Pharmaceutical Process Validation 3rd Ed 1993

  Copyright © 2003 Marcel Dekker, Inc.

  Previous edition: Pharmaceutical Process Validation: Second Edition, Revised and Ex- (I. R. Berry, R. A. Nash, eds.), 1993. panded Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress.

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1 PRINTED IN THE UNITED STATES OF AMERICA

  Dedicated to Theodore E. Byers, formerly of the U.S. Food and Drug Administration, and Heinz Sucker, Professor at the University of Berne,

  Switzerland, for their pioneering contributions with respect to the pharmaceutical process validation concept. We also acknowledge the past contributions of Bernard T. Loftus and Ira R. Berry toward the success of Pharmaceutical Process Validation. Preface

  The third edition of Pharmaceutical Process Validation represents a new ap- proach to the topic in several important respects.

  Many of us in the field had made the assumption that pharmaceutical process validation was an American invention, based on the pioneering work of Theodore E. Byers and Bernard T. Loftus, both formerly with the U.S. Food & Drug Administration. The truth is that many of our fundamental concepts of pharmaceutical process validation came to us from “Validation of Manufactur- ing Processes,” Fourth European Seminar on Quality Control, September 25, 1980, Geneva, Switzerland, and Validation in Practice, edited by H. Sucker, Wissenschaftliche Verlagsegesellschaft, GmbH, Stuttgard, Germany, 1983.

  There are new chapters in this edition that will add to the book’s impact. They include “Validation for Medical Devices” by Nishihata, “Validation of Biotechnology Processes” by Sofer, “Transdermal Process Validation” by Neal, “Integrated Packaging Validation” by Frederick, “Statistical Methods for Uni- formity and Dissolution Testing” by Bergum and Utter, “Change Control and SUPAC” by Waterland and Kowtna, “Validation in Contract Manufacturing” by Parikh, and “Harmonization, GMPs, and Validation” by Wachter.

  I am pleased to have Dr. Alfred Wachter join me as coeditor of this edi- tion. He was formerly head of Pharmaceutical Product Development for the CIBA Pharmaceutical Company in Basel, Switzerland, and also spent a number of years on assignment in Asia for CIBA. Fred brings a very strong international perspective to the subject matter.

  Robert A . Nash Contents

   John M . Dietrick and Bernard T. Loftus

  

  . Chao, F. St. John Forbes, Reginald F. Johnson,

  Allen Y and Paul Von Doehren

  

  . Trubinski

  Chester J

   Michael J . Akers and Neil R. Anderson

  

Jeffrey S . Rudolph and Robert J. Sepelyak

   Toshiaki Nishihata

   Gail Sofer

   , Jr.

  Charlie Neal

  

  . Trappler

  Edward H

  

Christopher J . Sciarra and John J. Sciarra

  

Robert A . Nash

  

Kunio Kawamura

  

  . Peither

  Thomas L

  

  . Hall

  William E

  

Ludwig Huber

   Tony de Claire

   Mervyn J . Frederick

  

Peter H . Cheng and John E. Dutt

   James S . Bergum and Merlin L. Utter

   Nellie Helen Waterland and Christopher C . Kowtna

   Carl B . Rifino

   Dilip M . Parikh

   Kenneth G . Chapman

  

  . Wachter

  Alfred H Contributors Michael J. Akers Baxter Pharmaceutical Solutions, Bloomington, Indiana, U.S.A.

  Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

  Neil R. Anderson James S. Bergum Bristol-Myers Squibb Company, New Brunswick, New Jer- sey, U.S.A.

  Kenneth G. Chapman Drumbeat Dimensions, Inc., Mystic, Connecticut, U.S.A.

  Watson Labs, Carona, California, U.S.A.

  Allen Y. Chao Peter H. Cheng New York State Research Foundation for Mental Hygiene, New York, New York, U.S.A.

  Tony de Claire APDC Consulting, West Sussex, England

  Center for Drug Evaluation and Research, U.S. Food and

  John M. Dietrick Drug Administration, Rockville, Maryland, U.S.A. John E. Dutt EM Industries, Inc., Hawthorne, New York, U.S.A. Mervyn J. Frederick NV Organon–Akzo Nobel, Oss, The Netherlands William E. Hall Hall & Pharmaceutical Associates, Inc., Kure Beach, North

  Carolina, U.S.A.

  Agilent Technologies GmbH, Waldbronn, Germany

  Ludwig Huber

F. St. John Forbes Wyeth Labs, Pearl River, New York, U.S.A.

• Reginald F. Johnson Searle & Co., Inc., Skokie, Illinois, U.S.A.

  Kunio Kawamura Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan Christopher C. Kowtna DuPont Pharmaceuticals Co., Wilmington, Dela-

  ware, U.S.A.

• Bernard T. Loftus Bureau of Drugs, U.S. Food and Drug Administration, Washington, D.C., U.S.A.

  Stevens Institute of Technology, Hoboken, New Jersey,

  Robert A. Nash U.S.A.

  Diosynth-RTP, Research Triangle Park, North Carolina, Charlie Neal, Jr. U.S.A.

  Santen Pharmaceutical Co., Ltd., Osaka, Japan

  Toshiaki Nishihata APACE PHARMA Inc., Westminster, Maryland, U.S.A. Dilip M. Parikh

  PECON—Peither Consulting, Schopfheim, Germany

  Thomas L. Peither AstraZeneca Pharmaceuticals LP, Newark, Delaware, U.S.A. Carl B. Rifino Pharmaceutical Consultant, St. Augustine, Florida, U.S.A. Jeffrey S. Rudolph Sciarra Laboratories Inc., Hicksville, New York, U.S.A. Christopher J. Sciarra Sciarra Laboratories Inc., Hicksville, New York, U.S.A. John J. Sciarra

  AstraZeneca Pharmaceuticals LP, Wilmington, Delaware,

  Robert J. Sepelyak U.S.A.

  BioReliance, Rockville, Maryland, U.S.A.

  Gail Sofer

  Lyophilization Technology, Inc., Warwick, Pennsylva-

  Edward H. Trappler nia, U.S.A.

• Retired

  Chester J. Trubinski Church & Dwight Co., Inc., Princeton, New Jersey, U.S.A. Merlin L. Utter Wyeth Pharmaceuticals, Pearl River, New York, U.S.A. Paul Von Doehren Searle & Co., Inc., Skokie, Illinois, U.S.A.

Alfred H. Wachter Wachter Pharma Projects, Therwil, Switzerland

Nellie Helen Waterland DuPont Pharmaceuticals Co., Wilmington, Dela-

  ware, U.S.A.

  Introduction Robert A. Nash Stevens Institute of Technology, Hoboken, New Jersey, U.S.A.

I. FDA GUIDELINES

  The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation [1]:

  Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meet- ing its predetermined specifications and quality characteristics.

  According to the FDA, assurance of product quality is derived from care- ful and systemic attention to a number of important factors, including: selection of quality components and materials, adequate product and process design, and (statistical) control of the process through in-process and end-product testing.

  Thus, it is through careful design (qualification) and validation of both the process and its control systems that a high degree of confidence can be estab- lished that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable.

  According to the FDA’s Current Good Manufacturing Practices (CGMPs)

  21CFR 211.110 a:

  Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to the following, where appropriate [2]:

  1. Tablet or capsule weight variation

2. Disintegration time

  

3. Adequacy of mixing to assure uniformity and homogeneity

  4. Dissolution time and rate

  5. Clarity, completeness, or pH of solutions

  The first four items listed above are directly related to the manufacture and validation of solid dosage forms. Items 1 and 3 are normally associated with variability in the manufacturing process, while items 2 and 4 are usually influenced by the selection of the ingredients in the product formulation. With respect to content uniformity and unit potency control (item 3), adequacy of mixing to assure uniformity and homogeneity is considered a high-priority con- cern.

  Conventional quality control procedures for finished product testing en- compass three basic steps:

  1. Establishment of specifications and performance characteristics

  2. Selection of appropriate methodology, equipment, and instrumenta- tion to ensure that testing of the product meets specifications

  3. Testing of the final product, using validated analytical and testing methods to ensure that finished product meets specifications. With the emergence of the pharmaceutical process validation concept, the fol- lowing four additional steps have been added:

  4. Qualification of the processing facility and its equipment

  5. Qualification and validation of the manufacturing process through ap- propriate means

  6. Auditing, monitoring, sampling, or challenging the key steps in the process for conformance to in-process and final product specifications

  7. Revalidation when there is a significant change in either the product or its manufacturing process [3].

II. TOTAL APPROACH TO PHARMACEUTICAL PROCESS VALIDATION

  It has been said that there is no specific basis for requiring a separate set of process validation guidelines, since the essentials of process validation are em- bodied within the purpose and scope of the present CGMP regulations [2]. With this in mind, the entire CGMP document, from subpart B through subpart K, may be viewed as being a set of principles applicable to the overall process of manufacturing, i.e., medical devices (21 CFR–Part 820) as well as drug prod- ucts, and thus may be subjected, subpart by subpart, to the application of the principles of qualification, validation, verification and control, in addition to change control and revalidation, where applicable. Although not a specific re- quirement of current regulations, such a comprehensive approach with respect to each subpart of the CGMP document has been adopted by many drug firms.

  A checklist of qualification and control documentation with respect to CGMPs is provided in Table 1. A number of these topics are discussed sepa- rately in other chapters of this book.

III. WHY ENFORCE PROCESS VALIDATION?

  The FDA, under the authority of existing CGMP regulations, guidelines [1], and directives [3], considers process validation necessary because it makes good engineering sense. The basic concept, according to Mead [5], has long been

  

Checklist of Qualification and Control Documentation

Table 1

  Qualification and

Subpart Section of CGMPs control documentation

A General provisions B Organization and personnel Responsibilities of the quality con- trol unit C Buildings and facilities Plant and facility installation and qualification Maintenance and sanitation

  Microbial and pest control D Equipment Installation and qualification of equipment and cleaning methods E Control of components, containers Incoming component testing proce- and closures dures F Production and process controls Process control systems, reprocess- ing control of microbial contami- nation

  G Packaging and labeling controls Depyrogenation, sterile packaging, filling and closing, expire dating H Holding and distribution Warehousing and distribution pro- cedures

  I Laboratory controls Analytical methods, testing for re- lease component testing and sta- bility testing J Records and reports Computer systems and information systems K Return and salvaged drug products Batch reprocessing

  Sterilization procedures, Air and water quality are covered in appropriate subparts of Table 1. applied in other industries, often without formal recognition that such a concept was being used. For example, the terms reliability engineering and qualification have been used in the past by the automotive and aerospace industries to repre- sent the process validation concept.

  The application of process validation should result in fewer product re- calls and troubleshooting assignments in manufacturing operations and more technically and economically sound products and their manufacturing processes. In the old days R & D “gurus” would literally hand down the “go” sometimes overformulated product and accompanying obtuse manufacturing procedure, usually with little or no justification or rationale provided. Today, under FDA’s

  Preapproval Inspection (PAI) program [4] such actions are no longer accept-

  able. The watchword is to provide scientifically sound justifications (including qualification and validation documentation) for everything that comes out of the pharmaceutical R & D function.

IV. WHAT IS PROCESS VALIDATION?

  Unfortunately, there is still much confusion as to what process validation is and what constitutes process validation documentation. At the beginning of this introduction several different definitions for process validation were provided, which were taken from FDA guidelines and the CGMPs. Chapman calls process validation simply “organized, documented common sense” [6]. Others have said that “it is more than three good manufactured batches” and should represent a lifetime commitment as long as the product is in production, which is pretty much analogous to the retrospective process validation concept.

  The big problem is that we use the term validation generically to cover the entire spectrum of CGMP concerns, most of which are essentially people, equipment, component, facility, methods, and procedural qualification. The spe- cific term process validation should be reserved for the final stage(s) of the product/process development sequence. The essential or key steps or stages of a successfully completed product/process development program are presented in [7].

  The end of the sequence that has been assigned to process validation is derived from the fact that the specific exercise of process validation should never be designed to fail. Failure in carrying out the process validation assign- ment is often the result of incomplete or faulty understanding of the process’s capability, in other words, what the process can and cannot do under a given set of operational circumstances. In a well-designed, well-run overall validation program, most of the budget dollars should be spent on equipment, component, facility, methods qualification, and process demonstration, formerly called pro- cess qualification. In such a program, the formalized final process validation

  Table 2 The Key Stages in the Product/Process Development Sequence Development stage Pilot scale-up phase Product design 1 × batch size Product characterization Product selection (“go” formula) Process design Product optimization

  10 × batch size Process characterization Process optimization Process demonstration 100 × batch size Process validation program Product/process certification With the exception of solution products, the bulk of the work is nor- × batch size, which is usually the first scale-up mally carried out at 10 batches in production-type equipment.

  sequence provides only the necessary process validation documentation required by the regulatory authorities—in other words, the “Good Housekeeping Seal of Approval,” which shows that the manufacturing process is in a state of control.

  Such a strategy is consistent with the U.S. FDA’s preapproval inspection

  program [4], wherein the applicant firm under either a New Drug Application

  (NDA) or an Abbreviated New Drug Application (ANDA) submission must show the necessary CGMP information and qualification data (including appro- priate development reports), together with the formal protocol for the forthcom- ing full-scale, formal process validation runs required prior to product launch.

  Again, the term validation has both a specific meaning and a general one, depending on whether the word “process” is used. Determine during the course of your reading whether the entire concept is discussed in connection with the topic—i.e., design, characterization, optimization, qualification, validation, and/ or revalidation—or whether the author has concentrated on the specifics of the validation of a given product and/or its manufacturing process. In this way the text will take on greater meaning and clarity.

V. PILOT SCALE-UP AND PROCESS VALIDATION

  The following operations are normally carried out by the development function prior to the preparation of the first pilot-production batch. The development activities are listed as follows:

  1. Formulation design, selection, and optimization

  2. Preparation of the first pilot-laboratory batch

  3. Conduct initial accelerated stability testing

  4. If the formulation is deemed stable, preparation of additional pilot- laboratory batches of the drug product for expanded nonclinical and/ or clinical use. The pilot program is defined as the scale-up operations conducted subse- quent to the product and its process leaving the development laboratory and prior to its acceptance by the full scale manufacturing unit. For the pilot program to be successful, elements of process validation must be included and completed during the developmental or pilot laboratory phase of the work.

  Thus, product and process scale-up should proceed in graduated steps with elements of process validation (such as qualifications) incorporated at each stage of the piloting program [9,10].

  A. Laboratory Batch

  The first step in the scale-up process is the selection of a suitable preliminary formula for more critical study and testing based on certain agreed-upon initial design criteria, requirements, and/or specifications. The work is performed in the development laboratory. The formula selected is designated as the (1 × ) laboratory batch. The size of the (1 × ) laboratory batch is usually 3–10 kg of a solid or semisolid, 3–10 liters of a liquid, or 3000 to 10,000 units of a tablet or capsule.

  B. Laboratory Pilot Batch

  After the (1 × ) laboratory batch is determined to be both physically and chemi- cally stable based on accelerated, elevated temperature testing (e.g., 1 month at 45 °C or 3 months at 40°C or 40°C/80% RH), the next step in the scale-up process is the preparation of the (10 × ) laboratory pilot batch. The (10 × ) laboratory pilot batch represents the first replicated scale-up of the designated formula. The size of the laboratory pilot batch is usually 30–100 kg, 30–100 liters, or 30,000 to 100,000 units.

  It is usually prepared in small pilot equipment within a designated CGMP- approved area of the development laboratory. The number and actual size of the laboratory pilot batches may vary in response to one or more of the following factors:

  1. Equipment availability

  2. Active pharmaceutical ingredient (API)

  3. Cost of raw materials

  4. Inventory requirements for clinical and nonclinical studies Process demonstration or process capability studies are usually started in this important second stage of the pilot program. Such capability studies consist of process ranging, process characterization, and process optimization as a prereq- uisite to the more formal validation program that follows later in the piloting sequence.

C. Pilot Production

  The pilot-production phase may be carried out either as a shared responsibility between the development laboratories and its appropriate manufacturing coun- terpart or as a process demonstration by a separate, designated pilot-plant or process-development function. The two organization piloting options are pre- sented separately in Figure 1. The creation of a separate pilot-plant or process- development unit has been favored in recent years because it is ideally suited to carry out process scale-up and/or validation assignments in a timely manner. On the other hand, the joint pilot-operation option provides direct communication between the development laboratory and pharmaceutical production.

  Main piloting options. (Top) Separate pilot plant functions—engineering Figure 1 concept. (Bottom) Joint pilot operation. The object of the pilot-production batch is to scale the product and process by another order of magnitude (100 × ) to, for example, 300–1,000 kg, 300– 1,000 liters, or 300,000–1,000,000 dosage form units (tablets or capsules) in size. For most drug products this represents a full production batch in standard production equipment. If required, pharmaceutical production is capable of scal- ing the product/process to even larger batch sizes should the product require expanded production output. If the batch size changes significantly, additional validation studies would be required. The term product/process is used, since one can’t describe a product with discussing its process of manufacture and, conversely, one can’t talk about a process without describing the product being manufactured.

  Usually large production batch scale-up is undertaken only after product introduction. Again, the actual size of the pilot-production (100 × ) batch may vary due to equipment and raw material availability. The need for additional pilot-production batches ultimately depends on the successful completion of a first pilot batch and its process validation program. Usually three successfully completed pilot-production batches are required for validation purposes.

  In summary, process capability studies start in the development labora- tories and/or during product and process development, and continue in well- defined stages until the process is validated in the pilot plant and/or pharmaceu- tical production.

  An approximate timetable for new product development and its pilot scale-up program is suggested in

VI. PROCESS VALIDATION: ORDER OF PRIORITY

  Because of resource limitation, it is not always possible to validate an entire company’s product line at once. With the obvious exception that a company’s most profitable products should be given a higher priority, it is advisable to draw up a list of product categories to be validated.

  The following order of importance or priority with respect to validation is suggested:

A. Sterile Products and Their Processes

  1. Large-volume parenterals (LVPs)

  2. Small-volume parenterals (SVPs)

  3. Ophthalmics, other sterile products, and medical devices

  Table 3 Approximate Timetable for New Product Development and Pilot Scale-Up Trials

  Calendar Event months

Formula selection and development 2–4

  

Assay methods development and formula optimization 2–4

Stability in standard packaging 3-month readout (1 3–4

× size)

Pilot-laboratory batches (10 1–3

  × size) Preparation and release of clinical supplies (10 × size) and

establishment of process demonstration 1–4

  

Additional stability testing in approved packaging 3–4

6–8-month readout (1 × size) 3-month readout (10 × size)

  

Validation protocols and pilot batch request 1–3

Pilot-production batches (100 × size) 1–3

Additional stability testing in approved packaging 3–4

9–12-month readout (1 × size)

  6–8-month readout (10 × size) 3-month readout (100 × size) Interim approved technical product development report with

approximately 12 months stability (1 × size) 1–3

  Totals 18–36

B. Nonsterile Products and Their Processes

  1. Low-dose/high-potency tablets and capsules/transdermal delivery sys- tems (TDDs)

  2. Drugs with stability problems

  3. Other tablets and capsules

  4. Oral liquids, topicals, and diagnostic aids

VII. WHO DOES PROCESS VALIDATION?

  Process validation is done by individuals with the necessary training and experi- ence to carry out the assignment.

  The specifics of how a dedicated group, team, or committee is organized to conduct process validation assignments is beyond the scope of this introduc- tory chapter. The responsibilities that must be carried out and the organizational structures best equipped to handle each assignment are outlined iThe

  Table 4 Specific Responsibilities of Each Organizational Structure within the Scope of Process Validation Engineering Install, qualify, and certify plant, facilities, equipment, and sup- port system. Development Design and optimize manufacturing process within design limits, specifications, and/or requirements—in other words, the estab- lishment of process capability information. Manufacturing Operate and maintain plant, facilities, equipment, support sys- tems, and the specific manufacturing process within its design limits, specifications, and/or requirements. Quality assurance Establish approvable validation protocols and conduct process validation by monitoring, sampling, testing, challenging, and/ or auditing the specific manufacturing process for compliance with design limits, specifications, and/or requirements.

  Source : Ref. 8.

  best approach in carrying out the process validation assignment is to establish a Chemistry, Manufacturing and Control (CMC) Coordination Committee at the specific manufacturing plant site [10]. Representation on such an important lo- gistical committee should come from the following technical operations:

• Formulation development (usually a laboratory function)
• Process development (usually a pilot plant function)
• Pharmaceutical manufacturing (including packaging operations)
• Engineering (including automation and computer system responsibili- ties)
• Quality assurance
• Analytical methods development and/or Quality Control • API Operations (representation from internal operations or contract manufacturer)
• Regulatory Affairs (technical operations representative)
• IT (information technology) operations The chairperson or secretary of such an important site CMC Coordination Com- mittee should include the manager of process validation operations. Typical meeting agendas may include the following subjects in the following recom- mended order of priority:
• Specific CGMP issues for discussion and action to be taken
• Qualification and validation issues with respect to a new product/pro- cess

• Technology transfer issues within or between plant sites.
• Pre-approval inspection (PAI) issues of a forthcoming product/process
• Change control and scale-up, post approval changes (SUPAC) with respect to current approved product/process [11].

  VIII. PROCESS DESIGN AND CHARACTERIZATION Process capability is defined as the studies used to determine the critical process

  parameters or operating variables that influence process output and the range of numerical data for critical process parameters that result in acceptable process output. If the capability of a process is properly delineated, the process should consistently stay within the defined limits of its critical process parameters and product characteristics [12]. formerly called process qualification, represents

  Process demonstration

  the actual studies or trials conducted to show that all systems, subsystems, or unit operations of a manufacturing process perform as intended; that all critical process parameters operate within their assigned control limits; and that such studies and trials, which form the basis of process capability design and testing, are verifiable and certifiable through appropriate documentation.

  The manufacturing process is briefly defined as the ways and means used to convert raw materials into a finished product. The ways and means also include people, equipment, facilities, and support systems required to operate the process in a planned and effectively managed way. All the latter functions must be qualified individually. The master plan or protocol for process capabil- ity design and testing is presented i

  A simple flow chart should be provided to show the logistical sequence of unit operations during product/process manufacture. A typical flow chart used in the manufacture of a tablet dosage form by the wet granulation method is presented in

  IX. STREAMLINING VALIDATION OPERATIONS

  The best approach to avoiding needless and expensive technical delays is to work in parallel. The key elements at this important stage of the overall process are the API, analytical test methods, and the drug product (pharmaceutical dos- age form). An integrated and parallel way of getting these three vitally important functions to work together is depicted i

  Figure 3 shows that the use of a single analytical methods testing function is an important technical bridge between the API and the drug product develop- ment functions as the latter two move through the various stages of develop-

  

Table 5 Master Plan or Protocol for Process Capability Design and Testing

Objective Process capability design and testing Types of process Batch, intermittent, continuous Typical processes Chemical, pharmaceutical, biochemical

Process definition Flow diagram, in-process, finished product

Definition of process output Potency, yield, physical parameters

Definition of test methods Instrumentation, procedures, precision, and

accuracy Process analysis Process variables, matrix design, factorial design analysis Pilot batch trials Define sampling and testing, stable, extended runs

  Pilot batch replication Different days, different materials, different equip- ment Process redefinition Reclassification of process variables Process capability evaluation Stability and variability of process output, eco- nomic limits Final report Recommended SOP, specifications, and process limits

  Process flow diagram for the manufacture of a tablet dosage form by wet Figure 2 granulation method. The arrows show the transfer of material into and out of each of the various unit operations. The information in parentheses indicates additions of material to specific unit operations. A list of useful pharmaceutical unit operations is presented in

  Table 6 A List of Useful Pharmaceutical Unit Operations According to Categories Heat transfer processes: Cooking, cooling, evaporating, freezing, heating, irradiating, sterilizing, freeze-drying

  Change in state : Crystallizing, dispersing, dissolving, immersing, freeze-drying, neutral- izing : Agglomerating, blending, coating, compacting, crushing, crystallizing,

  Change in size densifying, emulsifying, extruding, flaking, flocculating, grinding, homogenizing,

milling, mixing, pelletizing, pressing, pulverizing, precipitating, sieving

  : Dehydrating, desiccating, evaporating, fluidizing, humidify- Moisture transfer processes ing, freeze-drying, washing, wetting : Centrifuging, clarifying, deareating, degassing, deodorizing, dia-

  Separation processes lyzing, exhausting, extracting, filtering, ion exchanging, pressing, sieving, sorting, washing

  : Conveying, filling, inspecting, pumping, sampling, storing, trans- Transfer processes porting, weighing

  Source : Ref. 13.

  ment, clinical study, process development, and process validation and into pro- duction. Working individually with separate analytical testing functions and with little or no appropriate communication among these three vital functions is a prescription for expensive delays. It is important to remember that the concept illustrated in can still be followed even when the API is sourced from outside the plant site or company. In this particular situation there will probably be two separate analytical methods development functions: one for the API manufacturer and one for the drug product manufacturer [14].

X. STATISTICAL PROCESS CONTROL AND PROCESS VALIDATION

  Statistical process control (SPC), also called statistical quality control and pro- cess validation (PV), represents two sides of the same coin. SPC comprises the

  various mathematical tools (histogram, scatter diagram run chart, and control chart) used to monitor a manufacturing process and to keep it within in-process and final product specification limits. Lord Kelvin once said, “When you can measure what you are speaking about, and express it in numbers, then you know something about it.” Such a thought provides the necessary link between the two concepts. Thus, SPC represents the tools to be used, while PV represents the procedural environment in which those tools are used.

  Figure 3 Working in parallel. (Courtesy of Austin Chemical Co., Inc.)

  There are three ways of establishing quality products and their manufac- turing processes:

  1. In-process and final product testing, which normally depends on sam- pling size (the larger the better). In some instances, nothing short of excessive sampling can ensure reaching the desired goal, i.e., sterility testing.

  2. Establishment of tighter (so called “in-house”) control limits that hold the product and the manufacturing process to a more demanding stan- dard will often reduce the need for more extensive sampling require- ments.

  3. The modern approach, based on Japanese quality engineering [15], is the pursuit of “zero defects” by applying tighter control over process variability (meeting a so-called 6 sigma standard). Most pharmaceuti- cal products and their manufacturing processes in the United States today, with the exception of sterile processes are designed to meet a 4 sigma limit (which would permit as many as eight defects per 1000 units). The new approach is to center the process (in which the grand average is roughly equal to 100% of label potency or the target value of a given specification) and to reduce the process variability or noise around the mean or to achieve minimum variability by holding both to the new standard, batch after batch. In so doing, a 6 sigma limit may be possible (which is equivalent to not more than three to four defects per 1 million units), also called “zero defects.” The goal of 6 sigma, “zero defects” is easier to achieve for liquid than for solid pharmaceutical dosage forms [16].

  Process characterization

  represents the methods used to determine the critical unit operations or processing steps and their process variables, that usu- ally affect the quality and consistency of the product outcomes or product attri- butes. Process ranging represents studies that are used to identify critical process or test parameters and their respective control limits, which normally affect the quality and consistency of the product outcomes of their attributes. The follow- ing process characterization techniques may be used to designate critical unit operations in a given manufacturing process.

A. Constraint Analysis

  One procedure that makes subsystem evaluations and performance qualification trials manageable is the application of constraint analysis. Boundary limits of any technology and restrictions as to what constitutes acceptable output from unit operations or process steps should in most situations constrain the number of process variables and product attributes that require analysis. The application of the constraint analysis principle should also limit and restrict the operational range of each process variable and/or specification limit of each product attri- bute. Information about constraining process variables usually comes from the following sources:

• Previous successful experience with related products/processes
• Technical and engineering support functions and outside suppliers
• Published literatures concerning the specific technology under investi- gation

  A practical guide to constraint analysis comes to us from the application of the Pareto Principle (named after an Italian sociologist) and is also known as the 80–20 rule, which simply states that about 80% of the process output is governed by about 20% of the input variables and that our primary job is to find those key variables that drive the process.

  The FDA in their proposed amendments to the CGMPs [17] have desig- nated that the following unit operations are considered critical and therefore their processing variables must be controlled and not disregarded:

• Cleaning • Weighing/measuring
• Mixing/blending
• Compression/encapsulation
• Filling/packaging/labeling

B. Fractional Factorial Design

  An experimental design is a series of statistically sufficient qualification trials that are planned in a specific arrangement and include all processing variables that can possibly affect the expected outcome of the process under investigation. In the case of a full factorial design, n equals the number of factors or process variables, each at two levels, i.e., the upper ( +) and lower (−) control limits. Such a design is known as a 2n factorial. Using a large number of process

  9

  variables (say, 9) we could, for example, have to run 2 , or 512, qualification trials in order to complete the full factorial design.

  The fractional factorial is designed to reduce the number of qualification trials to a more reasonable number, say, 10, while holding the number of ran- domly assigned processing variables to a reasonable number as well, say, 9. The technique was developed as a nonparametric test for process evaluation by Box and Hunter [18] and reviewed by Hendrix [19]. Ten is a reasonable number of trials in terms of resource and time commitments and should be considered an upper limit in a practical testing program. This particular design as presented in does not include interaction effects.

XI. OPTIMIZATION TECHNIQUES

  Optimization techniques are used to find either the best possible quantitative formula for a product or the best possible set of experimental conditions (input values) needed to run the process. Optimization techniques may be employed in the laboratory stage to develop the most stable, least sensitive formula, or in the qualification and validation stages of scale-up in order to develop the most sta-

  Table 7 Fractional Factorial Design (9 Variables in 10 Experiments) Trial no.

  X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ X ₇ X ₈ X ₉ 1 − − − − − − − − −

• 2 − − − − − − − −

  3 − − − − − − −

  4 − − − − − −

  5 − − − − −

  6 − − − −

  7 − − −

  8

• − + + + + + −

  9

• − + + + +

  10

  Worst-case conditions: Trial 1 (lower control limit). Trial 10 (upper control limit). X variables randomly assigned. Best values to use are RSD of data set for each trial. When adding up the data

• and − are now numerical values and the sum is divided by 5 (number of +s or −s). by columns, If the variable is not significant, the sum will approach zero.

  ble, least variable, robust process within its proven acceptable range(s) of opera- tion, Chapman’s so-called proven acceptable range (PAR) principle [20].

  Optimization techniques may be classified as parametric statistical meth- ods and nonparametric search methods. Parametric statistical methods, usually employed for optimization, are full factorial designs, half factorial designs, sim- plex designs, and Lagrangian multiple regression analysis [21]. Parametric methods are best suited for formula optimization in the early stages of product development. Constraint analysis, described previously, is used to simplify the testing protocol and the analysis of experimental results.

  The steps involved in the parametric optimization procedure for pharma- ceutical systems have been fully described by Schwartz [22]. Optimization tech- niques consist of the following essential operations:

  1. Selection of a suitable experimental design

  2. Selection of variables (independent Xs and dependent Ys) to be tested

  3

  3. Performance of a set of statistically designed experiments (e.g., 2 or

  2

  3 factorials)

  4. Measurement of responses (dependent variables)

  5. Development of a predictor, polynomial equation based on statistical and regression analysis of the generated experimental data

  6. Development of a set of optimized requirements for the formula based on mathematical and graphical analysis of the data generated

XII. WHAT ARE THE PROCESS VALIDATION OPTIONS?

  The guidelines on general principles of process validation [1] mention three options: (1) prospective process validation (also called premarket validation), (2) retrospective process validation, and (3) revalidation. In actuality there are four possible options.

A. Prospective Process Validation

  process is put into commercial use. Most validation efforts require some degree of prospective experimentation to generate validation support data. This particu- lar type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The for-

  malized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily

  :

  1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements (completion of installation

  qualification

  )

  In prospective process validation, an experimental plan called the validation

  3. The design, selection, and optimization of the formula have been completed

  4. The qualification trials using (10 × size) pilot-laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have been provided

  5. Detailed technical information on the product and the manufacturing process have been provided, including documented evidence of prod- uct stability

  6. Finally, at least one qualification trial of a pilot-production (100 × size) batch has been made and shows, upon scale-up, that there were no significant deviations from the expected performance of the process

  The steps and sequence of events required to carry out a process validation assignment are outlined iThe objective of prospective validation is to prove or demonstrate that the process will work in accordance with a validation master plan or protocol prepared for pilot-product (100 × size) trials.