validation for clinical manufacturing

40

Validation for Clinical ManufacturingWarren CharltonConsultant, WHC Bio Pharma, Inc., Greenville, North Carolina, U.S.A.

Tom IngallineraConsultant, Charleston, South Carolina, U.S.A.

Danny ShiveMetrics, Inc., Greenville, North Carolina, U.S.A.

INTRODUCTION

The focus of this chapter is Validation of CTM forPharmaceutical Products. A review of validation activi-ties have been compiled for a range of drug products(e.g., non-Sterile, Sterile, Biotech, Blood/ Plasma, andNasal Inhalants). Basic to all CTM products for humantesting is the need for validation of analytical methods,equipment, utilities and other unique drug-specificfactors such as environmental monitoring of the asepticprocessing area used in the sterile filling. The selectedproducts have very distinct differences in complexityranging from non-sterile powders to the potentiallyvery complex biotech product that is ultimately asepti-cally filled and freeze-dried.

The intent of this chapter is to provide an under-standing of “what” is needed, “when” it is needed but not“how” they are validated or developed. In support ofdeveloping an overall Validation Master Plan this chapterprovides validation activities, a flowchart of validation/-critical activities by Phase (e.g., pre-IND to Phase 3),product-specific validation/supporting information, aDevelopment Protocol Example and Contract Manufac-turer Requested Drug Product Information.

SOLID DOSE DISCUSSION

Equipment Qualification (IQ and OQ)It is understood within the pharmaceutical industry thatmajor equipment and utilities directly involved in proces-sing pharmaceuticals for human use, including clinicaltrial material, must be qualified (1). This involves, at aminimum, IQ and OQ, and, if appropriate, PQ. Anexcellent guide for the planning and execution of IQ/OQ/PQ is the ISPE Baseline Guide for Commissioningand Qualification (2). Not only should major processequipment, such as granulators, mills, tablet presses,capsule fillers, etc., be qualified, but utilities directlyimpacting the process should be qualified as well. Thisincludes, but is not limited to, HVAC, compressed air, andpharmaceutical water systems.

Process ValidationValidation of pharmaceutical processes began in the late1970s, based on comments by field inspectors andfollowed up by the establishment of the principles ofvalidation for sterile injectables. The FDA Guideline onGeneral Principles of Process Validation was issued in1987 (3), and is still in effect. Amajor focus of validation ofsolids (although certainly not the only one) has beencontent uniformity of blends and uniformity of dosageunits. In October 2003, the FDA published a draftGuidance (4) on blend uniformity following extensivework by the PQRI Blend UniformityWorking Group. ThisGuidance allows for reduced testing of blends duringroutine commercial batch manufacture provided certaincriteria are met, but it does not address (nor was itintended to address) clinical batch validation. Sincemany, if not most, clinical batches are unique withregard to batch size, formulation, or process, theapproach for many firms has been to create a protocolfor each unique batch and to let that batch data standon its own. In some situations, especially in Phase3 clinical testing, a formulation and process may bewell established, and a number of identical batchesmay be required over some months, or years. In thesecases, the process can be validated much like a commer-cial product/process is validated, as long as theformulation, process, and batch size do not change.

Abbreviations used in this chapter: API, active pharmaceuticalingredient; BP, bubble points; CBER, Center for Biological Evalu-ation and Research; CDER, Center for Drug Evaluation andResearch; CDRH, Center for Devices and Radiological Health;CE, comparability exercise; cGMP, current good manufacturingpractice; COA, Certificate of Analysis; CTM, clinical trial material;CVM, Center for Veterinary Medicine; ELISA, enzyme-linkedimmunosorbent assay; EMEA, European Medicines EvaluationAgency; EU, European Union; FDA, Food and Drug Adminis-tration; GC, gas chromatography; HPLC, high-performance liquidchromatography; HVAC, heating, ventilation, and air-conditioning;IND, investigational new drug; IQ, installation qualification; ISPE,International Society for Pharmaceutical Engineering; NDA, newdrug application; OQ, operational qualification; PAG, polyacryl-amide gel; PAT, process analytical technology; PNU, proteinnitrogen units; PQ, performance qualification; PQRI, ProductQuality Research Institute; QA, quality assurance; RID, radialimmunodiffusion; SIP, sterilization in place; SOPs, standard oper-ating procedures; USP, United States Pharmacopeia; WFI, water forinjection.

Change control becomes vitally important here, toensure that changes are tracked in relation tovalidation documentation.

A healthy debate could be easily initiated amongindustry experts regarding what stage in the continuumof dosage form development that clinical batch vali-dation is expected. Most industry experts will agreethat Phase 3 requires a level of validation, or “verifica-tion,” resembling commercial process validation. Manywill perform at least a limited level of “verification” inPhase 2 to ensure that clinical batches used at this stageare uniform and have the quality and purity that isexpected. The greatest debate would no doubt be gener-ated at Phase 1. Many persons will do no more testingthan that required to show that clinical batches in Phase

1 meet the minimum requirements of USP and thelimited specifications established at this early stage.Others will go further and test blends for uniformityand test more than USP requires for tablet or capsuledissolution and uniformity of dosage units.

The FDA has an expectation of some track record ofvalidation or “verification” testing of clinical batchesduring all phases of clinical batch manufacture. Seeprotocol outline (Appendix A) presented for consider-ation in “verifying” the adequacy of the manufacturingprocess of clinical batches in the early stage of develop-ment (Phase 1) whose formulation and process are notfinalized. For Phase 3 clinical batches, a validationprotocol may closely resemble that of a commercialproduct.

Validation Activities

Initial validation of testingequipment

Initial viral clearance studies(biologicals/ blood products)

Start human trials (safety)o Ensure product produced in

a qualified facility (i.e.,trained people and validatedprocesses and equipment)

o EMEA requires an“Authorized Person” who isresponsible for ensuring thatthere are systems in placethat meet the requirementsof Annex 13 and shouldhave a broad knowledge ofthe pharmaceuticaldevelopment and clinicaltrial process

o Major process equipmentand utilities impacting theprocess should be qualified

o Process Validation asneeded to ensure productsafety, quality anduniformity of IND products

o In-process testing (PAT) (8)

Supporting ActivitiesAPI: clear understanding of processDefining Properties (e.g., solubilityhygroscopicity, melting points)Initial Analytical MethodsInitiate Reference StandardsSpecification developmentBiologicals: initiate studies on viralclearance and protein characterizationProcess and Assay development asneeded (e.g., Biologicals)Initiate Clinical Manufacturing

Analytical methodso Suitability confirmedo Acceptance limits tabulated

for Validation includingimpurities/ isomers

o USP/ICH guidelines apply

Change control in placeInitiate stability studiesSubmit IND applicationFlow charting to demonstrateknowledge of process

Certificates of analysis for alldrugs/chemicals, excipients,components and batch results needto be available

Batch sizing for eventual scale-upBatch acceptance limits includingimpurities are essential

Initiate process validation plan forunique and complex processes (e.g.,all sterile manufacturing processes;sterilizing operations; those affectingpotentially adverse microbial growthor removal of endotoxins)

Biologicals/other products ifappropriate: conduct viral clearancestudies

Specifications in place (drug,chemicals, component, etc.)

PHASE

1

Figure 1 Validation/critical activities

flowchart by phase. Source: FromRefs. 5 and 6. (Continued )

542 VII: MANUFACTURING RELATED ACTIVITIES

STERILE CTM DISCUSSION

Parenteral clinical supplies present numerous challenges.During preclinical and Phase I, very little is known aboutthe chemistry, dose, toxicity, and pharmaceutical proper-ties of the drug. One must take a systematic approach toget the drug into humans as quickly as possible. This iscritical in order to establish a “go” or “no-go” for aspecific compound. Many development dollars andyears can be wasted on elaborate formulation and

analytical methodology only to find that the drug isineffective or not safe.

Developing specifications is a priority duringpreclinical and Phase I. Early in the developmentprocess keep the drug product simple, either a simplesolution or a lyophilized powder for injection. Start byevaluating your active compound for its preformulationattributes (e.g., solubility, salt selection, pH solubilityprofile, osmolality, and density) and physicochemicalproperties (e.g., color, odor, melting point, hygroscopicity,

Validation Activities

Validation of analytical proceduresValidation master plan developedValidation protocols established/approved

Validation of development batches(small scale)

Validation master plan documentapproved. Change control in place

Production scale Validation (IQ,OQ and PQ)

Media fills for sterile operations

Manufacture validation batches (PQ/conformance batches)–normally 3

Validation summaries

Validation team reviews the MasterPlan and signs off verifying allrequirements have been met with thelast signature by QA (note: typically atleast three team members fromdifferent areas for the company)

Supporting Activities

Quality systems should be reviewed toensure all systems are in place

Viral clearance studies are operational andcontinue to be expanded (biologicalprocesses and as needed to ensure safety)Preliminary specifications, tests,acceptance criteria and limits areoperational and continue to be expanded(tabulated and validation in process)

Complete understanding of manufacturingprocess, site of production, and batchrelease requirementsCritical manufacturing steps should beidentified (e.g., training, equipment,process, storage, environment,sterilization) and verified that controlleddocumentation and/or validation arecompleted

Qualify and validate assayso Tabulation of assay results

availableo Justification of impurity

specificationDrug product filter validation completedSpecifications are in place and fullvalidation report available (5)

Conduct pivotal trialsSubmit regulatory license application

· Pass pre-approval inspection. Note:normally expect FDA at one or more ofthese batches to view operation

Obtain regulatory approval in writingProduct can be shipped

PHASE

2

PHASE

3

Figure 1 (Continued )

40: VALIDATION FOR CLINICAL MANUFACTURING 543

and optical activity). The effects on heat, light, pH,oxygen and ionic strength on the stability of thecompound need to be confirmed. If the solubility of thedrug is limited, co-solvents and other formulationchanges may be necessary.

Initial container/closure can be a glass ampule or avial with a coated closure when limited compatibilitydata is available. Clear glass is preferred over amber, toallow inspection of the solution before injection. Alternatecontainer/closure systems should be evaluated indevelopment. Initial storage of clinical supplies can berefrigerated or frozen, until more data is available.Note: Always attempt to limit potential issues thathave not yet been determined (e.g., protect the productfrom light unless sure of no impact; store activesand finished product under conditions that are certainnot to be of any issue until data are available todemonstrate storing under normal room temperatureis adequate).

The safety necessary to start Phase I clinical studiesis determined by the preclinical/toxicology studies. Thematerials and formulation used in the preclinical/tox-icology studies should be similar in purity. One of thechallenges in using a single formulation is the fact thatyou may need to dose small animals with 5 to 100 timesthe dose/kg of body weight to see toxicity and allow for asafety margin. The lyophilized formulation allows forflexibility in reconstitution which lets one prepare amore concentrated solution for dosing animals.

Manufacture of early-stage clinical supplies needsto be made in a facility that adheres to cGMPs withQuality Systems in place and excellent past regulatoryhistory. High-speed filling equipment is rarely warrantedduring early-stage manufacturing. Terminal sterilizationshould be the first choice if possible. Data need to beavailable if terminal sterilization is not aviable alternative.

Use of disposable technologies (e.g., plastic tanks,bags, etc.) fits well with potential potent and hazardouscompounds that are not highly defined in the early stagesof development. Product containment using disposablesreduces the cleaning validation requirements but requiresthe need for extractable studies. Sterile drug filter vali-dation studies should use drug product from theconformance batches (Note: Drug product submitted inthe NDA and the conformance batches must be the sameconcentration and formulation).

Batch records can be difficult. Each batch maychange in size, concentration, container/closure andmanufacturing process. A complete history documentingthese changes is critical for preparing documentationfor filing.

VALIDATION REQUIREMENTS UNIQUETO STERILE CTM DRUGS

The intent of this section is to provide regulatory expec-tations of processes utilized in the manufacture of sterile drugsthat must be validated (i.e., IQ, OQ and PQ unless indicateddifferently) and systems/controls in place prior to produ-cing clinical trials for human use.1. Processes and associated equipment that sterilize

and/or depyrogenate drug, components, product

contact equipment and product must be validated(IQ, OQ and PQ) prior to CTM Batches. Someexamples are:a. Steam sterilization

i. Product path componentsii. SIP cyclesiii. Freeze Dryers

b. Terminal sterilization of the producti. Steam Autoclaveii. Gamma radiationiii. Sterile Filtrationiv. Others

c. Depyrogenation of componentsi. Dry heat tunnels/ovensii. Stopper washing (3 log reduction)

d. Sterilization of all equipment and processesassociated with product and product contactsurfaces (e.g., tanks, fillers, stoppering)

e. Utilities (e.g., WFI, pure steam, air/nitrogen andclean rooms)

f. Special equipment and sterilizing systemsi. Isolatorsii. Hydrogen peroxide sterilizationiii. Chlorine dioxide sterilizationiv. Others

2. Drugs, chemicals and excipients tested per Endotoxinspecifications. Bioburden specifications should alsobe in development.

3. Filter validation Phase I–IIa. WFI soluble products can initially use WFI

BP/forward flow results prior to and aftersterile filtration. Prior to post-filtration integritytesting the filter should be purged (i.e., cleanedusing WFI). Double filtration provides anadditional assurance.

b. Recommend that Phase 3 product used validatedproduct BP/forward flow results (i.e., final drugproduct BP to be filed for NDA).

c. Validation PQ batches should not begin untilfilter validation data is available.

4. Analytical test methods are required prior to firstCTM batch to verify cleanliness.

5. Media fills:a. The first media fill demonstration batch is

usually used to test the integrity of thecontainer closure.

b. If the container closure is new to the filling line(e.g., different size or closure) the containerclosure requires three media fills unless equi-valence or bracketing can be justify less.

6. Hold times at all stages within the processa. Validation justification as compared to actual

allowance and product records (e.g., in and outof cold rooms for visual inspection; product indelivery systems and verification of potentialvariations in temperatures)

b. Process hold times and ramps (e.g., freezedrying)

7. Environmental monitoring room validation: Environ-mental validation of the room and associatedfilling/processing equipment in static and dynamicconditions is expected. Data should include smokevideos which can be used as training aids foraseptic processing.


8. EM Training and Qualification of Operators/Staff:Verification of personnel training to not adverselyaffect the sterility of the batch during normalrun conditions.

VALIDATION REQUIREMENTS UNIQUE TO PLASMA/BLOOD PRODUCTS AND BIOLOGICALS

Blood/plasma and biological products while having thehigher level of regulatory requirements associated withsterile drugs; require additional verifications and controlsto ensure the public is protected. The following areexamples that are typical of these products.

Plasma/Blood Products Special Areas of Attentionand/or Validation

1. Process steps used for viral inactivation/removal(e.g., filtration, pH adjustment, chromatography,etc.) (9)a. Log reduction of clearanceb. Specific viral testing performed

2. If from blood or blood components:a. Certification that donors have met FDA blood

donor requirementsb. Materials have been screened per FDA blood

product material requirements3. For contract manufacturing/filling. Lots received

should include COA that states the following havebeen tested:a. Adventitious viral agentsb. Mycoplasma (culturable and nonculturable)

Biotechnology Protein Manufacturing

1. Changes in the manufacturing process shouldinclude a CEa. An effect on efficacy and/or safety might be

expected or cannot be ruled out.b. Need to justify that the change in the manufac-

turing process will not effect efficacyand/or safety.

c. If amodification of the product is detected duringthe CE it may indicate the need for further precli-nical and/or additional clinical data.

d. Potential for altering the profile and ratio of theimpurities. The biological impact of changesshould be considered prior to adminis-tration in humans.

2. Storage and Shipment (e.g., shipment, receipt, coldroom storage, cryogenic/frozen product storage,thawing, and product delivery system/fillingprocess temperature control)—Validation of Storageand Handlinga. Require significant controls/validation to ensure

the proper in-process control.b. When batches are scaled up this also requires

attention in the CE.3. Process validation should include a Risk Assessment

to ensure all parameters/controls have beenconsidered in the overall Validation Master Plan.a. A quality risk assessment would review all

unit operations/processes (flow chart of total

operation from materials received throughproduct shipment) that may affect the productsidentity, strength, quality and purity. Included inthis risk assessment should be an understandingof the impact of process variables (e.g., tempera-ture, mixing speed, process time, flow rates,column wash volume, reagent concentrations,and buffer pH) and developing alert andaction limits.

b. A thorough knowledge of the processing steps ofall ingredients when supplied by others is critical.Changes to their processes/equipment/formula-tion, etc., should have impact underchange control.

VALIDATION REQUIREMENTS UNIQUE TONASAL PRODUCTS (TABLE 1)

Nasal products provide a less invasive method of admin-istration than injectables and patients are more willing touse them when compared to self-injection. While it is aneasy alternative to the patient, it is a very complex anddemanding process requiring significant understandingof the associated development, processing and controls.This is a developing area of Validation with expectation ofcontinuing new advances in products, drug deliverysystems, processing operations, environmental require-ments, and of course regulation.

With delivery systems to the lungs or to the nasalmucosa including:& Aqueous-based oral inhalation& Pressurized metered inhalers& Dry powder inhalers

Table 1 Tests for Inhalation vs. Nasal Products

Inhalation products Nasal products

Single dose fine particle mass Demonstrated deposition is

localized in the nasal cavity

Individual stage particle

distribution

Droplet formation—particle

size distribution and full

characterization of the

product

Droplet size distribution and

drug output

Initial priming of container

Re-priming of the container

Compatibility

Effect of moisture

Safeguards to prevent multiple

dosemetering of dry powder

inhalers

Breath-activated devices—

data provided to

demonstrate all target

groups capable of triggering

the device

Dry powder inhaler reservoir

systems need a count

indication for when the

number of actuations

indicated have been

delivered

Note: This table is provided to describe some regulatory difference in expec-tations for each dosage form.


& Products for nebulization& Metered-dose nebulizers

1. Inhalation Sprays are intended for delivery to thelungs and contain therapeutically active ingredientsand excipients. The use of preservatives or stabilizingagents is discouraged. Aqueous-based oral inhala-tion-based drug products are required to bemanufactured sterile (21 CFR 200.51). Manufacturersmust also comply with 211.113(b) which requiresthem to establish and follow written proceduresdesigned to prevent microbiological contamination,including validation of any sterilization processes.

2. Nasal spray products and pressurized metered-doseinhalers are designed to apply sprays to the nasalcavity and therefore are not subject to this rule forsterilization (6).

3. Unique validation/testinga. Particle size test and limits

i. Validated multipoint particle sizingmethod (e.g., laser diffraction)

ii. Acceptance criteria to assure consistent sizedistribution in terms of total particles in agiven size range

iii. Acceptance criteria set based on theobserved range of variation and shouldtake into account the particle distributionof batches that showed acceptableperformance in vivo, aswell as the intendeduse of the product

iv. If alternate sources of drug substance areproposed evidence of equivalence shouldinclude appropriate physical character-ization and in vitro performance studies

b. Development tests conductedi. Minimum fill justificationii. Extractable/leachablesiii. Delivered dose uniformity/particle mass

through container lifeiv. Shaking requirementsv. Actuator dispositionvi. Low-temperature performancevii. Cleaning requirementsviii. Performance and temperature cyclingix. Physical characteristicx. Robustnessxi. Preservative efficacy

The above information is a brief sampling of all thevalidation and operational needs of each type of nasal-type product. Please refer to the FDA and EU guidelinesfor more specific information. These products are oftenunique with the product and corresponding deliverysystem defining what needs to be validated andcontrolled during the manufacturing, filling, storage,testing and distribution of these products (10–13).

CONCLUSION

The intent of this chapter on Clinical ManufacturingValidation was to provide an understanding of what isneeded anda logical sequence of events required to bring aproduct through the regulatory process. In support ofthese objectives various points to consider in under-standing the validation needs and roadmap are provided.

This will become even more important as the newdrugs/drug delivery systems become more integratedmaking it harder to understand the differences betweendifferent drugs as new technologies become reality.

Note: Significant regulatory activity is in progressas this chapter was being developed. So expect furtherchanges in regulatory expectations.

APPENDIX A

Clinical Batch Verification Protocol (Phase 1)PurposeThe purpose of this Process Verification Protocol is toprescribe the testing to be performed as it will apply to abatch intended for clinical trial use.

Procedure

1. Protocol contentThe protocol may contain the following sections:a. Product information (name and strength)b. Protocol approval signaturesc. Reference documents (a listing of any and all

documents to be cross-referenced such as,but not limited to, analytical standards, develop-ment or scale-up reports, SOPs and engineeringstudies)

d. A statement of purpose for the testing describedin the protocol

e. Rationale for the sampling plan and the accep-tance criteria for the tests

f. Description of the equipment and the processg. Critical process steps to be verified by the testing

i. For solids: includes but not limited to,blend time, mill speeds, and screen sizes.

ii. For sterility: includes but not limited to,temperatures, dissolution time, mix speed,dissolved oxygen, pH, density, andosmolality.

iii. For lyophilized products: residual moistureafter cycle.Other attributes to be tested in process

are prefiltration bioburden and endotoxins.h. Test functions: Based on knowledge from

development and scale-up, a list of processsteps which are to be tested should be listed.Each test function should show the acceptancecriteria based on development work along with arationale for that criteria.

i. Test criteria: A description of sampling includingsample size, location, number of samples alongwith a rationale for these.Note: For blend samples, sample size will be a

weight equivalent to 1 to 3 dosage units.j. The verification protocol will specify samplingmethods and tests. Test data will be attached, andthe document will be approved certifying that allacceptance criteria were met. Unless specified bythe client, theminimum testing is listed in Table 2.This verification will be performed on a batch-

by-batch basis. The data will be summarized andincluded in a final package with the approvedprotocol.


k. Results: Assemble the results, write an analysisand conclusion and assemble the final package.The analysis and conclusion will state whether ornot the test results met the acceptance criteria. Ifthe acceptance criteria are not met, a full expla-nation is required.

l. Routing for Approval: The finished package isattached to the batch record and routed forapproval to the same individuals who approvedthe protocol initially.

This protocol is presented as an approach to satis-fying the expectations of the FDA that an individual batchmeets all its specifications (14).

APPENDIX B

Contract Manufacturing Requested Product Infor-mation (15) (Information Needed to SupportProduction and Stability)

1. Product classification: Examples: Diluent, smallmolecule pharmaceutical, fermentation derived, cellculture derived, cytoxic, anti-infective

2. Status (Phase 1, Phase 2, Phase 3, Commercial)3. Registered by: FDA (CDER, CBER, CDRH, CVM),EMEA, or others

4. Timetable by phase5. Type of service needed

a. Aseptic manufacturingb. Aseptic fillingc. Lyophilizationd. Validation

i. Analyticalii. Equipmentiii. Process

e. Stability studiesf. Labeling and packagingg. Regulatory

6. Analytical: types of methods needed or supplied forexample:a. HPLCb. GCc. Karl Fisher moisture analysisd. Oxygen headspace analysise. TLCf. Optical rotationg. UV/visualh. pH (provide range)i. Specific gravityj. Infrared spectrophotometerk. Lowry protein determinationl. PNUm. SDS-PAGEn. RIDo. PAG isoelectric focusingp. ELISAq. Others

7. Microbiologicala. Bioburden determinationb. USP particulate testingc. Bacteriostasis/fungi stasis Validationd. Bacterial and fungal identificatione. Endotoxin (gel-clot method)f. Sterility testingg. USP antimicrobial preservative effectivenessh. Container closure Integrity test (microbial

ingress)i. Others

8. Raw material specifications9. Storage Conditions for bulk, in-process, on-test, ship-ping and associated validation

10. Formulation requirementsa. Aseptic additions required?b. Batch documentationc. Special equipment and the need for dedication

i. Disposable processingii. Tanksiii. Mixing/recirculationiv. Filling requirementsv. Temperaturevi. Light protectionvii. Inert gas blanketingviii. Product density and viscosityix. Special process or techniquesx. Product incompatibility

d. Handling Precautionse. Product and API material safety data sheetsf. Disposal requirements

11. Componentsa. Presterilized and cleaned?b. Validation requirements?c. Specificationsd. Surface treatmente. Manufacturerf. Stopper

i. Typeii. Silicone treatment/limits

g. Closure12. Filtration and filling

a. Aseptically filled or terminally sterilizedb. Filter

i. Single or redundant

Table 2 Minimum Testing Requirements

Process stepSampling(minimum) Tests

Non-sterile Solid

Dosage

Initial Blend Top, middle, bottom

of container

Assay (for blend

uniformity)

Final Blend Top, middle, bottom

of container

Assay (for blend

uniformity)

Compressing or

capsule filling

Beginning, middle,

and end of run

Content uniformity,

assay,

dissolution,

dosage unit

weights

Sterile Products

Initial

Compounding

Top, middle, bottom

of mixing vessel

Assays, density, pH,

osmolality

Filling Beginning, middle

and end of fill

Assays, oxygen in

headspace, fill

weights

Lyophilizing or

terminal

sterilization

Beginning, middle,

end of load

Assay, moisture,

reconstitution

time, pH, oxygen

in headspace


ii. Validation of integrity testiii. Sterilization validation

c. Filleri. Type of filling pumps required& Positive displacement

& Rolling diaphragm& Ceramic pumps& Stainless Steel pumps& Glass& other

& Time–pressure fillii. Sterilization validation of unique itemsiii. Fill weight testing/validationiv. Container abuse studiesv. Others

& Nitrogen overlay required?& Headspace analysis required?& Protection from light?& Temperature requirements

d. Inspection and labelingi. 100% visual inspectionii. Automatic inspection for:

& Headspace volume (fill level)& Particulate& Container integrity& Bulk vial identity

iii. Labels13. Process Validation

a. Microbial filter retention studyb. Media fillsc. Terminal sterilization cycle developmentd. Cleaning verificatione. Mixing verificationf. Fill homogeneityg. Others

14. Lyophilizationa. Cycle development

i. Time/temperature limits between fillingand loading

ii. Nitrogen or inert gas purge during cycleiii. Ramp rate during coolingiv. Ramp rate during heatingv. Product loading temperature and

cycle rampsvi. Product pressure limits during cycle

based on critical pointsvii. Eutectic and/or collapse pointsviii. End-product moisture requirementix. End-point pressure (full vacuum vs.

partial vacuum)

x. Have you seen issues with powder onshelves after development cycles?

xi. Stopper tested to ensure it does not stickto shelf after stoppering?

REFERENCES

1. SpataroME, Bernstein DF. Managing clinical trial materials:investigational product change control. Pharm Tech 1999;23(10):144–50.

2. Pharmaceutical Engineering Guides for New and Reno-vated Facilities. Commissioning and Qualification. Vol. 5.Tampa, FL: ISPE, 2001:83–99.

3. Guideline on General Principles of Process Validation.Washington, DC: Center for Drugs and Biologics andCenter for Devices and Radiological Health/Food andDrug Administration, 1987.

4. Guidance for Industry, Powder Blends and FinishedDosage Units—Stratified In-Process Dosage Unit Samplingand Assessment (Draft). Washington, DC: Center for DrugEvaluation and Research (CDER)/Food and Drug Admin-istration, 2003.

5. FDA Guidance for the Industry, Preparation of Investiga-tional New Drug Products, March 1991.

6. EMEA Guideline on the requirements to the chemical andpharmaceutical quality documentation concerning investi-gational medicinal products in clinical trials, November,2004.

7. Annex 13: Manufacture of Investigational MedicinalProducts, EMEA document dated July 1, 2004.

8. FDA Draft guidance/6672, Q8 Pharmaceutical Develop-ment, dated 2/7/2005.

9. EMEA Guideline on assessing the risk for virus trans-mission. New chapter 6 of the note for guidance onplasma derived medicinal products, November, 2004.

10. EMEA Draft Guideline on the pharmaceutical Quality ofInhalation and Nasal Products, dated July 30, 2005 for endof consultation.

11. FDA Guidance for Industry, Sterility Requirements forAqueous-Based Drug Products for Oral Inhalation.

12. CDER Guidance for Industry—Sterility requirements foraqueous based drug products for oral inhalation—smallentity compliance guide, November, 2001.

13. CDER Guidance Document – Nasal Spray and InhalationSolution, Suspension and Spray Drug Products: Chemistry,Manufacturing and Controls Documentation, July 2002.

14. Hartman BW, Motise P J. Human Drug CGMP Notes.Washington, DC: Center for Drug Evaluation and Research(CDER)/Food and Drug Administration, 1999.

15. Contract Manufacturing Requested Product Information-provided by Hollister Stier Spokane Washington.


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