. Part 11 requires drug makers, medical device manufacturers, biotech companies, biologics developers and other FDA-regulated industries to implement controls. These include system validations, audits, audit trails, electronic signatures, documentation for software and systems involved in processing electronic data, which are (a) required to be maintained by the FDA predicate rules or (b) used to demonstrate compliance to a predicate rule.

The K-Patents Process Refractometers facilitate the technical controls necessary for 21 CFR Part 11 compliance.

The K-Patents refractometers have an Ethernet communication solution, which facilitates electronic data records for FDA 21 CFR Part 11 adherence. The transmitter uses the IP protocol to communicate over the Ethernet to any type of computer. This eliminates human error and allows for an easy refractometer generated measurement and diagnostic data capture for storage, analysis and reporting.

K-Patents provides a software package for data downloading. Full software specifications are freely available for users, who wish to develop their own communications program. Access to the refractometer and the generated data can be restricted to authorized personnel using password protection. Together with the user's own procedural and administrative user controls, compliance with the 21 CFR Part 11 is assured.

Instrumentation

The K-Patents Process Refractometer PR-23 series offers the pharmaceutical industry many specifically designed technological advantages.

These include:

- Process wetted materials: Stainless steel AISI316L, PTFE Teflon, Sapphire, Spinel, EPDM, Viton.

- Pharma mini flow cell PMFC with electro-polished wetted material (Ra 0.4μm/15μ inch) for low volume pharmaceutical and biochemical pilot processes.

- Electro-polished wetted materials to secure surface roughness of Ra<0.4μm/15μ inch.

- No animal derived media is used in the polishing and finishing processes.

PHARMACEUTICALS AND BIOCHEMICALSAPPLICATION NOTE 6.01.00 PHARMACEUTICAL PROCESSING

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- Optional sensor models to suit small or large scale processes: pilot (PR-23-AC, PR-33-S), production (PR-23-GP/AP).

Instrumentation Description FOR LABORATORY, PILOT AND PRODUCTION SCALES:

K-Patents Sanitary Compact Refractometer PR-23-AC for small pipe line sizes of 2.5 inch and smaller. The PR-23-AC sensor is installed in the pipe bend. It is angle mounted on the outer corner of the pipe bend directly, or by a flow cell using a 3A Sanitary clamp or Varivent® connection.

FOR PRODUCTION SCALES:K-Patents Sanitary Probe Refractometer PR-23-AP for installations in large pipes, tanks, cookers, crystallizers and kettles, and for higher temperatures up to 150°C (300 °F). Installation through a 3A Sanitary clamp.

FOR PRODUCTION SCALES:K-Patents Process Refractometer PR-23-GP is an industrial refractometer for large pipe sizes and tanks, cookers, crystallizers and kettles. Installation through a flange or clamp connection.

Refractive Index (nD) 1.3200 – 1.5300, corresponding to 0-100 Brix. Measurement range: