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					                                     Process
                                            Validation
                                     How Much to Do and When to Do It
                                                                 Anurag S. Rathore, Joseph F. Noferi, Edward R. Arling,
                                                                          Gail Sofer, Peter Watler, and Rhona O’Leary



        The trick to process                  rocess validation is defined in the               Validation often requires a joint effort —




                                     P
 validation, these industry                   supplementary information section of          planning and expertise from several groups. Units
          experts argue, is to
                                              the Federal Register as “a QA function        or departments that help create the validation
      understand that it is a
                                              that helps ensure drug product quality        package often include process development,
     process that stretches
through the whole product                     by providing documented evidence that         engineering, manufacturing, quality assurance,
   life cycle. Some secrets                   the manufacturing process consistently        and quality control. Some of the critical process
  of success: Take a team                     does what it purports to do” (1). It has      validation activities are described in the “Critical
     approach; focus on the          also been defined as the act of “establishing          Activities box” (2–4).
        timing of the various        documented evidence that provides a high degree            A big dilemma during process validation
stages of validation; avoid          of assurance that a specific process will consis-      development is how much to do and when to do
  some common mistakes
                                     tently produce a product meeting its predeter-         it. Although it is essential to be thinking of vali-
   (see page 20); and build
                                     mined specifications and quality attributes” (2).      dation as early as possible, the validation process
         your documentation
                   as you go.           Process validation is required in license           often changes as the product goes from phase 1 to
                                     submissions for all products regulated by CBER         phase 3 and beyond. Creating the package too
                                     or CDER and usually is a subject of intense            early — doing too much too soon — can mean
                                     scrutiny and lots of activities that culminate in an   redoing a lot of the work. Insights into those
                                     acceptable validation package. FDA expects that        “how much” and “when” questions are shared
                                     each step of a CGMP manufacturing process              here by some process experts from our industry.
                                     must be controlled to maximize the probability
                                     that the finished product meets all quality and        JOSEPH F. NOFERI AND EDWARD R. ARLING
                                     design specifications.                                 Quality Assurance, Pharmacia Corporation
                                                                                            Validation has become one of the pharmaceutical
                                                                                            industry’s most recognized and discussed
                                                                                            subjects. It is a critical success factor in product
                                                                                            approval and ongoing commercialization.
                                                                                            Defined, it is the “act of establishing documented
                                                                                            evidence that provides a high degree of assurance
                                                                                            that a specific process will consistently produce a
                                                                                            product meeting its predetermined specifications
                                                                                            and quality attributes.” Despite the simplistic defi-
                                                                                            nition, validation is subject to variable
                                                                                            interpretations both by industry and by regulators.
                                                                                               Approach and philosophy. Our industry’s
                                                                                            approach to validation is often flawed. We tend
                                                                                            to think deductively — indeed, companies train
                                                                                            us to think deductively. We order our thoughts
                                                                                            and approach problem resolution by listing
                                                                                            options and selecting the optimum course, priori-
                                                                                            tizing issues and selecting actions. Deductive
                                                                                            thinking identifies a solution and looks for all the
                                                                                            problems that might be solved by the solution.
                                                                                            Inductive thinking results in an analytical rather
18         BioPharm   OCTOBER 2002
than a systemic approach to problem resolution.             Validation is about control — that is, adequate
Analysis focuses on structure; it reveals how           controls supporting and surrounding the process
components work. Synthesis focuses on function;         — without which, the validation will fail. For bio-
it reveals why components operate as they do.           pharmaceuticals, the more frequently misvalidated
Systems thinking is synthesis, putting things           activities include maximum cell age, impurity
together. Analysis is taking them apart. The two        profiles, column resin life, and viral clearance.
approaches are complementary: Analysis yields               Critical success factors. Success requires leader-
knowledge; synthesis yields understanding (5).          ship and management with a focus on quality
    Process validation requirements. Validation is a    across all functional areas. Preparing and planning
dynamic process. It is expected to follow a             can never be overemphasized. The small costs in-
timeline stretching from initial design through         curred up front pale when compared with reper-
ongoing commercial operation — the product life         forming the entire exercise. Validation should be
cycle. Typical expectations are that design qualifi-    written as if FDA were the customer. The agency
cation (DQ), installation qualification (IQ), and       is the reviewer. And of course, corrective actions
operational qualification (OQ) should be                to solve any validation problems need to be im-
nearly complete early in the development process,       plemented before a preapproval inspection.
at phase 1 and 2. Process qualification (PQ) should                                                                 Critical Activities
be complete at end of phase 3. But everything           GAIL SOFER                                                  Some of the critical process
evolves with the process, and that process is           Regulatory Services, BioReliance Corporation
                                                                                                                    validation activities include
usually a moving target until registration.             Regulations mandate compliance with Good Manu-
                                                                                                                    the following (2–4).
    Controls must be applied to all manufacturing       facturing Practices (GMP) for the manufacture of
                                                        clinical trial materials (6,7). Validation is one com-      • Create a validation master
steps, critical starting materials, components, and
                                                                                                                     plan (VMP) that shows
the master cell bank. Those controls need to            ponent of the GMPs, but it is not feasible to com-
                                                                                                                     “when” and “what” activities
increase as the process develops toward final           plete validation before a process is fully developed.
                                                                                                                     will be performed.
isolation and purification. Those controls must         Instead, it is important to understand what is re-
                                                        quired for phase 1, 2, and 3 clinical trials. Under-        • Develop a strategy that
cover all process steps identified as critical —
                                                                                                                     allows revisiting the VMP as
those steps that can affect the quality and purity of   standing the requirements means that the needs of
                                                                                                                     the process “changes” from
the final product. The subcomponents that affect        the patient and the expectations of the regulatory
                                                                                                                     a phase 1 process to a
the process include equipment, facilities and utili-    agencies are considered. From both patient and reg-          phase 3.
ties, systems, computers, cleaning, analytical          ulatory perspectives, safety is critical. An under-
                                                                                                                    • Identify components that
method transfers, and sterilization among others.       standing of the risks associated with product source,
                                                                                                                     will take place at small and
A frequent problem is the failure to address the        manufacturing methods, and the product itself is es-
                                                                                                                     at large scale.
life cycle of the system as a whole — most valida-      sential for making decisions about what has to be
                                                        validated for the various clinical trial phases.            • Know the implications of
tion efforts focus on individual subcomponents of
                                                                                                                     CGMP on raw material
the process and stop after three commercial runs.          Phase 1. Validation “must-haves” for the earliest
                                                                                                                     usage, facility maintenance,
    Process validation requirements for active          clinical trials include those related to safety. Annex
                                                                                                                     documentation
pharmaceutical ingredients (API) differ from            13 to the EU GMP Guide: Manufacture of Investi-              requirements, utilities,
those for finished dosage forms (drug products).        gational Medicinal Products states that “Validation          equipment cleaning, and
The standards vary with the type of API, the            of the sterilization process is no different than for        personnel training.
range of specifications, and “other factors.” For       licensed product. Virus clearance, where relevant,
                                                                                                                    • Define “critical” process
drug products, the regulators expect validation of      and removal of other impurities of biological origin         parameters.
all manufacturing steps: cleaning, weighing,            should be no less rigorous than for licensed product
                                                                                                                    • Identify process parameters
measuring, mixing, blending, filling, packaging,        and should, therefore, be validated” (7). The
                                                                                                                     as “critical” and “noncritical.”
and labeling. For an API, the expectation is that       product must also be shown to be stable during the
                                                        time it is at the clinic, and that can require valida-      • Determine the proven
all critical processing steps determined to affect
                                                        tion or, at least, qualification of stability-indicating     acceptable range (PAR) and
the quality and purity of the API be validated.
                                                                                                                     the normal operating range
    Frequent problems. Regulatory expectations at       assays. The catch is that validation of a process re-
                                                                                                                     (NOR) for each critical
each functional stage often exceed the best efforts     quires validated assays. Before phase 1, sponsors’
                                                                                                                     process parameter.
of those charged with translating management            assays are often still in the research unit, performed
                                                        by only one or, at best, a few people.                      • Demonstrate that critical
directives into direct action. The “Validation
                                                                                                                     parameters can be
Steps Often Missed” sidebar illustrates each               Sterility and mycoplasma testing. Sterility and
                                                                                                                     monitored and controlled
functional stage and the problems inspectors            mycoplasma testing are crucial to the safety of a
                                                                                                                     during manufacturing runs.
frequently find there. It is not intended to be         biotechnological product produced in mammalian
                                                        or insect cells. Sterility assays are essential not             —Courtesy of Anurag Rathore
all-inclusive and should not be construed as
definitive.                                             only for aseptic processing validation but also for
                                                        establishing product stability. Sterility assays are
                                                                                                                   BioPharm   OCTOBER 2002          19
                                         also used to determine the acceptability of             to be shipped, then shipping conditions must also
                                         unprocessed bulk for further processing. These          be validated to demonstrate no loss of bacteria,
                                         assays must be validated according to the latest        fungi, or mycoplasma.
                                         regulatory requirements, such as 21 CFR 610.12             Viral clearance validation is usually contracted
                                         (8), United States and European pharmacopoeia           out: The assays are validated by a testing com-
                                         standards, or FDA Points to Consider.                   pany and each sponsor’s test article is evaluated
                                            Sterility and mycoplasma assays can’t be             for interference and cytotoxicity. But validation
                                         considered validated without stasis testing to          of process scale-down is often overlooked in the
                                         ensure that the test article doesn’t interfere with     rush to get into the clinic.
                                         the assays, which can cause false negatives that           Scale-down. Time and money are wasted if
                                         can lead to adverse patient reactions that can          virus clearance evaluation studies are performed
                                         potentially terminate clinical trials. If samples are   without a validated scale-down model of the
                                                                                                 process. Validation requires that the sponsor
Validation Steps Often Missed                                                                    understands critical process and control parame-
                                                                                                 ters, uses qualified equipment and validated
Regulatory expectations at each functional stage often exceed the best efforts of
those charged with translating management directives into direct action. The
                                                                                                 assays, and follows a protocol defining the study
following list of items that frequently cause problems if missed is not intended to              and the expected outcome. A sponsor must also
be all-inclusive and should not be construed as definitive.                                      understand what each unit of operation does and
At the design qualification (DQ) stage, elements often missed include:
                                                                                                 how output is measured. Unfortunately, at this
                                                                                                 early stage of development, many of the assays
 • Adequate description of the equipment’s intended use
                                                                                                 that enable that understanding are not validated.
 • Clear specifications for all critical design parameters                                       At worst, a sponsor might lack understanding of
 • Setting design parameters that allow future flexibility (for example, the                     what a unit of operation accomplishes.
  process will likely change, but the equipment may not)                                            Take, for example, an immobilized protein A
 • Specifications that take CGMPs into account.                                                  column used to purify a monoclonal antibody
At the installation qualification (IQ) stage, elements often missed include:                     (MAb). Initially, product yield might be deter-
 • A list of all equipment that, when operating, has the potential to affect product             mined using high-performance liquid chromatog-
  quality or process performance                                                                 raphy (HPLC) and a total protein assay. But what
 • As-built drawings and specifications for all purchased equipment, new or used                 about activity and impurities associated with the
                                                                                                 eluted antibody? Without an impurity profile or
 • Verification that all purchased equipment and its installation meets the
  original intent (functional specifications and design parameters), including
                                                                                                 without knowing how much of a MAb’s biologi-
  applicable building, electrical, plumbing, and other such codes                                cal activity has been retained, the control parame-
                                                                                                 ters (such as flow rate and pH) cannot be estab-
 • Preventive maintenance plans and schedules for all such equipment.
                                                                                                 lished with certainty. A sponsor in this situation
At the operational qualification (OQ) stage, elements often missed include:
                                                                                                 should go back and understand both purity and
 • Process operating parameters for each module, including those designated                      impurity profiles. The assays used to determine
  as critical                                                                                    those profiles are unlikely to be validated at this
 • An OQ protocol designed to demonstrate that the equipment used in each                        stage, but they must be “qualified.” Typically, a
  module operates as intended throughout each process operating parameter                        reference standard is run along with each assay to
  range                                                                                          ensure the assay is working according to protocol.
 • Task reports describing the successful execution of each OQ protocol                             Which viruses? Another issue in viral clearance
 • A list identifying each module (step, unit of operation, or stage) of the                     studies is how many and which viruses to use in the
  process.                                                                                       first studies so that clinical trials can begin. The
At the performance qualification (PQ) stage, elements often missed include:                      opinion of regulatory agencies varies. If a sponsor
 • A fully defined process, including identifying critical processes and their                   intends to begin clinical trials worldwide, it is
  acceptable operating parameter range (traceable to development reports or                      essential to understand the latest regional concerns
  small-scale supporting studies) and defining potential adverse consequences                    related to viral safety so that validation of virus
 • Completed product specifications                                                              clearance will stand up to regulatory scrutiny.
                                                                                                    Other impurities of biological origin. Developing a
 • Scientific rationale or basis for criteria — usually exists but is poorly
  documented                                                                                     validated assay that demonstrates the removal of
                                                                                                 impurities (such as host cell proteins) for phase 1
 • IQ and OQ steps completed and reports written, reviewed, and approved
                                                                                                 is seldom possible. There is one exception. By
 • Operating personnel trained and qualified
                                                                                                 using a parental cell line and similar culture con-
 • Change control procedures in place.                                                           ditions to produce multiple products, a generic
                                                                —Courtesy of Joseph F. Noferi    assay can be validated and qualified for each new
                                                                                                 product. However in other situations, the host cell
20            BioPharm   OCTOBER 2002
                                                                                               larger virus panels are used, mass balance analyses
                                          5.075                                                are attempted, and duplicate runs are tested. For
                                          5.050 A
                                                                            UCL 5.0554         chromatography steps that claim to remove
                                                  B                                            viruses, end-of-resin lifetime studies are performed
 Figure 1. Control chart showing          5.025
                                                  C                                            to demonstrate consistent virus clearance.
               that operator skill,       5.000 C
                                                                            Avg 5.0089
                                                                                                  Preventing surprise. One of the most common
   manufacturing equipment, and                   B                                            FDA form 483 observations is the lack of process
written instructions are sufficient       4.975 A
                                                                                               validation. Planning ahead during early develop-
                                                                            LVL 4.9624
    to adjust oxidation pH to the         4.950                                                ment can prevent unpleasant surprises, such as
                                                  1 2 3 4 5 6 7 8 9
  same set-point from lot to lot.                                                              specifications that are so tight they cannot be met,
                                                        Lot Number
        —Courtesy of Peter Watler                                                              analytical assays that can be performed only by one
                                                                                               operator and so are not validatable, or a process
                                       protein population is unlikely to be consistent         that cannot be scaled up or down without redesign.
                                       until the scale and conditions of the final culture     Surprises like that result in processes that cannot be
                                       have been established.                                  validated and often multiple failed batches.
                                           Enzyme-linked immunosorbent assay (ELISA)              I find that for new processes and products, the
                                       kits on the market may be sufficient for clinical       greatest validation problems arise when insuffi-
                                       trial material, but companies are still required by     cient resources and insufficient time are budgeted
                                       today’s regulations to develop their own assays         for understanding and optimizing production. For
                                       for licensed product. The development of those          biological and biotechnological products, phase 1
                                       assays is time-consuming — they can take more           validation activities are carried out to ensure safety
                                       than a year. Planning ahead is essential. In addi-      and the manufacturing process should be control-
                                       tion to host cell proteins, other impurities for        lable. Phase 2 manufacturing processes should be
                                       which validated assays may be required include          well-controlled and better understood with vali-
                                       any toxic or potentially immunogenic substances.        dated assays that demonstrate that control. Phase 3
                                           Phase 2. During phase 1 and 2 clinical trials,      should be very well controlled and full process
                                       the process is generally improved. Both upstream        validation should take place during this phase.
                                       and downstream processes change, analytical
                                       methods are usually transferred to QC during this       PETER WATLER
                                       stage, and potency assays validated. No specific        Pilot Plant Engineering, Amgen Inc.
                                       process validation activity is required at this         Process validation demonstrates the consistency
                                       stage, unless the changes made to improve the           of multiple batches at full-scale. The validation
                                       process have the potential to affect the results of     shows that the process is operated in a consistent
                                       previously performed validation studies for steril-     manner and that contaminants are reproducibly
                                       ity, virus clearance, and specific impurity             reduced to acceptable levels. That is accomplished
                                       removal. However, while the process is being            by monitoring those parameters that demonstrate
                                       optimized, assay validation efforts should              consistent operation of the process, consistent
                                       continue so that process validation at pilot or full    formation of the product, and consistent removal
                                       scale for licensure can take place during phase 3.      of the contaminants. Processes can be validated
                                           Phase 3. Sometime before phase 3, the process       through two distinct metrics: operational parame-
                                       is, hopefully, finalized to avoid bridging studies in   ters (inputs) and performance parameters (out-
                                       the clinic. Assays not yet validated must now be        puts). Operational parameters are process control
                                       validated so that process validation required for       set-points for variables such as flow rate, tempera-
                                       biologics licensure can be completed during phase       ture, and concentration. These parameters define
                                       3. This is the phase of heavy-duty validation and       the process recipe and are used to demonstrate
                                       requires equipment qualification, then process val-     that the facility, equipment, and staff can execute
                                       idation during three or more consecutive batches.       the process consistently. Performance parameters
                                       Cleaning validation and lifetime studies for chro-      reflect the outcome of a given step and indicate
                                       matography columns are important validation             that the process gave the desired result.
                                       elements. Clearance studies to remove host cell            Process validation is an investment in future pro-
                                       proteins, DNA, viruses, and other impurities may        duction because it sets the bar by which the process
                                       eliminate lot release testing. Some clearance stud-     will be judged at future inspections. Process valida-
                                       ies are performed at a smaller scale than manufac-      tion is the point at which the science of the process
                                       turing, so the small-scale model must be validated.     can be explained to regulatory agencies. Following
                                       Once the process is finalized, viral clearance stud-    validation, regulatory agencies are looking for con-
                                       ies are carried out again. At this stage, however,      sistent process operation within the ranges and
22           BioPharm   OCTOBER 2002
                                          meeting the criteria specified in the validation. Sci-           Operational control parameters are input variables
                                          entific arguments explaining operation and perfor-           with set-points or ranges specified in the manufac-
                                          mance outside of specified ranges are likely to fall         turing procedure to define how a process is
                                          upon deaf ears. Therefore it is essential to generate        executed. Control charts can be used to demon-
                                          bench and pilot scale process data that establish key        strate that the set-points are consistently achieved
                                          parameters and their acceptance criteria before              within the specified ranges. Typical operational
                                          process validation in the GMP facility.                      parameters include pH, raw material quantities, re-
                                             When to validate. Process validation is                   action times, flow rates, temperature, and pressure.
                                          expensive, involving copious sampling, extensive             For example, the control chart in Figure 1 shows
                                          analysis, and detailed documentation. Because of             that operator skill, manufacturing equipment, and
                                          the complexity and cost, process validation is best          written instructions are sufficient to adjust oxida-
                                          performed during phase 3 trials following the deci-          tion pH to the same set point from lot-to-lot.
                                          sion to file a Biologics License Application (BLA).              Performance parameters are output variables that
                                          This “delayed” strategy offers several advantages.           reflect the outcome of a given step, indicating that
                                          The process is better understood, which means that           the process performed as expected. Validation
                                          key parameters and acceptance criteria can be bet-           should demonstrate that the process is capable of
                                          ter specified. In addition, the commercial process is        consistently removing three classes of contami-
                                          in place at this point, and validation does not have         nants: process-related, host cell-related, and prod-
                                          to contend with process changes, adjustments, and            uct-related. Process-related contaminants are
                                          inexperience that can lead to deviations from the            reagents required by the process (for example,
                                          validation protocol. By the time products enter the          guanidine, glycerol, and antifoam). Host cell-
                                          regulatory review phase, the likelihood of product           related impurities are derived from the organism
                                          success increases to 90%, meaning that there is less         used to generate the product (for example, nucleic
                                          risk that process validation will have been for              acids, CHO proteins, and endotoxins). Product-
                                          naught. Then too, although process validation is a           related contaminants are variants and isoforms of
                                          required component of a BLA submission, it is not            the target protein (for example, oxidized, deami-
                                          required for clinical trials.                                dated, aggregated, and clipped forms). The valida-
                                             What to validate. Demonstrating process consis-           tion should also demonstrate at which step the
                                          tency requires multiple, full-scale batches. Three           contaminant is removed and at what point in the
                                          to five consecutive purification runs from three             process it meets acceptance criteria. Table 1
                                          consecutive fermentation lots should generate suf-           shows that E. coli proteins were reduced by the
                                          ficient consistency data. Process validation can be
                                                                                                       filtration step, significantly reduced at cation ex-
                                          made more efficient and more consistent by using
                                                                                                       change 1, and further reduced to below the
                                          templates that identify key input and output para-
                                          meters for a unit operation. For example, consis-            acceptance criteria by cation exchange 2.
                                          tent operation of a tangential-flow filtration step              Process consistency is also shown by monitor-
                                          can be shown by monitoring cross-flow rate,                  ing yield and product concentration at each step.
                                          transmembrane pressure (TMP), temperature, re-               With sufficient advance planning, earlier process
                                          tentate tank volume, and diafiltration volume.               data, and careful execution, the data from the
                                          Consistent performance of this step can be shown             validation should demonstrate that the manufac-
       Table 1. Validation results        by monitoring excipient removal, protein contam-             turing procedure consistently and effectively
        demonstrating that E. coli        inant removal, product concentration, product re-            yields product that meets specifications. It will
   proteins were reduced by the           covery, pH, and conductivity. Such parameters                also demonstrate that the process can be operated
  filtration step, significantly at       demonstrate that the step achieved its purpose in            consistently and that the process, product, and
 cation exchange 1, and further           the process. These validation templates for unit
                                                                                                       host cell contaminants are reduced to acceptable
    reduced to below acceptance           operation can be customized to address any
                                                                                                       levels.
  criteria by cation exchange 2.          unique specifics of the process or product.
       —Courtesy of Peter Watler


                                                                          Purification Lot Number (% w/w)

 Process Stream                         23004             23006               23007                23008                23010              Average

 Oxidation                              6.39               4.60                13.4                6.78                  11.8                8.60
 Filtration                             4.13               3.26                 2.42               4.83                   7.31               3.58
 Cation exchange 1                      0.915              0.494                0.64               0.532                  1.18               0.65
 Cation exchange 2                      0.009              0.003                0.004              0.003                  0.011              0.006
 Purified bulk                          0.007              0.014                0.003              0.009                  0.023              0.011

24            BioPharm   OCTOBER 2002
                               RHONA O’LEARY                                              variability. Such runs may include running the
                               Process Sciences, Genentech, Inc.                          process at the extremes of its operating ranges,
                               Manufacturing processes for biologicals are                testing different feedstocks, using different lots of
                               continually optimized as the product moves through         resins, testing cell culture components or peptone
                               various stages of development, from the preclinical        lots, among others. Sometimes we perform these
                               stage through the investigational new drug (IND)           runs at the 400 liter scale, more often at lab scale.
                               filing to the common technical document (CTD) fil-         The timing of these scaled-down runs also
                               ing and on to approval. The early-stage product may        provides the scientist with the ability to incorpo-
                               have a basic and somewhat unpolished manufactur-           rate last minute changes that result from data
                               ing process. By midstage the process is optimized          gathered during these runs to further optimize
                               and becomes more robust. By the end of develop-            and improve the robustness of the process.
                               ment, the final manufacturing process is fully char-           It is sometimes easy to overlook the impor-
                               acterized, validated, and qualified.                       tance of a complete evaluation of the robustness
                                   Development validation activities. At Genentech,       of the process for both cell culture (or fermenta-
                               our goal is to have the manufacturing process              tion) and recovery before finalizing the process.
                               completely finalized before the manufacturing              Although it is hoped that the manufacturing
                               campaign that supplies the phase 3 clinical trials.        process will run at its optimum operating condi-
                               That means that the critical process parameters            tions on a routine basis, knowing how the process
                               have been identified, the operating ranges have            works under conditions beyond its optimum set
                               been set, and the process is deemed robust                 points (such as flowrate, pH, and temperature
                               enough to tolerate the manufacturing environ-              excursions) is important. If the process is running
                               ment and produce marketable product.                       close to the edge of failure, the time to discover
                                   Phase 1 process validation activities. Validation      and correct that is before finalizing the process.
                               evolves along with development of the process,             The studies performed at this stage require fully
                               and different types and levels of validation are           developed analytical assays, and those assays are
                               appropriate at the various developmental stages.           examined to ensure the process meets the accep-
                               At the time of IND filing, the only validation             tance criteria set in the Certificate of Analysis.
                               requirement is a demonstration that the process            Although this phase of development is not
                               removes retroviral particles. If modifications are         considered part of the official validation process,
                               made as the process moves through development,             if well documented, it can become the foundation
                               the process for removing retroviruses must be              on which the process validation program is based.
                               reassessed. Complete process validation is not                 Final process with product in phase 3 trials. Genen-
                               required until the CTD is filed.                           tech finalizes the manufacturing process for the
                                   Phase 2 and 3 process validation activities. Valida-   start of the phase 3 clinical trials — that is, the ma-
                               tion is performed after the process is fully devel-        terial that is made in the manufacturing campaign
                               oped and finalized. Process validation can be a            to supply the phase 3 trials is from the fully devel-
                               combination of manufacturing-scale and scaled-             oped, fully characterized, and finalized manufac-
                               down studies. The qualification runs are performed         turing process. No process changes are expected
                               on validated equipment, at full manufacturing              beyond this stage. At this point, the analytical as-
                               scale, in the facility in which the product is to be       says are also finalized and are used to release the
                               routinely manufactured. The validation studies             material to the clinic. Once that product is manu-
                               performed at manufacturing scale typically include         factured, some of that material can be used to sup-
                               the validation of the process to clear impurities          port process validation. Validation of the analyti-
                               (host cell proteins and DNA) and small molecules           cal methods and the definition of the control
                               and the cleaning of resins and membranes.                  system begin at this stage.
                                   Scaled-down studies typically include the vali-            Generic process validation activities. Some of the
                               dation of resin lifetimes, in-process hold times,          validation studies we perform are common across
                               buffer stability, virus validation, harvest criteria,      many of our processes: viral validation, resin and
                               filter extractables, resin leachables, and cell age.       membrane sanitization and storage, buffer stability,
                               Genentech has found that a combination of                  filter extractables, and resin leachables. Rather than
                               manufacturing-scale and scaled-down studies                continuing to repeat these studies time and time
                               provides the best overall process validation plan.         again, we developed matrices to support a wide
                                   Before phase 3, evaluate robustness. Before the        variety of conditions — conditions that typically
                               process is finalized several scaled-down runs are          reflect our most common operating parameters.
                               performed to evaluate process robustness. These                We try to assess the worst-case situation, after
                               runs provide an adequate history of the process’           which all other conditions are well covered by
26   BioPharm   OCTOBER 2002
                                       those conditions. For example, by testing the ability    be taken, distinct commonalities underlie all the
                                       of a particular resin matrix (such as Sepharose) to      approaches described. The validation approaches
                                       be sanitized in the presence of a protein mixture,       discussed here seek to overcome challenges often
                                       we can use that study to support the same sanitizing     encountered during development of a validation
                                       agent for all other similar protein mixtures, on sim-    program for biotechnology products. An accept-
                                       ilar resin matrices. If we did not adopt such an ap-     able validation program addresses the following
                                       proach, it is likely that the huge workload currently    difficulties encountered by others:
                                       required for process validation would be doubled.         • Lack of overall strategy
                                       The ability to develop such large matrices for our        • Failure to consult early with the regulatory
                                       various processes is reflective of the large number         authorities
                                       of products that have been validated in Genentech         • Inadequate product definition
                                                                                                 • Failure to follow CGMP regulations
                                       in recent years. A smaller company might not have
                                                                                                 • Poorly defined cell bank genealogy
                                       the luxury of developing the necessary database of
                                                                                                 • Inadequate analytical procedures
                                       information to support a matrix design, but it could      • Too many process changes after validation
                                       use the worse-case scenario to cover not just a sin-        activities have been completed
                                       gle product, but also many future products.               • Not enough process characterization or
                                          Process validation is a combination of efforts. The      qualification
                                       importance of documentation is also frequently            • Commencing process validation too early
                                       overlooked. Throughout all phases of develop-             • Inappropriate acceptance criteria.
                                       ment, we try to capture all development work and
                                       all decisions in development reports. These              VALIDATION PERSPECTIVES
                                       reports, in turn, support any questions that the         We hope that this article is useful to those in the
                                       regulatory agencies may have about how a                 biopharmaceutical industry who are currently in-
                                       process was developed or why certain decisions           volved in validation activities and especially use-
                                       were made. These reports are stored in a database        ful to those who are planning to start validation
                                       for easy access. They also serve as a resource into      activities in the near future.
                                       the development history if an employee leaves               This article series presents opinions and
                                       and as guidance for new employees.                       viewpoints of some of the industry experts on issues
                                          The biostatisticians are also on hand to assist       that are routinely faced in process development and
                                       in the design of characterization studies and to         manufacturing of biopharmaceuticals.
                                       evaluate process robustness, frequently using
                                       fractional factorial designs. Sometimes these            REFERENCES
                                                                                                 (1) FDA, “Current Good Manufacturing Practices;
                                       results are incorporated into resin lifetime                  Proposed Amendment of Certain Requirements for
                                       studies. Quality assurance, analytical chemistry,             Finished Products: Supplementary Information,”
                                                                                                     Federal Register 61(87), p. 20104 (3 May 1996).
                                       and process development groups work closely                   Available at www.fda.gov/cber/genadmin/cgmp.pdf.
                                       together to ensure that all appropriate studies are       (2) Sofer G. and Hagel L., “Validation,” Handbook of
                                                                                                     Process Chromatography: A Guide to Optimization,
                                       performed, that the data are audited for accuracy,            Scale-up, and Validation (Academic Press,
                                       and that reports are generated and approved.                  New York, 1997), pp. 119–243.
                                          Developing a manufacturing process that will           (3) Martin-Moe S. et al., “Validation of Critical Process
                                                                                                     Input Parameters in the Production of Protein
                                       ultimately receive regulatory approval and yield a            Pharmaceutical Products: A Strategy for Validating
                                       marketable product requires a development plan                New Processes or Revalidating Existing Processes,”
                                                                                                     PDA J. Pharm. Sci. Technol. 54(4), 315–219
                                       that follows regulatory requirements. The devel-              (July/August 2000).
                                       opment plan must have goals that are met during           (4) Seely R.J. et al., “Defining Critical Variables in Well-
                                                                                                     Characterized Biotechnology Processes,” BioPharm
                                       development before it moves onto the next stage.              12(4), 33–36 (April 1999).
                                       In addition, we have found that having standard-          (5) Noferi J.F., Arling E.R., and Worden D.E., “Beyond
               Corresponding author                                                                  QSIT,” BioPharm 15(4), 40–44, 67 (April 2002).
                                       ized study designs, protocols, and reports have
       Anurag S. Rathore, GG3K,                                                                  (6) Center for Drug Evaluation and Research, Guideline on
    700 Chesterfield Parkway North,
                                       led to successful validation programs. The                    the Preparation of Investigational New Drug Products
                                       program described has undergone four FDA                      (Human and Animal) (FDA, Rockville, MD, March
             Chesterfield, MO 63017                                                                  1991). Available at www.fda.gov/cder/guidance/
  anurag.s.rathore@pharmacia.com;      preapproval inspections since 1998.                           old042fn.pdf.
        Joseph F. Noferi, Esq. and                                                               (7) European Commission, “Annex 13 Manufacture of
                                                                                                     Investigational Medicinal Products” Medicinal Products
      Edward R. Arling are also at     MEETING THE CHALLENGE                                         for Human and Veterinary Use: Good Manufacturing
            Pharmacia Corporation,     In this article, experts from different companies in          Practices, Vol. 4, Draft 1, F2/AN D(2001)
               www.pharmacia.com.      our industry have outlined the strategy that they             (Enterprise Directorate-General, Brussels, Belgium,
       Gail Sofer is at BioReliance,                                                                 November 2001).
                                       use to arrive at a validated process that can be          (8) “General Biological Products Standards: Sterility,”
 Peter Watler is at Amgen Inc., and                                                                  Code of Federal Regulations: Food and Drugs,
Rhona O’Leary is at Genentech, Inc.
                                       submitted to regulatory agencies. Although it is
                                                                                                     Title 21, Part 610.12 (U.S. Printing Office, Washington,
                                       interesting to see the different approaches that can          DC, revised 1 April 2001). BP
28           BioPharm   OCTOBER 2002

				
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