Handbook Of Pharmaceutics Scientists And Reviewers.pdf

1 HANDBOOK OF PHARMACEUTICS For Pharmaceutical Scientists and Reviewers Compiled & Edited Masih Jaigirdar 2 Preface Pharmaceutics is the discipline of pharmacy that deals with the process of turning a[.]

HANDBOOK OF

PHARMACEUTICS

For Pharmaceutical Scientists and Reviewers

Compiled & Edited: Masih Jaigirdar

Preface

Pharmaceutics is the discipline of pharmacy that deals with the process of turning a new chemical entity (NCE) or old drugs into a medication to be used safely and effectively by patients It is also called the science of dosage form design There are many chemicals with pharmacological properties, but need special measures to help them achieve therapeutically relevant amounts at their sites of action

Pharmaceutics helps relate the formulation of drugs to their delivery and disposition in the body

Pharmaceutics deals with the formulation of a pure drug substance into a dosage form Branches of pharmaceutics include:

Pure drug substances are usually white crystalline or amorphous powders Before the advent of medicine

as a science, it was common for pharmacists to dispense drugs as is Most drugs today are administered

as parts of a dosage form The clinical performance of drugs depends on their form of presentation to the patient

Though the subject Pharmaceutics is only studied or in the educational curricula of the College of

Pharmacy in different universities across the globe, but its use and at least some knowledge is needed or essential for the other technical disciplines personnel in the pharmaceutical industry as a formulator, analyst, process engineer and regulatory affairs It is also very important for a reviewer in the regulatory agency, going through the section P.3 Drug Product and Process Development of the application, to understand the basics of pharmaceutics for authentic endorsement or approval of an application from quality perspective

This Hand book of Pharmaceutics is a reference work containing a compilation of information collected and edited by the initiator and made it easy by using his education in pharmaceutics and 45 years of professional experience; with over 10 years in the public service as CMC reviewer and 35+ years in the private sector (Pharmaceutical Industry) as Product Development Scientist, writing and collecting many scientific articles and giving many presentations to the audience at the scientific seminars of ISPE and AAPs and for the training as a mentor of the FDA CMC reviewers For this task of compilation the editor has utilized his own exposure and experience in the field by covering multiple subjects and technologies

in a way that would not be merely a review of the literature but in depth review and interpretation Each chapter begins by assuming either the reader is not very familiar with the subject or would be a refresher

P.S: This version of the Handbook of Pharmaceutics is only for the use of academic and scientific purpose and only its electronic or printed copies may be distributed among the user but not to be published by anybody for their financial benefit without the permission of the editor

About the Compilation and Editor

Masihuddin Jaigirdar by profession a Pharmaceutical Scientist, before retiring, was a senior Quality Reviewer, US Federal Government (G.S-14-8) with FDA/OPQ/OPMA Division III Beside his quality reviews of many

applications including INDs, NDAs and over 500 ANDAs/Amendments for a period of over ten years; he has also contributed/participated in FDA OGD/OPMA various scientific working groups as a team member In October 2020 for his dedication to the FDA through his 10 years of exemplary service as an exceptional employee and mentor, received the certificate of appreciation from the CDER; FDA

He has M Pharm and Post Graduate Education in Pharmaceutical Science/Technology and over 35 years of diverse experience in the Pharmaceutical Industry in the field of Formulation Development, Process Technology Transfer, Process Optimization, and Scale-up of products and Manufacturing for Brand and Generic Pharmaceuticals in US and Overseas (Europe & Middle East)

As a formulation scientist he has proven success of generating many Abbreviated New Drug Applications (ANDAs)

of Paragraph IV Paradigm defending them at litigation and got agency approval He has worked for many worlds reputed Pharmaceutical Companies

He was the Associate Director and Research Leader of R&D Product Development; expertise in Modified Release Technology for Actavis (former Watson) Pharmaceuticals in Corona, California

Masih was Senior Principal Scientist, for the generic division of Marion Merrill Dow (MMD), Hoechst Marion & Russel, Aventis; (Chelsea Laboratories), in Cincinnati, Ohio

Just before joining FDA in September 2010, he was with the Product Development Group of Mylan, in Morgan Town, West Virginia

GLOBAL EXPOSURE:

Masih started his professional career in early 70’s, joining the then E.R.Squibb & Sons in their overseas

pharmaceutical plant in Bangladesh In the 80’s was trained by ASTRA Development AB, Sodertalje, Sweden, for the position of Head of Process Technique/Technology Transfer, for the newly build pharmaceutical plant KIPICO

of the Kuwait (Middle East) government He was responsible and conducted the Validation Program for Product’s Process: Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) in conjunction with technical experts from ASTRA Sweden for all pharmaceutical dosage forms

Provided technical support and troubleshooting to existing products and process

Has written and revised production methods, batch production records, SOPs and validation protocols

Field of Knowledge/Experience/Exposure/Expertise

Solid Oral Dosage: Immediate Release, Modified Release (Controlled Release & Delayed Release)

Semi Solids: Ointment, Cream, Gel and Suppositories Technologies

Liquids: Internal-Liquid (Oral Solution, Suspension, Elixirs, and Emulsion); Injectable: SVP & LVP, Peritoneal Dialysis and Hemodialysis solutions, ophthalmic preparations and Nasal Spray etc

Contribution and Accomplishments

Masih was routinely sought out by his peers for his insight on both scientific and regulatory challenges when reviewing applications (e.g., scale-up considerations for a variety of finished dosage forms) and has trained and mentored a number of Chemistry Reviewers He has been a routine trainer for new reviewers in multiple offices within the Office of Pharmaceutical Quality (OPQ); and has presented training sessions on many manufacturing process related topics

He provided valuable input and actively participated in a number of important working groups and committees that had a direct impact on review work being completed in OGD, and OPQ, including OGD’s Quality by Design (QbD) Working Group and OGD’s Risk Assessment Team, and OPF’s Continual Learning Committee

Masih was also well regarded for his mentorship and training abilities which have been shared across multiple offices When in the Office of Generic Drugs (OGD) he presented and participated in Study Lunch Series, served on the Training Faculty for new review chemists that formally trained

approximately 65 new chemists, and served as official mentor for his division

During his tenure in the Office of Pharmaceutical Quality (OPQ), he continued to serve on a Continual Learning Committee that emphasizes and enhances review and inspection processes For this endeavor

he received a Leadership Excellence Award in 2016

Awards: Masih has received many awards during his 10 years’ service with the agency

 Certificate of Appreciation for valuable service to the AAPS Modified Release as Learning

Opportunity Manager, in November 2020 – November 2021

 Certificate of Appreciation for dedication to the FDA through his 10 years of exemplary service as an exceptional employee and mentor, October 13, 2020

 Award received (group): In Recognition of the OPF Training and Development Team sponsoring cross-OPQ training and development activities, December 13, 2016

• Leadership Excellence; OPF Continual Learning Committee, September 16, 2016

• Certificate of Appreciation: Risk Based Review Pilot Program, February 10, 2014

• Excellence in Mentoring: Training Faculty for New Chemist Reviewers; For outstanding efforts in training over 65 new chemists in the review of Chemistry, Manufacturing, and Control portion of the ANDA in 2013

• OGD Chemistry Risk-Based Review Groups; for demonstrating the feasibility, effectiveness and

efficiency of risk-based review in the chemistry evaluation of ANDAs

• Speaker at OPF Knowledge Sharing Seminar Series

• CDER Office of Generic Drugs, Certificate of Appreciation; “Role of Scale-up Strategy in Product

Development and Formulation, March 14, 2011

Review and Notice to Readers

It is a very nicely written handbook; Concise, yet very informative with current information I suggest that every scientist working in the pharmaceutical industry involved in dosage form development, especially one relatively new in the field and without much formal training in pharmaceutics, should read the book Indeed, since there are not many pharmaceutics programs in the academia teaching physical pharmacy and drug formulation, most of the new formulators in the industry and regulatory agencies do not have pharmaceutics background I believe that they will be much benefitted by reading this book I recommend the publication of this handbook at a relatively low price so that the book gets wide circulation and acceptance by the pharmaceutical community

From: Abu Serajuddin

Sent: Monday, February 15, 2021 1:42 PM

Abu T M Serajuddin, PhD, FAPhA, FAAPS

Professor of Industrial Pharmacy

From: Larry Augsburger

Emeritus Professor at University of Maryland Baltimore

University of Maryland Baltimore

Severna Park, Maryland, United States

Forwarded Oct 4 at 10:42 PM

larryaugsburger@gmail.com

Arrangement of Contents

Chapter 1: Background Information

Chapter 2: Generic New Product Introduction & Product Development Process Solid Dosage (Tablet) Chapter 3: Solid Dosage Form

Chapter 4: Mixing and Granulation Solid Dosage (Powder, Tablet and Capsules)

Chapter 5: Hard Gelatin Capsule Chapter

Chapter 6: Soft Gelatin Capsule

Chapter 7: Pharmaceutical Coating

Chapter 8: Solid Dosage Manufacturing Process Testing and Sampling Considerations

Chapter 9: Pharmaceutical Excipients for Solid Dosage

Chapter 10 Semi-Solids Dosage

Chapter 11: Liquid Dosage

Chapter 12: Parenteral Medications

Chapter 13: Lyophilization Process

Chapter 14: Typical Pilot-scale Lab Apparatus & Equipment

Chapter 15: Role of Scale-up Strategy in Product Development

Chapter 1: Background Information

Drugs/Medicines are used for: against disease, medical or health conditions

They either come from chemical or biological source

Can be broadly classified into two main as per therapeutic (Pharmacological) category:

1 Chemo-therapeutic agents (drugs),

2 Biological-drugs

Chemo-therapeutic drugs: Drugs made of chemicals A few examples are of the following groups:

Analgesics/Antipyretics; Analgesic/Hypnotics; hypertensive; diabetics; depression; cholesterols, etc

Anti-Biologicals: Drug derived from biological source or fermentations: Anti-biotic, Vitamins etc

These are well known as drug substance and are produced in bulk quantities by their manufacturer

However, for doctor/physician/Nutritionist prescribe them to a patent or individual in specific quantity (dose) to be taken/used/applied per recommendation

Many of these doses can be as little as a few micrograms and up to 1000mg or more The question arise how to deliver them to such specific quantity/quantities?

Pharmaceutical Dosage form became the media/mode of delivery to the patient/user to take/use/apply specified quantity one time or multiple times depending on the requirement

Pharmaceutical Dosage Form: Dosage forms (also called unit doses) are essentially pharmaceutical

products in the form in which they are delivered for use, typically involving a mixture of active

pharmaceutical ingredient (API) and inactive ingredient (excipients)

Depending on the method/route of administration, dosage forms come in several types These include

in general broadly in following main three groups: Solids, Liquid and Semi-solids

Solids: Powder, Powder for reconstitution as solutions or suspensions, Pill, Tablet, and Capsule

Semi-Solids: Ointment, Cream & Gels

Various dosage forms may exist for a single particular drug: due to different medical conditions or patient population (Pediatric, adult and geriatric) can warrant different routes of administration

Liquids: Internal & External Liquids

Internal Liquids: Oral Solution & Suspension, Emulsion, Dialysis solution, Parenteral and Ophthalmic

liquids

External Liquid: Disinfectants, Sanitization Liquid, Hospital Germicidal Liquids, etc

Chapter 2: Generic New Product Introduction & Product Development Process

Solid Dosage (Tablet)

Generally Generic Firm will have a New Product Selection Committee (NPSC) This committee

evaluate/explore before selecting and finalizing to introduce a new drug product into market

These are:

1 Strategies: Pharmaceutics, Analytical and Bio-Pharmaceutics

2 Market Barriers: Patient & Exclusivities

3 Market Analysis: Projected Forecast (Units, Dollars), anticipated market share based on being number

1, 2, 3 and so forth player

4 API availabilities

5 Time line

Stage 1: Literature Search

 Literature Search

 FDA-FOI

 On-line search of FDA/CDER info

 Patent Evaluation

 USP, BP, JP, EP, Merck, Florey etc

 Summary Basis of Approval

 Data Base guidelines for test methods, dissolution, impurities, Bio-study parameters etc

 Orange Guide + FDA/CDER www.patent consultant

Stage 2: API Sourcing

 Sourcing of Active Pharmaceutical

Ingredient (API); Drug Substance

 Have Potential Supplier lists

 US agent for API

 US & International Suppliers from (Europe, Asia, etc.)

 Request Technical Binder & DMF Information

 Request samples & CoA and Specifications

 At least two suppliers for full evaluation

Stage 3: API Evaluation and Procurement

 Evaluation of Active Pharmaceutical

Ingredient (API)

 Purchase of API

 At least 2-3 potential API supplier

 DMF availability & Status

 Compliance with USP monograph

 Impurity profile and stability

 Potential polymorphic forms

 Commitment for physical specification (micronized)

 Statement of non-patent infringement

 In g/kg quantities for method

development & pre- formulation study

Stage 4: API Testing (Early Sample Quantity)

Chemical testing by R&D Analytical Laboratory  Chemical testing as per:

 USP monograph (if present)

 Pharmacopeia Forum (if available)

 In-house method (based on API

manufacturer

Stage 5: Bulk API Testing

Chemical testing by R&D Analytical Laboratory

(Full physical & chemical characterization)

Physico-chemical evaluation of Innovator’s

Product by R&D Pharmaceutics Laboratory

 At least 3 different lots in smallest and largest pack size

 Evaluation of physical parameters (Shape, Size, Dimension, Score, Color, Embossing for Logo)

 Container/Closure system (packaging materials, dunnage: cotton, polyester, rayon; desiccant; odor absorbent, oxygen scavenger etc.)

 Physical testing for:

 Weight, Thickness, Hardness, LOD, Friability, Disintegration etc

 For MR Tablets: Evaluation of tablet’s disintegration behavior:

 Erosion Vs Congealing characteristics

Microscopic observation of Innovator’s

Product by R&D Pharmaceutics

 By slight crushing of tablet with a mortar & pestle and observing under microscope for:

 Particles Vs granules for particle size, crystal shape & habit

 Differentiation on the presence specific excipients can be verified from

microscopic observation e.g., Lactose modified Vs Anhydrous Lactose, Cross-linked cellulose, Starch and Avicel have a specific shapes and

morphology and maybe detected

Dissolution profile of Innovator’s Product

by R&D Analytical Laboratory

 USP monograph and FDA method - (where present) Dissolution; 12 unit Dissolution Profile

 In case of Modified Release Tablet: In Water, 0.1N HCl, pH 4.5 Buffer, and pH

6.8 Buffer

Phases of Product Development

 Prototype Batch (Feasibility study)

 Optimized Batch (Characterization study)

 Exhibit Batch (ANDA Submission)

 Production Batch (Commercialization)

Stage 7: FEASIBILITY STUDY BATCHES

 Drug-Excipient compatibility using DSC methods and stability assessment

 Accelerated Stability: 40°C/75% RH ; Time points 0 up to 3 months

 Stress Stability: 60°C up to 3 weeks

 Qualitative and Quantitative Composition

 Matching dissolution with RLD

 All excipients within IIG limits

 Process and Equipment Train Identified

 Container/Closure with either accelerated or stress stability established

 IVIVC or BE by Pilot Bio

Stage 8: Manufacturing Process

• Dry mixing, dry granulation and/'or Slugging

• Determination of order of mixing

• Determination of pre-mixing (in Granulator)

• Determination of fluid addition (if relevant)

• Determination of granulation time

 Moisture Activated Dry (MAD) Granulation (chopper I & II)

• Determination of torque end-point value

• Determination of Drying parameters

• Determination of LOD limits

• Determination of testing temperature for checking LOD limits

(State machine used e.g Mettler™,

Computrac™)

Stage 9: Container Closure System

Evaluation of suitable Container-Closure System

Choice of container-closure-liner system including:

• Material composition,

• Type of thermoplastic resin and resin pigments,

• Manufacturers and suppliers,

• Liners and seals used by closure manufacturer,

• Dunnage :( cotton, polyester, rayon), odor absorbent and desiccants

• Manufacturer's DMF numbers for all component parts

Stage 10: Scale-up

Scale-up batch prepared if larger batch size scale up problems anticipated

Process Characterization batch and Scale-up batch may be evaluated as a single batch

Stage 11: Process Characterization (Optimization)

Documented verification that the process and/or total process related system performs as intended throughout all anticipated operating ranges

GRANULATION OPTIMIZATION  Effect of granulation parameters

 Granulation time

 Speed of choppers (I & II) or mixer blades

DRYING

 Solvent addition rate and overall amount

 Ratio of intra-granulate Disintegrant and binders agents

 Milling Configuration & Screen size

 Adjusting mill screen size up or down to fine

 tune hardness

 Evaluation of optimized granulate and tablet attributes

 FB Drying temperature versus target LOD and

 range limits and the effect on granulate and tablet properties (flow, capping, sticking)

BLENDING

COMPRESSION

P.C REPORT

Effect of level of lubricant

 Lubricant Split into two parts (pre-blending and

 final blending)

 Effect of Blending Time

 Response: Content Uniformity and Dissolution

 Profile

 Evaluation of unit dose sampling vs Content

 Uniformity

 Effect of hardness on tablet properties

 (Aging, dissolution, friability)

 Evaluation of Hardness Range Limits

 Evaluation of stability results of optimized mfg process

 Prepare PC Report This Process Characterization Report forms part of the product Development Report

Stage 12: ESTABLISHING AND IN-VITRO IN-VIVO CORRELATION

profiles) and other relevant media versus Innovator's product

• Perform IVIV Bioavailability Study (where relevant)

Establish a Level A or C correlation without adjusting dissolution parameters and time scale

• Adjust the dissolution parameters or time scale to achieve a Level A or C correlation (adjust only if necessary)

Level A correlation:

An IVIVC that correlates the entire in vitro and in vivo profiles has regulatory relevance and is called a Level A Correlation This level of correlation is the highest category of correlation and represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of the drug from the dosage form

Level A correlation is the most preferred to achieve; since it allows bio waiver for changes in manufacturing site, raw material suppliers, and minor changes in formulation The purpose of Level A correlation is to define a direct relationship between in vivo data such that measurement

of in vitro dissolution rate alone is sufficient to determine the biopharmaceutical rate of the dosage form.[1]

Level C correlation:

Level C correlation relates one dissolution time point (t50%, t90%, etc.) to one mean

pharmacokinetic parameter such as AUC, Tmax or Cmax This is the weakest level of

correlation as partial relationship between absorption and dissolution is established since it does not reflect the complete shape of plasma drug concentration time curve, which is the critical factor that defines the performance of a drug product

Due to its obvious limitations, the usefulness of a Level C correlation is limited in predicting in vivo drug performance In the early stages of formulation development Level C correlations can

be useful when pilot formulations are being selected while waiver of an in vivo bio-equivalence study (bio-waiver) is generally not possible

CRITICAL AND IMPORTANT FACTORS CONSIDERED DURING PRODUCT

DEVELOPMENT

Developers are encouraged to develop IVIVC for IR dosage forms, where applicable

to the BCS, (Biopharmaceutical Classification System) in the expectation that the information will be useful in establishing appropriate dissolution specifications and thus permit certain post approval formulation and manufacturing changes to be effected, - without additional bioequivalence studies

The objective of developing an IVIVC is to establish a predictive mathematical

model describing the relationship between in-vitro dissolution settings and the actual in-vivo drug-plasma parameters found, (such as AUC, Cmax, Tmax)

The in-vitro dissolution settings are adjusted (via media, pH agitation) until a I : I

correlation is achieved (Level A) or a single dissolution point and a plasma parameter is shown to correlate (Level C)

When more than one point correlates a multiple Level C is obtained - which may possibly be upgraded to a Level A with additional development work

This matching of dissolution settings with plasma levels, that are derived from a

specific IR formula and its corresponding manufacturing process, is in fact simply an arbitrary set of values that establish the so called 'predictive mathematical model'

An IVIVC should be evaluated to demonstrate that predictability of the in-vivo

performance of the drug product (i.e derived from the plasma parameters) from its in vitro dissolution characteristics (e.g equipment s e t t i n g s / and

manufacturing changes) is maintained over the product's dissolution profile

Biopharmaceutics Classification System (BCS)

BCS represents a convenient way to look at solubility and permeability characteristics of drug substances The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from immediate- release (IR) solid oral dosage forms: dissolution, solubility, and intestinal permeability According to the BCS, drug substances are classified as follows:

Class 1: High Solubility—High Permeability

Class 2: Low Solubility—High Permeability

Class 3: High Solubility—Low Permeability

Class 4: Low Solubility—Low Permeability

The recommended methods for determining solubility, permeability, and in vitro

dissolution are discussed below

The permeability class boundary is based indirectly on the extent of absorption (fraction

of dose absorbed, not systemic bioavailability) of a drug substance in humans and directly on measurements of the rate of mass transfer across human intestinal

membrane Alternatively, nonhuman systems capable of predicting the extent of drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods) In the absence of evidence suggesting instability in the gastrointestinal tract, a drug substance

is considered to be highly permeable when the extent of absorption in humans is

determined to be 90 percent or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose

C Dissolution

In this guidance, an IR drug product is considered rapidly dissolving when no less than

85 percent of the labeled amount of the drug substance dissolves within 30 minutes, using U.S Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes, (2) a pH 4.5 buffer, and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes A review of the approved products indicates that most of the oral solutions and syrups are developed for BCS Class 1 and BCS Class 3 APIs This is to be expected because the compounds are highly soluble in water or gastrointestinal pH media However, it is noted that there are a few BCS class

2 and class 4 compounds that are formulated as oral solutions or syrups These

products utilize special techniques such as salt formation, micronization, and

complexation with resins, cosolvents, or surfactants for solubilization in order to

formulate as homogeneous oral liquid dosage forms Table 1 shows the list of all 382

products and their BCS classification based on the values obtained from literature This table will be updated as more information becomes available

Stage 13: Exhibit Batch (ANDA Submission)

 Batch size at least 100,000 units or 1/10th

of the commercial batch Minimum three

batches

 Formula & Process Optimized

 Matching dissolution with RLD

 All excipients within IIG limits

 Process and Equipment Train Selected

 Container/Closure with 3 months

accelerated stability established

 BE by Pivotal Bio or IVIVC

PRODUCTION FACILITIES

 Pivotal batch MUST be compressed in a production tableting machine (or production type with same principle and operation)

BATCH DOCUMENTATION

 Preparation of FINAL Master Formula and Processing Instructions

REVIEW and AUTHORIZATION

 Review of FINAL formula, manufacturing process and control parameters with production personnel and QA Staff Pivotal authorization signatures (RD; QA-QC; RA; and Production) attached

OPERATING CONDITIONS

 Operation of production and control personnel during Pivotal manufacture, aided by development team

TECHNOLOGY TRANSFER REPORT

 The preparation of a Technology Transfer Document (TTD) This TTD forms part of the overall Product Development Report

Stage 14: BIOEQUIVALENT STUDY

Bioequivalence: A scientific basis on which generic and brand name drugs are compared with

one another Drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions Proof of bioequivalence is crucial for generic drugs, and must be demonstrated in ANDAs

BE STUDY Fasted Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples

BE STUDY [Food Effect] Perform Food Effect Biostudy on Pivotal Lot Samples (See food

effect guidelines, where appropriate) HIGHEST DOSAGE Biostudy generally performed on highest strength of product One or two studies Fasted and Food Effect Study may be required

Stage 15: Process Validation:

Establishing through documented evidence, a high degree of assurance that a specific process will consistently yield a product that meets predetermined specifications and quality

 Process Validation Report

 Showing intra-batch similarity

 Showing inter-batch similarity between Bio-batch (Pivotal) and the Commercial Validation Lots

Stage 16: Production Batch (Commercial)

 Batch size not more than 10 times of ANDA batch

 Qualitative Composition same as ANDA batch

 Process and Equipment Train Same or Scale-up size (within 10 times of ANDA batch

equipment)

Chapter 3: Solid Dosage Form

By the very name/description it is understood that both the drug and its mode of delivery is through/by

a solid medium Generally pharmaceutical solid dosage comes into following categories:

Powder, Pills, Tablets, Capsules and Medicated Lozenges, etc

Powder: As a dosage form can be of a single drug substance, or combination of multiple drug

substances They can be for either internal or external use

Powders for internal use: Can be powder for re-constitution with water as solution or suspension taken orally or as injection given IM

Tablets: A solid dosage form prepared from powders or granules by compaction It is the most common

and widely used pharmaceutical dosage form and very popular for its convenience of use mostly orally

or inserted into other body cavity, sublingual, buccal, vagina or rectum and Chewable tablets

Based on their release in the stomach tablets can be classified into two main groups

1 Immediate Release Tablet (IR Tablet): Immediate release tablets are made to disintegrate and

release their dosage form with no special rate controlling features, such as special coatings and other techniques Immediate release tablets are those which disintegrate swiftly and get dissolved

to release the medicaments Generally these types of tablets after taken orally releasing its active into stomach within a maximum of 30 to 90 minutes

2 Modified Release Tablet (MR Tablets): This can be again re-classified into three different

categories; a) Delayed Release Tablet, b) Sustained Release Tablet, and c) Extended Release Tablet

Delayed Release Tablet: The release of the drug is delayed to either: Partial delay to by-pass the

esophagus or full delay to by-pass the stomach

Sustained Release Tablet: The release of the drug is sustained for at least 12 hours, so that patient can

take the daily dose in twice daily regimen

Extended Release Tablet: The release of the drug is extended for more than 20 hours, so that patient

can take the medicine once daily regimen

Capsules: Hard Gelatin Capsule (HGC) and Soft Gelatin Capsule (SGC)

Formula design for Multi Strength Tablets; Based on drug load (% API content) in the final formula, it

could be as follows:

 Dose Proportional Design: Typically this formula design is used when the drug load is moderate to

high Where the final weight of the tablet for any strength would be proportional to the % API concentration in the formula, i.e as the strength goes low the final tablet weight will also be low E.g., for a drug product having three strengths; 5mg, 10mg and 15mg, if the final weight of the 5mg tablet is 50mg Then for the 10mg and 15mg to be dose-proportional has to be 100mg and 150mg respectively The dose proportional formula design gives the advantage of making a common blend for all the strengths and then divides it proportionately to make the final tablet Their tablet shape can be round but of different diameter No need of using color for identification

 Formula Similar Design: In this case the final tablet weight is same irrespective of its strength

Generally, this type of formula design is used for the low to moderate drug load (%API) in the formula The advantage of this system design is the drug load being low to moderate; the main formula design is based on the excipient load The functional excipient concentration and amount remains the same The final weight is adjusted by the main diluent q.s by subtracting the API amount The disadvantage of this formula design is, unlike dose-proportional formula design, it does not allow making a common blend However, as the final tablet weight is same irrespective of the strength, to identify each of the strength, typically different colors or shape is used to differentiate among them, e.g (round, triangle and oval)

 Neither dose-proportional Nor Formula Similar: Although it is very uncommon but there are a few

drug products in tablet form for its multi strength did not follow the above two design Their each of the strength has its own final weight; is neither proportional nor same as the other strength This is mostly found with some Brand Product However, by its Physico-chemical characterization the generic formulator would be able to identify the main reason Typically, this is may be as follows:

 For its multi strength tablets mostly for the low to moderate drug load the formula design has two separate common blends I) A dose-proportional high concentrate (% API) blend for the API with a portion of the main diluent, also some time with the dissolution enhancer (for BCS II type DS) Ii) A separate common blend made of mostly all functional excipient and rest of the main diluent The final blend for the each strength is made taken dose-proportional amount from the blend 1 having the API and taking same amount of the 2nd blend irrespective of the strength Thus the final weight

of the table become different from each other but not dose proportional

Example: Say a firm for its multi strength tablet 10mg, 15mg and 20mg tablets has made a formula

design not dose-proportional or formula-similar They have made 100,000 tablets, two separate

common blends as follows:

A API concentrate blend (Dose-Proportional): 45kg and divide it proportionately into 10kg, 15kg

and 20kg

B A separate common blend of other functional excipient of another 300kg and divide it into three

separate lots of 100kg each Then they mix this two sub lots of blend as follows:

a For the 10mg Tablet: Blend A 10kg + Blend B 100kg = 110kg

b For the 15mg Tablet: Blend A 15kg + Blend B 100kg = 115kg

c For the 20 mg Tablet: Blend A 20kg + Blend B 100Kg = 120kg

Now the final weight of the tablets would be as follows:

10mg Tablet: 110mg, 15mg Tablet: 115mg and the 20mg Tablet: 120mg Hence, neither dose

proportional nor formula similar For identity they could be differentiated by their shape However, this

type of formula design is very uncommon and confusing to a formulator

Chapter 4: Mixing and Granulation Solid Dosage (Powder, Tablet and Capsules)

Mixing is a unit operation that involves manipulation of a heterogeneous physical system with the intent to make it more homogeneous Mixing can be achieved by the following processes

 Hand Mixing (Using Spatula)

 Mortar & Pestle (Trituration)

 Tumbling & Shaking (Diffusion)

 Shear Mixing (Low Shear: Planetary Mixer, High Shear- Mixer-Granulator)

 Fluid Bed Process

Type of Mixing:

 Diffusion Mixing : by Random movement (Using Blender or Bin)

 Convection Mixing: Displacement of group of particles from one place to another (Auger Mixer, Ribbon Mixer)

 Shear Mixing: By effecting mechanical energy to change the configuration of ingredients (High Shear Intensive Mixer)

Mode of Mixing:

Geometric Dilution: In Pharmaceuticals this is mostly used for making an intermediate

concentrate pre-mix for actives, colors or any other ingredient in a very small amount in the product composition

Ordered Mixing; It is a non-randomized process In this process materials are selectively mixed

based on their physical characteristics (cohesive, adherence, ruggedness, irregular shape, coating, and/or flow properties) this process is widely used in the Pharma Industry and can be achieved in a number of ways:

Mechanical: By Dividing and Recombining, Mixing & Screening

 Selective mixing of the low drug load <5% API with a carrier with irregular surface area (e.g Anhydrous Lactose, Mannitol etc.) Thus the career excipient due to its rugged irregular surface attaches the low amount drug substance forming an API-carrier mixture concentrate for ultimate BU and CU of the drug product

 Selective mixing of high drug load >50% API of non-cohesive property with a cohesive ingredient to induce compaction for a Direct Compression (D.C) Process

• Auger Mixer & Ribbon Mixer

• Low-shear Planetary Mixer

• High-shear Intensive Mixer

Testing for Compressibility & Flowability of Powder, Blend and Granules:

Compressibility = Tapped Density - Bulk density X 100

have not been granulated (wet or dry)

Granulation: In this process powder particles are adhered into larger, multi-particle entities

called granules This bondage between particles is achieved either by compression/compaction

or by using a binding agent Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use

In the majority of cases this will be in the production of tablets or capsules, when granules will

be made as an intermediate product and have a typical size range between 0.2 and 0.5 mm,

Reasons for granulation:

To prevent segregation of the constituents of the powder mix:

Segregation is due to differences in the size or density of the components of the mix, the

smaller and/or denser particles concentrating at the base of a container with the larger and/or less dense ones above them An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur It is also important to control the particle size distribution of the granules because, although the individual components may not segregate, if there is a wide size distribution the granules

themselves may segregate If this occurs in the hoppers of capsule-filling machines or tablet

machines, products with large weight variations will result This is because these machines fill

by volume rather than weight, and if different regions in the hopper contain granules of different sizes (and hence bulk density), a given volume in each region will contain a different weight of granules This will lead to an unacceptable distribution of the drug content within the batch of finished product

To improve the flow properties of the mix:

Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well

Poor flow will often result in a wide weight variation within the final product owing to variable fill

of tablet dies etc

Granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties

To improve the compaction characteristics of the mixture:

Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same formulation are often more easily compacted and produce

stronger tablets This is associated with the distribution of the adhesive within the granule Often solute migration occurring during the post granulation drying stage results in a binder-rich outer layer to the granules This in turn leads to direct binder–binder bonding, which assists the consolidation of weakly bonding materials

To reduce the hazard of toxic dust powders:

The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders

Suitable precautions must be taken to ensure that such dust is not a hazard during the

granulation process Thus granules should be non-friable and have a suitable mechanical strength

Dry Granulation: In the dry methods of granulation the primary powder particles undergo;

Granulation: (aggregation) under high pressure without the use of a liquid using one of the following processes Generally conducted by: Making large size tablet (Slug) in a tablet

press/slugging or passing the powder material between two counter rotating rollers producing sheet or ribbon by a roller compactor/chelsonator Then the intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to

separate the desired size granules The unused fine material may be reworked to avoid waste

Roller compactors

Moisture Activated Dry Granulation (MAD-Granulation): This process involves moisturizing

the powder blend to a pre-determined LOD to achieve compaction for a direct compression (D.C) method of manufacture

Hot-Melt Granulation: In these process molten materials is used as the granulating liquid

API is either co-melted or dispersed in the molten stage of the vehicle and then cooling it to solidification This process is used mainly for the following purpose

 For poorly soluble API for enhancing solubility and dissolution

 To protect moisture sensitive API

 To achieve sustained or extended release

 API or formulation ingredients are moisture sensitive

 Unable to withstand elevated drying temperature

 Formulation ingredients has sufficient inherent binding cohesive properties

 To improve flow property and die filling

Process Parameters, In-process Tests & Scale-up factors for Dry Granulation

 Process Parameters, & In-process

Tests

• Particle size distribution

• Bulk & Tap Density

• For Roller Compactor:

• Feed, Augur speed, Screen Size, speed

Tip-• Roller Pressure & Gap

When Moisture Activated Dry Granulation (MAD-Granulation)?

• High load API with efflorescence, becoming powder with no compaction property

• Needs moisture to keep its crystallinity

• Usually a mixture of humectant with water is sprayed in a Fluid Bed Processor or High Shear Mixer Granulator to achieve desired LOD without involvement of drying process

• Finally lubricant is added to obtain a blend for direct compression

at a constant rate until all is added

Further mixing is continued until pre-determined granulation end-point is reached (by measuring the resistance/constrain on the impeller (ohms) or consumption of the electric energy (watts)

In the fluid bed processor both granulation and drying is achieved in a continuous process The end point is reached by achieving the desired LOD and product temperature

Steps in Wet Granulation Process

Dry Mixing: Intra-granular ingredients with or without the API is intimately mixed in the bowl of LSMG, HSMG or FBPD

Wet granulation involves the massing of a mix of dry primary powder particles using a

granulating fluid The fluid contains a solvent which must be volatile so that it can be removed

by drying, and be non-toxic The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (binding agent) which is used to ensure particle

adhesion once the granule is dry Further mixing of the wet mass is continued to achieve

granulation end-point

In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can then be recycled

Typical liquids include water, ethanol and isopropanol, either alone or in combination The primary advantages of water are that: it is non-flammable, which means that expensive safety precautions not be taken Water is commonly used for economic reasons The disadvantages of water as a solvent are that:

 It may adversely affect drug stability, causing drug hydrolysis

 It needs a longer drying time than do organic solvents, that

 Increases the length of the process and again may affect stability because of the extended exposure to heat

Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required Fluidized-bed granules are similar to those prepared by the wet granulation, but possess greater porosity and the granule surface is

covered by a film of binding agent

Wet granulators: There are many types of granulator used in the pharmaceutical industry for

Low-Shear Mixer granulators: A low shear

planetary mixer with a grilled-beater is used

for initial powder mixing The paddle of the

mixer agitates the powders followed by wet

massing of the mixed substrate by adding the

granulating liquid continuing the agitation

High-Shear Mixer granulator:

Generally, this type of granulator has a

stainless steel mixing bowl containing a

three-bladed main impeller, which revolves in the

horizontal plane, and a three-bladed chopper

(breaker blade) which revolves either in the

vertical (Collette Gral) or the horizontal plane

(Diosna or T.K Fielder)

 The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a few minutes

 Granulating liquid is then added using either a pressurized pot or peristaltic pump via a port

in the lid of the granulator while the impeller is turning

 The granulating fluid is mixed into the powders by the impeller

 The chopper is usually switched on when the moist mass is formed, as its function is to break up the wet mass to produce a bed of granular material

 Once the granules have been produced, the granular wet-mass is discharged, passing through a wire mesh which breaks up any large aggregates, into the bowl of a fluidized-bed drier

Advantages of High-Shear Mixer/granulation:

Mixing and granulation are all performed within a few minutes in the same piece of equipment

Disadvantages of High-speed mixer/granulation:

The process needs to be controlled with care as the granulation progresses so rapidly that a usable granule can be transformed very quickly into an unusable, over-granulated mass It is also sensitive to variations in raw materials However, these situation or problem is over come and or controlled using a suitable monitoring system to indicate the end point of the granulation process, i.e when a granule of the desired properties has been attained Usually monitoring the

amperage or resistance (torque) measuring ohm by a strain gauge installed within the impeller Process Parameters, In-process Tests & Scale-up factors for Wet-Granulation

 Process Parameters, & In-process Tests

 Dry Mix : Impeller & Chopper speed, Mixing Time

 Granulating Liquid Making: Impeller speed, mixing

time

 Addition of granulating liquid: Amount, Rate of

addition, Impeller & Chopper speed

o Scale-up factor

o Same Tip speed of impeller

o Same granulating liquid addition time

o Same or close to same initial LOD for the wet mass

Tray Drying: The granules are collected on trays and transferred to a drying oven

Tray drying has following three major disadvantages;

Drying Process

Drying is a mass transfer process consisting of

the removal of water /solvent by evaporation

from a solid

 Tray Drying: (Convective forced air helps

in heat transfer)

 Fluid Bed Drying: (material for drying is on

a lifted fluid bed (air) with continuous heat transfer)

 Freeze Drying: (is a drying method where the solvent is frozen prior to drying and is then sublimed) (Used for biologicals)

1 The drying time is long

2 Dissolved material can migrate to the

upper surface of granules’ bed, as the,

solvent is only removed from the upper

surface of the bed on the tray, popularly

known as “Case Hardening” effect

3 Granules may aggregate owing to bridge

formation at the points of contact of the

granules

Fluid Bed Processing and Drying

Fluidized-bed Processor (Glatt)

 The powder particles are

fluidized in a stream of air

 Granulating fluid is pumped

from a reservoir and sprayed

using pressurized pot or a

peristaltic pump from a nozzle

on to the bed of powders

 Heated and filtered air is blown

through the bed of unmixed

powders to fluidize the

particles and mix the powders

Advantages of fluidized-bed granulation

 In the conventional method of the wet-granulation processes, require separate equipment

for granulation, wet milling and drying However, for the fluid-bed processing all these are

performed in one unit, saving time, transfer losses and time and labor costs Thus very

convenient and economic

 The process can be automated once the conditions affecting the granulation have been

optimized

Disadvantages of fluidized-bed granulation

 The equipment is expensive

Optimization of process parameters affecting granulation needs extensive development work.

Spray granulation and drying

 Granular product is made from a

solution or a suspension rather

than initially dry primary powder

particles

 The resultant granules are

free-flowing hollow spheres and the

distribution of the binder in such

granules results in good

compaction properties

 Spray-drying can convert hard

elastic materials into more ductile

ones

 The primary advantages of the

process are the short drying time

and the minimal exposure of the

product to heat owing to the short

residence time in the drying

chamber

 This means that little deterioration

of heat-sensitive materials takes

place

Process Parameters, In-process Tests & Scale-up factors for Drying

Spray Drying for Bioavailability Enhancement

Spray drying is an effective and popular method to manufacture the ASDs that increase the bioavailability of low solubility APIs Amorphous solid dispersions (ASDs) improve the solubility

of Develop-ability Classification System (DCS) class IIb compounds Spray drying technology is one method of manufacturing high-quality ASDs Drug developers have found that the solubility

of DCS class IIb compounds can be enhanced by mechanization and related techniques that expand the surface area of the drugs’ molecules To improve the solubility of DCS class IIb compounds, drug developers produce ASDs of the drugs Spray drying is one of two methods used to create ASDs The spray drying process begins with the dissolution of the API and one

or more polymer excipients into an organic solvent Polymers stabilize the API’s amorphous state by physically separating the drug’s molecules Because of the random order of the API molecules inside the polymer matrix, ASDs completely release drugs without inducing re-

 A commonly used process involves:

 Separation of wet massing

 Extrusion of this wet mass into rod-shaped

granules and subsequent Spheronization

of these granules

Advantages of granulation using Extrusion/Spheronization

 Extrusion/Spheronization process is used to make uniformly sized spherical particles

 It is used primarily to produce multi-particulates for controlled drug release applications

 The major advantage over other methods of producing drug loaded spheres or pellets are the ability to incorporate high levels of active ingredients without producing excessively large particles (minimal excipients)

 Ideal flow behavior and dosability

 Compact structure

 Low hygroscopicity

 High bulk density

The main steps of the process are:

1 Dry mixing of ingredients to achieve homogenous powder dispersion

2 Wet massing to produce a sufficiently plastic wet mass

3 Extrusion to form rod-shaped particles of uniform diameter

4 Spheronization to round off these rods into spherical particles

5 Drying to achieve the desired final moisture content

6 Screening to achieve the desired narrow size distribution

Comminution (size reduction) Milling

 Size reduction/milling of the dried granules is required for:

 Eliminate segregation during mixing by producing uniformity of particle size between

granules and extra-granular material

 Improve flow property and die/capsule shell filling

Size reduction Process & Equipment

Mode of Mixing: by Random movement; tumbling

Equipment: V-Blender, Slant-cone Mixer, and Double-cone Mixer & Bin Blender

It is mostly used for the following steps of mixing during drug product manufacturing

Pre-Lube Mixing:

 In this stage generally the dried/milled granules is mixed with extra-granular ingredients in a diffusion type of blender or within the primary mixer i.e., HSMG or FBPD

 Extra-granular ingredients: (Disintegrant, Anti-adherent, Glidant, Colorants, Flavors,

etc.).[For Modified Release tablets, Natural or synthetic Polymers]

 At Development Phase: (Sample is taken @ different mixing time to determine pre-lube mixing time for blend uniformity)

Lube-Mixing:

 In this stage finally the lubricant is mixed with the blend to achieve the final blend for

compression or Encapsulation

 Blend sample is taken for: BU, Assay, B/T Density, Sieve Analysis and LOD

 Scale-up factor: To have same total number of revolutions

Process Parameters, In-process Tests & Scale-up factors for Blending

 Bulk & Tap Density

 Sieve Analysis for particle size

Materials or substrate processed/used for tablet compression:

After the preparation of granules (in case of wet granulation) or milled slugs/compacts after commination/size reduction process (in case of dry granulation) or mixing of ingredients (in case

of dry blend-direct compression), they are compressed to get final product The compression is done either by single punch machine (stamping press) or by multi station machine (rotary

press) The tablet press is a high-speed mechanical device It 'squeezes' the ingredients into the required tablet shape with extreme precision It can make the tablet in many shapes, although they are usually round or oval Also, it can press the name of the manufacturer or the product identification into the top of the tablet

Compressed tablets can be round, oblong, or unique in shape; thick or thin; large or small in diameter; flat or convex; unscored or scored in halves, thirds, or quadrants; engraved or

imprinted with an identifying symbol and/or code number; coated or uncoated; colored or

uncolored; one, two, or three layered

Tablet diameters and shapes are determined by the die and punches used in compression The less concave the punches, the flatter the tablets; conversely, the more concave the punches, the more convex the resulting tablets Punches with raised impressions produce recessed impressions on the tablets; punches with recessed etchings produce tablets with raised

impressions or monograms Logos may be placed on one or on both sides of a tablet,

depending on the punches

Type of Tablet Press: There are Manual and Automatic Tablet Press

Manual Tablet Press: Generally, is of single punch or multi-tip single punch They are mostly

used for research and/or initial pharmaceutical product development work for evaluating API’s compaction characteristics for direct compression or dry granulation method of tablet

manufacturing Making disc of API for intrinsic dissolution test, etc e.g Carver Press, Natoli Laboratory Tablet Press The compression force is generally exerted by spring load pressure, pneumatic pressure or hydraulic pressure

Automatic Tablet Press:

Based on their design and running principle can be of two types; i) Single punch Tablet Press and ii) Rotary Tablet Press

i) Single punch Tablet Press: These single punch automatic tablet press are

generally used for making slugs for dry-granulation process or for low volume production of some shaped tablet for body cavity (vaginal or anal) insertion e.g Manesty or Stokes, F3 Tablet Press: Single station, 4-ton compression pressure, 7/8" max tablet diameter, 11/16" max depth of fill, rated 42-85 tablets per minute

ii) Rotary Automatic Tablet Press: is a mechanical device that unlike the single

punch tablet press has several tooling station which rotates to compress granules/powder mixture into tablets of uniform size, shape (depending on the punch design) and uniform weight It was developed to increase the output of tablets

Compression stages in a rotary tablet press:

Stage 1 Filling: Top punch is withdrawn from the die by the upper cam Bottom punch is low in

the die, so powder falls in through the hole and fills the die The punch-die cavity is made of die and lower punch Then the position of lower created the volume of the cavity This volume is appropriately adjusted for the weight of granules to be compressed to make the tablets

Stage 2 Metering: Bottom punch moves up to adjust the powder weight-it raises and remove

the excess granules from the compression machine At this stage, the required weight (volume)

of the granules to be compressed into tablets is controlled by the height of the lower punch in the die and the height of the lower punch is controlled by the fill cam

Stage 3 Compression: Top punch is driven into the die by upper cam Bottom punch is raised

by lower cam Both punch heads pass between heavy rollers called compression roller to

compress the powder The compression rollers push the punches towards the die to form the product

Stage 4 Ejection: Top punch is withdrawn by the upper cam Lower punch is pushed up and

expels the tablet is removed from the die surface by surface plate

Rotary Tablet Press based on tooling size is of two type, D tooling Tablet press and B tooling Tablet Press:

There are two internationally recognized standards for tablet compression tooling, the “TSM” and the “EU” standards Both “TSM” and “EU” standards identify the physical tool configuration for “B” and “D” type tablet compression tools, their critical dimensions, and associated

tolerances assuring tablet quality and an efficient tablet press operation

The “TSM” tooling standard is recognized in the Americas and is considered exclusive in the United States “TSM” stands for the Tablet Specification Manual and is published, revised, and distributed by the American Pharmacist Association in Washington, DC The “TSM” standards, once known as the “IPT” standards, were originally developed in 1968 by a committee

consisting of major US pharmaceutical companies Their motivation was an attempt to maintain standardization for “B” and “D” tablet compression tooling, which provides interchangeability between tablet presses The “TSM” provides engineered drawings that are a valuable reference for troubleshooting and tool inspection Today, the “TSM” committee consists of professionals from the tablet press, tooling, and tablet manufacturing industries The “TSM” also includes useful information such as standard cup configurations for round tablets and a reference to common bisects for breaking tablets into multiple uniform dosages

The “EU” tooling standard is internationally recognized and is more widely used than its

counterpart, the “TSM” standard “EU,” which is the acronym for “Euro-standard” and “Euro norm,” is considered the European standard for interchangeable “B” and “D” type compression tools The “EU” standards were created by Trevor Higgins in an attempt to establish a tooling

“norm” that provides tool interchangeability with the most common “B” and “D” type European tablet presses The “EU” standard is printed and distributed by I Holland Ltd, Nottingham, UK

Drug Product CQAs Impacted by Tablet Compression Process

Critical Process Parameters Critical Quality Attributes Additional points to check in the

Batch Records

 Type of Tablet Press (model,

geometry, number of stations)

 Hopper design, height, angle,

vibration

 Feeder Mechanism

(gravity/forced feed, shape of

wheels, direction of rotation,

number of bars)

 Feed frame type and speed

 Feeder fill depth

 Tooling design (e.g

dimension, score configuration,

quality of the metal)

 Maximum punch load

 Press speed/dwell time

 Pre-compression force

 Main compression force

 Punch penetration depth

 Thickness/dimensions

 Tablet porosity/density/solid fraction

Records the following: During

Set-up and Compression Run Machine Type/ Single punch/Rotary; Double sided/Bi-layer

Tooling Type, Description, # of Stations

Press Speed (Low and High Feeding of the press: Gravity or Force

Sampling for: Weight, Thickness, Hardness, and Friability

Challenges tests: (During product development to set hardness range)

High weight/Low hardness:

Friability & Thickness Low Weight/High Hardness:

Thickness, & Dissolution profile Uniformity of dosage unit (By content uniformity/AV value) Dissolution Test (Disintegration Test if required)

Assay

Measuring of Compression Force

Although the compression force is one of the main CPP for making a tablet by applying

pressure to a material/substrate (powder or granules) However, in the tablet press this is not a unit measurement for the recording in the Batch Manufacturing Record, rather its output the CQA tablet hardness is measured/tested and recorded as the in-process control Typically, the compression force is obtained/provided in a tablet press is by a) coiled spring load pressure, b) Pneumatic pressure or c) Hydraulic pressure In the tablet press the pneumatic pressure or hydraulic pressures (PSI) are recorded in a meter located at the pressure application pump This meter has a green and red area with middle Typically, at the start of compression process the operator of the tablet press will either open the air vent or pump the handle to obtain the required compression force by pneumatic or hydraulic pressure respectively However, for the spring-loaded pressure the operator will screw the wheel of the spring-load plunger to get the pressure on to the lower compression roller

However, for the research purpose or in the product development of a very special project a tablet press would be instrumented with a strain gage at some practical position of the machine that would undergo a force proportional to the force exerted by the upper punch and recorded in

a chart recorder Now-a-days some modern tablet press have facilitated measuring/recording the compression force and even has a printer chart recorder or electronic monitor As stated in the above recording this CPP, the tablet compression force should not be a hard and fast

requirement for the BMR

Instrumentation

Modern rotary production tablet presses are typically equipped to measure pre-compression and main compression forces Additionally, measurement and monitoring of tablet ejection force can prove to be beneficial for specific problem products and for production troubleshooting However, for most pharmaceutical products’ proper product development and optimization work eliminate the need to instrument a production machine for ejection force Rotary tablet presses can also be equipped to measure both upper punch and lower punch pull-down forces These measurements are primarily made to detect tight- running punches and are necessary on

production machines only if the machine monitoring system uses direct force measurement for these functions Tablet scrape-off force can also be measured, but this is only recommended on development machines Scrape-off forces are typically below 6 N Therefore, instrumentation of

a tablet stripper requires highly sensitive instrumentation that is easily damaged

Pre-compression and main compression forces are normally measured for the upper punches These forces are typically measured using strain gauges arranged in a full Wheatstone bridge Strain gauges are basically resistors applied to the metal surface in a specific orientation Under load, the member deflects and the strain change the resistance of the gauge The change in resistance is proportional to the applied force However, due to design differences, some