cGMP in the USA - Pharma Manufacturing · PDF file» Points to inspect » Laboratory support » Regulatory approaches. cGMP Implementation Tools cGMP Implementation Tools • cGMP

FDA cGMPChina

Training Program

December 5-7, 2005Ying Jie Convention CenterBeijing University Beijing

FDA FDA cGMPcGMPChina China

Training ProgramTraining Program

December 5December 5--7, 20057, 2005Ying Jie Convention CenterYing Jie Convention CenterBeijing University BeijingBeijing University Beijing

cGMP in the USANicholas BuhayDeputy Director

Division of Manufacturing & Product QualityOffice of Compliance, CDER, FDA

Introduction toDrug

Current Good Manufacturing Practice Of US FDA

An OutlineAn OutlineAn Outline

• Legal bases for cGMP

• cGMP legal principles

• cGMP Implementation Tools

• cGMP Resources

• Overview of cGMP Requirements

• Integrity of Records and Data

FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)

“A drug shall be deemed adulterated if:... the methods used in, or the facilitiesor controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice ...”

more...

FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)FD&C Act; 501(a)(2)(B)

“to assureassure that such drug meets the requirements of this Act as to safetyand has the identity and strength, and meets the quality and puritycharacteristics, which it purports or is represented to possess.”

cGMP legal principlescGMPcGMP legal principleslegal principles

• Quality built into product– By “taking care” in making

medicine– Can’t ‘test’ into product the quality

• Without/Inadequate cGMP– Product(s) adulterated(defects

need not be shown)– Firm and its management are

responsible


• Non-compliance = eventual problems

– Superpotency/subpotency

– Contamination

– Misbranding

– Bioavailability

– Safety and efficacy

cGMP Legal PrinciplescGMPcGMP Legal PrinciplesLegal Principles

• Scope– Ingredients (APIs + excipients)– Finished dosage forms administered

to humans/animals»OTC, Rx products»Biologics, veterinary drugs»Drugs undergoing study(IND, etc)

– Manufacturers, test laboratories, packagers(including pharmacies)


• Excluded from the cGMPrequirement

– Positron emission tomography, per FDAMA (own cGMP to be developed)

– Drug products compounded per Section 503 Pharmacy Compounding (FDAMA)


• Current = dynamic

– Standards evolve over time

• Good practices

– Minimal standards

– Not “best practices”

» Unless “best” is, in fact, current minimal


• Feasible and valuable

– No threshold for “percentage” in practice

»Doesn’t have to be “predominant”

– Enforceable even if nobody is doing it

»Stronger case if someone is doing it

The cGMP RegulationThe The cGMPcGMP RegulationRegulation

• cGMP for Finished Pharmaceuticals 21 CFR 210, 211– First issued: June 1963– Today’s version: September 1978– Scope

»Dosage forms for human/vet/biologics»OTC, Rx, IND, NDA, Medical Gases»Not: pharmacies, ingredients, non-

clinical research, etc


• cGMP for Finished Pharmaceuticals 21 CFR 210, 211

– Substantive

» Force and effect of law

– Constitute major part of (not entire) cGMP

more...


• cGMP for Finished Pharmaceuticals 21 CFR 210, 211– Establish “what to” do, not “how to” do

»Minimal standards »Maximum flexibility»Specific enough to address

problems• e.g., Penicillin contamination

control»Technology neutral»Scalable

cGMP Implementation Tools

cGMPcGMP Implementation Implementation ToolsTools

• Compliance Policy Guides– Specific actions we do related to cGMP– Examples:

» Sub Chapter 410 Bulk Drugs• The regulations for finished

pharmaceuticals will be applied as guidelines for bulk drugs

» Sub Chapter 420 Compendial (USP)/Test Requirements Ex:USP not required for release test

» Other Sub Chapters• Labeling and Repackaging• Stability/Expiration• Process Validation• Etc



• cGMP Guidance Documents– Principles:

»Not requirements»Agency “current thinking”»Detailed, technical»Expression of “How to” meet “what

to” do (requirements)– Shape industry behavior

»offers routes to efficiency in meeting cGMP requirement, evaluation of compliance



• cGMP Guidance Documents (Examples)– General Principles of Process

Validation– Compressed Medical Gases– Sterile Drug Products Produced by

Aseptic Processing– Guideline on the Preparation of

Investigational New Drug Productsmore...



• cGMP Guidance Documents

– Investigating Out of Specification Test Results for Pharmaceutical Production

– Manufacturing, Processing or Holding of Active Pharmaceutical Ingredients



• cGMP Compliance Programs –Instructions to FDA inspectors

– Drug Manufacturing Inspections Program

» Systems-based assessment of site

– Preapproval Inspection Program

» Points to inspect

» Laboratory support

» Regulatory approaches



• cGMP Guides to Inspection of….

– Help field investigators apply cGMP

»Uncover need for cGMP changes

»Specific to topics (e.g., cleaning validation)

cGMP ResourcescGMPcGMP ResourcesResources

• Internet WWW site by DMPQ– http://www.fda.gov/cder/dmpq

»cGMP regulations and ongoing changes

»Preamble to the cGMP regulation»Division subject contacts»Medical gases»Active pharmaceutical ingredients»Human Drug cGMP Notes/Policy»etc.

Overview of cGMPrequirements in the

regulation

Overview of Overview of cGMPcGMPrequirements in the requirements in the

regulationregulation• cGMP Regulations

– 21 CFR 210» Status of the regulations» Applicability of the regulations» Definitions

• Batch• Lot• In-process material• Quality control unit• Representative sample• etc


regulation


regulationregulation

• cGMP Regulations– 21 CFR 211

» Subpart A General Provisions» Subpart B Organization an Personnel» Subpart C Buildings and Facilities» Subpart D Equipment» Subpart E Control of Cmpnts/Cntr/Closures» Subpart F Production and Process Controls» Subpart G Packaging and Labeling Controls

more...


regulation



– 21 CFR 211

»Subpart A General Provisions

•this is minimum cGMP


regulation



– 21 CFR 211

»Subpart B Organization and Personnel

• There shall be a quality control unit

• quality control unit responsibility to approve/reject

Overview of cGMPrequirements

Overview of Overview of cGMPcGMPrequirementsrequirements


» Subpart C Buildings and Facilities• buildings shall be….suitable• operations to be in specifically defined

areas….separate…. Or such other control systems for ….operations as are necessary to prevent contamination or mix-ups…. (see list, includes aseptic processing)

• “separate” facilities for penicillin• building….shall be….clean and sanitary



• cGMP Regulations

– 21 CFR 211

»Subpart D Equipment

• surfaces ….shall not be reactive, additive, or absorptive

• Equipment….shall be cleaned, maintained and sanitized….




» Subpart E Control of Components, Containers and Closures

• containers and closures ….handled in a manner to prevent contamination.

• Testing or examination of c/c/c’s• test to identify each component• tests on components for conformance with

specs• test c/c/c’s microscopically, for

adulterants, microscopically




» Subpart F Production and Process Controls• written procedures for production and

process control• formulated not less than 100 %• portions of components identified,

examined by a 2nd person before dispensed for use in manufacture

• sampling and testing of in-process materials and products, some specified

• time limits• reprocessing allowed, but controlled




» Subpart G Packaging and Labeling Controls• examination, approval of labels, labeling• strict control over labeling issue, and

return to stock• written procedures, physical separation of

labeling operations• examination of materials before use• inspection of facilities immediately before• tamper resistant packaging (for OTC

products)• expiration dating




– 21 CFR 211

» Subpart H Holding and Distribution

» Subpart I Laboratory Controls

» Subpart J Records and Reports

» Subpart K Returned and Salvaged Drug Products




– 21 CFR 211

»Subpart H Holding and Distribution

• quarantine before release

• store under appropriate conditions




»Subpart I Laboratory Controls• establish specs, standards,

sampling plans, test procedures• calibration, of laboratory equipment• test each batch of drug product• adequate acceptance criteria• validate test methods• conduct stability program

more....




» Subpart I Laboratory Controls• Special tests

– sterility and pyrogenicity– ophthalmic ointments for

foreign/abrasive particles– controlled release products for rate of

release• keep reserve samples• test non-penicillin products for penicillin

when reasonable possibility of exposure to presence of penicillin




»Subpart J Records and Reports• keep records, make available for

inspection• conduct annual review of each drug

product for changes to specs, control procedures

• keep equipment cleaning and use log

• keep component, container, closure and labeling records more....




» Subpart J Records and Reports• have SOP for master production and

control record, maintain record• use batch production and control records

for manufacture, keep records• records to be reviewed/approved by qual

control unit• complete data derived from all tests

necessary to assure compliance

more....




– 21 CFR 211

»Subpart J Records and Reports

• distribution records, with lot numbers(except medical gases)

• complaint files

Problem

– Drug Regulatory Program depends heavily on the reliability (i.e. truthfulness, completeness and accuracy) of data & information in records

– Applications for approval [AIP]

– Manufacturing Controls documentation [non-AIP]

– Historical experience with broad scale unreliability of data in records or in conduct related to records

Data and records that are not acceptable or

are misleading

Data and records that Data and records that are not acceptable or are not acceptable or

are misleadingare misleading

What are some characteristics of data that lack integrity?

» Untrue, made up, false, no source in an event

» Omission of significant data from the submission that is determined to be material to the review process. Data that is not submitted, but should have been

» Inaccurate (e.g. First data failed specs, retest data passes specs, no lab investigation, but retest data is submitted to the application.)

Records Must be TrueRecords Must be TrueRecords Must be True

• All data and information in records submitted to FDA & supporting documents in the possession of the applicant are accurate & true representations of –

– Actual tests performed & the test results

– Actual manufacturing & quality control steps & procedures associated with the development and manufacture of the submission batch (clinical/pilot or biobatch)

– any other actions and conditions associated with the application

Wrongful Acts

Any act or conduct that subverts the integrity of the review process, including, but not limited to the following:

– submitting fraudulent applications

– offering or promising a bribe or illegal gratuities

– making an untrue statement of a material fact (e.g. false statement, a misstatement or an omission of a fact)

– submitting unreliable data which results from system-wide or firm-wide behavior

Wrongful Acts (continued)

An untrue statement of material fact is a false statement, a misstatement or an omission of a fact that is important in the review process.

System-wide incompetence is also a wrongful act

When an untrue statement of material fact or system-wide incompetence is found, several steps are required to the invoke the AIP including:

– Documentation of a pattern or practice of wrongful acts.

– Ensuring that the untrue statements are material facts.

Pattern or Practice

Pattern- More than one instance of errors or acts involving the subject matter important to the evaluation of an application

Practice- An act or process of doing something affecting subject matter important to the evaluation of an application

A practice can be one or more acts or processes. A pattern or practice can occur in one or more applications.

If submitted to an Application

The AIP procedures broadly define the term, “application” to include, but not be limited to, any application, amendment, supplement or other submission made by an applicant.

“Submitted” is an understandable term and includes documents received by the review branch.

Wrongful acts also include omissions of data and/or information that should have been submitted to an application.

Food, Drug, and Cosmetic ActSection 505(e) (excerpt below)

Numbered Part 5

– The Secretary shall, after due notice and opportunity for hearing to the applicant,withdraw approval of an application with respect to any drug under this section, if the Secretary finds….

– (5) that the application contains any untrue statement of a material fact

TO INVOKE AIP

Documentation of a pattern or practice of wrongful conduct that raises significant questions about the reliability of data submitted to an application

- wrongful acts

- pattern or practice

- unreliable data

Restore FDA’s Confidence in Data???

Cooperation with investigators

Identification of involved individuals

Credible internal review & actions

Problem analysis/identify all instances of wrongful acts

Use of impartial auditor/Outside consultant

Audit Plan, audits, audit reports

Other measures as FDA deems appropriate

Restore FDA’s Confidence in Data

Corrective Action Operating Plan:

Analysis of audit findingsImplementation of auditor recommendationsActions taken to correct fraud/wrongful acts, e.g.Withdraw applications & recall products TimetableIdentification of persons assigned to complete and verify corrective actionsComprehensive ethics programProcedures for monitoring effectiveness of the planTraining in the requirements of the Act and 18 USC 1001

Corrective Actions Plan Evaluation

Monitor applicant’s actions/inquiries during internal review

Inspection to assess actions taken by applicant to determine if

Internal Review performed adequatelyCorrective Action Operating Plan

implemented adequatelySubmit recommendation to CDER to remove site from the policyExpect a long time to pass before restoration




»Subpart K Returned and Salvaged Drug Products

• if conditions cast doubt returned product shall be destroyed unless proved ok by test, examination, investigation

• salvage only if evidence from tests and inspection show all standards met

Input for cGMP ChangesInput for Input for cGMPcGMP ChangesChanges

• Establishment inspections– Industry changes/problems

• Defect reports/complaints/recalls• Litigation• Agency application reviews• Trade/scientific literature• Citizen petitions

Management of cGMPRegulatory Program

Management of Management of cGMPcGMPRegulatory ProgramRegulatory Program

• FDA/CDER– OC/Division of Manufacturing

and Product Quality– maintenance of the regulation– definitive interpretation– manage guidance development– develop, operate, evaluate

programs – train FDA/outreach to industry

We Have DiscussedWe Have DiscussedWe Have Discussed

• Legal bases for cGMP

• cGMP legal principles

• cGMP Implementation Tools

• cGMP Resources

• Overview of cGMP requirements

• Integrity of Records and Data

Montrose Metro Centre II Room 43811919 Rockville PikeRockville, MD 20852

Nicholas BuhayDeputy Director

Division of Manufacturingand Product Quality, HFD-320

Center for Drug Evaluation and Research

Phone: 301-827-8940 Fax: 301-827-8907E-mail: [email protected]

FDA CGMPChina

Training ProgramDecember 5-7, 2005

Ying Jie Convention CenterBeijing University Beijing

Counterfeit DrugsNicholas Buhay

Deputy DirectorDivision of Manufacturing & Product Quality

Office of Compliance, CDER, FDA

2

Counterfeit Drugs

• Not permitted:– Doing any act to cause a drug

to be a counterfeit– Sale or dispensing a counterfeit– Holding for sale or for

dispensing a counterfeit

3

Counterfeit Drugs• A drug, or container or labeling of

it, that falsely represents the drug to be– To be the product of another

manufacturer, processor, packer, or distributor

– To have been packed or distributed by another manufacturer, processor, packer, or distributor

4

Counterfeit Drug

• Not permitted: Why????

– Product lacks assurance of safety and efficacy

5

Counterfeit Drug

• Assurance of Safety and Efficacy results from– Knowledge of the pedigree (heritage) of

the shipment– Opportunity for regulatory attention to

confirm• Inspection of conditions and practices in

manufacture• Samples and tests• Review of information

6

Unapproved Drugs

• In USA, components (API + non-active ingredients) are specified by source factory in the approval of a new drug application (NDA or ANDA)

• Sometimes, also precursor chemicals are specified by source factory

7

Unapproved Drugs

• The use of other materials different from materials from the specified source factory may be counterfeiting, but

• Definitely the product made is an ‘unapproved new drug’

8

Example:

• Tablets look like ‘Viagra’ but

• Tablets not manufactured, processed or distributed by manufacturer approved by FDA

9

Example

• Acetaminophen API made by factory in Milan but,

• Label says product made by factory in Beijing

10

Example

• Buspirone API made by factory in India and,• Tablet manufacturer in USA uses the

buspirone API to make buspirone tablets but,

• Manufacturer’s FDA approved Abbreviated New Drug Application (ANDA) specifies tablet manufacturer must use only buspirone made by factory in Canada

11

Example

• Importer in New York buys methylphenidate made in factory in Guangdong and,

• Puts it into different drum labeled with name of factory in South Africa– Also, puts C of A data onto South Africa factory

letterhead document

12

Example

• The government of Russia orders Captopril Tablets to be made in a factory in Ireland and,

• A multinational company operated factories in Ireland and in Puerto Rico and,

• Captopril Tablets made in Puerto Rico factory of the company are shipped to Russia to fill the order

13

Example

• A company in China operates two factories, one in Shanghai and one in Tianjin, and,

• The factory in Tianjin is approved in an ANDA by FDA as source factory for cefuroxime but,

• The company sells cefuroxime made in the Shanghai factory for use in making the approved drug tablets– The company writes batch records showing

manufacture of this cefuroxime in the Tianjin factory

14

Example

• A multinational company operates factories in France and Italy; an FDA approved ANDA approves total synthesis of cefaclor in the Italy factory, but

• The company orders the factory in France to make a specified precursor and sends it to the Italy factory and,

• The Italy factory uses the precursor to complete the synthesis of cefaclor

• Italy factory sends cefaclor to USA– Italy factory makes batch records showing

complete synthesis

15

??Problem: Complex distributiona

• API source factory to• Trader (s) to • Importer to• Finished Pharmaceutical

Manufacturer• Carriers

16

??Solution

• Limit distribution system?• Markers?• Characterization/Identification?• Maintain ‘pedigree’?

17

Pedigree

• Process specific• Lot specific• Shipment specific

18

Pedigree

• Documentation– Batch records– Labels– Certificate of Analysis– Sales– Shipping– Declaration (Gates)– Receipt– Storage– Use

19

Pedigree

• Modern Technology– Packaging– Shipping– Electronics

20

Summary

• Counterfeiting of products are– Manufactured under unknown conditions and

practices– Manufactured with unknown process– Undesirable product event (adverse reaction,

product defect, etc) cannot be resolved

• Regulatory oversight process is undermined

• Loss of assurance

21

Concern validated

• Actual event:– Haiti 1996– Contaminated “Acetaminophen Syrup”

product• 3% Glycerin• Water, sugars• 14% Ethylene glycol (engine antifreeze)

• 80 children died

22

Concern validated

• Source of contamination– “Synthetic Glycerin” component

material– Used by Haiti manufacturer factory– Importer in Haiti– Trader in Netherlands (applied label to

read ‘Glycerin USP’– Trader in China– Manufactured in China (factory

unknown)

23

??Cause

• Manufacturer?• Trader (s)• Importer?• Terror??

24

FDA Approach to Thwarting Counterfeiting

Multi-Pronged Approach• Technology• State and Federal Regulatory

Action• Secure Business Practices• Education and Reporting• International Collaboration

25

Technology

• Authentication Technologies• Track and Trace Technologies

• No magic bullet – must use layered approach

• Technology alone probably insufficient without secure business practices

26

Authentication Technology

• Inks, Holograms, Taggants etc.• FDA recommends use of one or

more on products/packaging, particularly those likely to be counterfeited

• Manufacturers to use on a product specific basis after doing a cost/benefit analysis

• No requirements for any particular technology

27

Track and Trace Technology

Requires:• Mass Serialization• Infrastructure – hardware and

softwareCan be accomplished with:• Radiofrequency Identification

(RFID) Technology • 2D Bar Codes

28

Conclusion

Counterfeit Drugs will be an ongoing problem

• Sophistication

FDA’s multi-pronged approach will make deterring and detecting counterfeits more feasible

• Layered approach

29

Conclusion

• Don’t counterfeit• It is a social threat• It is a business threat• Participate in development of

distribution integrity

30

Conclusion

• We must protect our children, our sick, our revered elders

• We will be watching• We will appreciate your help

FDA FDA cGMPcGMP InspectionsInspectionsPeking University 2005Peking University 2005

Robert C. Horan, PhDRobert C. Horan, PhDFDA Pharmaceutical InspectorateFDA Pharmaceutical Inspectorate

New York DistrictNew York District

FDA InspectionsFDA Inspections

Periodic (biennial) comprehensive Periodic (biennial) comprehensive cGMPcGMP

PrePre--Approval Inspection(PAI)Approval Inspection(PAI)

““For causeFor cause””

Inspection may involve more than one Inspection may involve more than one assignment and will verify corrections to assignment and will verify corrections to previous inspections.previous inspections.

All inspections cover All inspections cover GMPsGMPs

Foreign Inspections by Foreign Inspections by Country in FY 2004Country in FY 2004

India14%

Germany14%

Italy10%

China7%

United Kingdom7%

Canada7%

France5%

Japan5%

Switzerland4%

Spain4%

Ireland4%

Others19%

ForeignForeign Inspection in FY 2004 Inspection in FY 2004 by Firm Typeby Firm Type

API51%

Dosage27%

Intermediates10%

Control Lab2%

Both API and Dosage9% Micronizer

1%

FDA FDA cGMPscGMPs for 21for 21stst Century Century InitiativeInitiative

Announced 8/2002Announced 8/2002; ; objectives includeobjectives include::

Encourage adoption of new technologiesEncourage adoption of new technologiesPromote industry use of modern quality system Promote industry use of modern quality system approachesapproachesEncourage riskEncourage risk--based approaches which focus based approaches which focus on critical elementson critical elementsEnsure FDA review, compliance and inspection Ensure FDA review, compliance and inspection policies based on statepolicies based on state--ofof--art pharmaceutical art pharmaceutical sciencescience

FDA FDA cGMPscGMPs for 21for 21stst Century Century InitiativeInitiative

Systems Based InspectionsSystems Based Inspections

RiskRisk--Based Approach to Manufacturing and RegulationBased Approach to Manufacturing and Regulation

Pharmaceutical InspectoratePharmaceutical Inspectorate

PAT Guidance document/ PAT TeamPAT Guidance document/ PAT Team

Quality Systems Guidance documentQuality Systems Guidance document

Process Validation (Compliance Policy Guide revised; Process Validation (Compliance Policy Guide revised; Guidance being revised)Guidance being revised)

21 CFR Part 11 Electronic Records Guidance (risk21 CFR Part 11 Electronic Records Guidance (risk--based; geared toward GMP documents)based; geared toward GMP documents)


Cadre of most experienced investigators who are Cadre of most experienced investigators who are dedicated to drug inspectionsdedicated to drug inspections

Intensively trained along with quality reviewers Intensively trained along with quality reviewers and compliance staff in FDA headquarters (HQ)and compliance staff in FDA headquarters (HQ)

Overall goal is to have PI work closely with HQ Overall goal is to have PI work closely with HQ personnel personnel –– more efficiently integrate review more efficiently integrate review and inspection functionsand inspection functions


FDA Review staff, Compliance Officers and FDA Review staff, Compliance Officers and PI candidates attended training modules PI candidates attended training modules which focused on:which focused on:

Current Regulatory ProgramsCurrent Regulatory Programs

Advanced Quality SystemsAdvanced Quality Systems

PAT and Modern Pharmaceutical TechnologyPAT and Modern Pharmaceutical Technology

Risk ManagementRisk Management


Field Investigators (18) from across U.S. Field Investigators (18) from across U.S. make up the Pharmaceutical Inspectoratemake up the Pharmaceutical Inspectorate

Screening process with certification boardScreening process with certification boardCompleted training with HQ personnelCompleted training with HQ personnelOne month detail working with HQ staffOne month detail working with HQ staffLevel III certification (highest level)Level III certification (highest level)Conduct Conduct PAIsPAIs, complex drug inspections, complex drug inspections

Process Analytical TechnologyProcess Analytical Technology

PAT is a system for PAT is a system for designingdesigning, , analyzinganalyzingand and controllingcontrolling manufacturing through manufacturing through ““realreal timetime”” measurements of critical measurements of critical quality attributes of raw and inquality attributes of raw and in--process process materials and processes, with the goal of materials and processes, with the goal of ensuring final product quality.ensuring final product quality.

See See FDA Guidance document on PATFDA Guidance document on PAT


Examples of PAT applications:Examples of PAT applications:

Continuous real time measurements of Continuous real time measurements of content uniformity of tablets during content uniformity of tablets during production (using near Infraproduction (using near Infra--Red)Red)

Near IR measurement of moisture level Near IR measurement of moisture level during API drying process to determine during API drying process to determine actual end of operation for each batchactual end of operation for each batch


A process is generally considered well A process is generally considered well understood when:understood when:

All critical sources of variability are identified All critical sources of variability are identified and explainedand explained

Variability is managed by the processVariability is managed by the process

““Quality cannot be tested into products; Quality cannot be tested into products; it should be builtit should be built--in or should be by in or should be by design.design.””

Process ValidationProcess Validation

Life Cycle ApproachLife Cycle Approach

Process validation Process validation beginsbegins withwith processprocessdevelopmentdevelopment and and continuescontinues beyondbeyond the initial the initial ““validationvalidation”” batchesbatches for as long as product is for as long as product is manufactured/marketedmanufactured/marketed

Sources of critical variability identified and Sources of critical variability identified and controlledcontrolled

Quality System role in maintaining validated Quality System role in maintaining validated state (quality built in; not tested into product)state (quality built in; not tested into product)

Process ValidationProcess Validation

FDA Compliance Policy Guide “Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients CPG 7132c.08”; revision date 12 March 2004

FDA Industry Guideline on Process Validation – currently being revised

System InspectionsSystem Inspections

QualityQuality

Facilities and EquipmentFacilities and Equipment

MaterialsMaterials

ProductionProduction

Packaging/LabelingPackaging/Labeling

Laboratory ControlsLaboratory Controls

Most Common GMP Most Common GMP Deficiencies by SystemDeficiencies by System

–– API/ Dosage Inspections for 2004/5API/ Dosage Inspections for 2004/5

Quality46%

Materials6%

Facilities & Equipment 17%

Packaging and Labeling1%

Production11%

Laboratory19%

““State of ControlState of Control””

Detailed inspection of a system so that the Detailed inspection of a system so that the findings reflect the state of control in that findings reflect the state of control in that system for every product (profile) classsystem for every product (profile) class

If one of the six systems is out of control, the If one of the six systems is out of control, the firm is considered out of controlfirm is considered out of control

A system is considered out of control based on A system is considered out of control based on GMP deficiencies which suggest lack of GMP deficiencies which suggest lack of assurance of quality assurance of quality

Quality SystemQuality System

Quality must be built into the processQuality must be built into the process

Quality is not tested into the productQuality is not tested into the product

Assurance of Quality comes fromAssurance of Quality comes from-- Design of robust process based on thorough Design of robust process based on thorough knowledge of that process and the sources of knowledge of that process and the sources of variabilityvariability

-- Effective Quality System in placeEffective Quality System in place

Role of Management in QSRole of Management in QSManagement is responsible for:Management is responsible for:

Organizational structureOrganizational structure

All ProcessesAll Processes

All ProceduresAll Procedures

Facilities & ResourcesFacilities & Resources

In short, everything to insure product quality, In short, everything to insure product quality, customer satisfaction and continuous customer satisfaction and continuous improvementimprovement

Quality System ResponsibilitiesQuality System Responsibilities

Assures overall compliance with Assures overall compliance with cGMPscGMPs

ReviewReview andand approvalapproval duties forduties for::1)1) Product Quality Reviews (Product Quality Reviews (atat leastleast annuallyannually))

2)2) Complaint reviewsComplaint reviews

3)3) Discrepancy/ failure investigationsDiscrepancy/ failure investigations

4)4) Change ControlChange Control

5)5) CAPA (Corrective And Preventive Action)CAPA (Corrective And Preventive Action)

Quality system Quality system (continued)(continued)

6)6) Reprocess/ ReworkReprocess/ Rework7)7) Validation/ RevalidationValidation/ Revalidation8)8) RejectsRejects9)9) Stability Failures/ Out of trend dataStability Failures/ Out of trend data10)10) Quarantine productsQuarantine products11)11) Documented GMP & Job Related TrainingDocumented GMP & Job Related Training

Laboratory Control SystemLaboratory Control SystemAdequate lab facilities under the Quality Unit which is Adequate lab facilities under the Quality Unit which is independent from Productionindependent from Production

Adequately staffed laboratories (supervisory and bench Adequately staffed laboratories (supervisory and bench personnel)personnel)

Written specifications for raw materials, intermediates, Written specifications for raw materials, intermediates, APIs, labels & packagingAPIs, labels & packaging

Written procedures for sampling, testing, approval or Written procedures for sampling, testing, approval or rejection of materials and for the recording and storage rejection of materials and for the recording and storage of dataof data

Change control for written procedures Change control for written procedures

Method validation/ revalidationMethod validation/ revalidation

Laboratory Control SystemLaboratory Control SystemReference Standards (primary; secondary)Reference Standards (primary; secondary)

Equipment QualificationEquipment Qualification

Calibration: written procedures, schedule, Calibration: written procedures, schedule, documentationdocumentation

Validation and Security for computerized Validation and Security for computerized handling of test results and related data; system handling of test results and related data; system for assuring integrity of all lab datafor assuring integrity of all lab data

Laboratory controls followed and documentedLaboratory controls followed and documented

Laboratory Control SystemLaboratory Control SystemWritten procedure (SOP) covering out of Written procedure (SOP) covering out of specification specification ““oosoos”” resultsresults

Investigation of Investigation of ““oosoos”” results conducted in a results conducted in a timely manner as per SOP and documented timely manner as per SOP and documented (complete records maintained). Conclusions (complete records maintained). Conclusions from from ““oosoos”” investigations documented and investigations documented and corrective actions/ need for addition corrective actions/ need for addition investigation identified and implemented.investigation identified and implemented.

““oosoos”” review included in Product Quality Reviewsreview included in Product Quality Reviews

Laboratory Control RecordsLaboratory Control RecordsDescription of samplesDescription of samples

Identification of method usedIdentification of method used

Raw data for sample/ standard preparation, reagentsRaw data for sample/ standard preparation, reagents

Complete record of all data from testingComplete record of all data from testing

Record of all calculationsRecord of all calculations

Statement of the test results; how compare with Statement of the test results; how compare with established acceptance criteriaestablished acceptance criteria

Signature of the person who performed each test; dates Signature of the person who performed each test; dates tests performedtests performed

Date/ signature of second qualified person who reviewed Date/ signature of second qualified person who reviewed original test records for accuracy, completeness and original test records for accuracy, completeness and compliance with established standardscompliance with established standards

Production SystemProduction SystemTraining (documented; jobTraining (documented; job--related)related)

Master production and control recordsMaster production and control records

Batch production and control recordsBatch production and control records

Change control procedureChange control procedure

Contemporaneous, accurate and complete batch Contemporaneous, accurate and complete batch production documentationproduction documentation

Implementation and documentation of inImplementation and documentation of in--process controls, tests, and examinationsprocess controls, tests, and examinations

Production systemProduction system (continued)(continued)

Adequate Adequate writtenwritten proceduresprocedures & & practicepracticefor chargefor charge--in of materialsin of materials

Identification of equipment with contents, Identification of equipment with contents, stage of manufacturing, statusstage of manufacturing, status

Equipment cleaning recordsEquipment cleaning records

Established time limits for completion of Established time limits for completion of production steps/stagesproduction steps/stages

Production systemProduction system (continued)(continued)

Deviations investigated and documented Deviations investigated and documented contemporaneously with investigationcontemporaneously with investigation

Process validation based on Process validation based on knowledgeknowledge of processof process((scientificscientific basisbasis for identifying critical steps/critical for identifying critical steps/critical process parameters/control points)process parameters/control points)

Justification and consistency of inJustification and consistency of in--process process specifications and final product specificationsspecifications and final product specifications

Data/information documented and available to Data/information documented and available to Quality Unit for review (trending, investigations etc.)Quality Unit for review (trending, investigations etc.)

Facilities & Equipment SystemFacilities & Equipment System

FACILITIESFACILITIES

Location, design, construction appropriate to Location, design, construction appropriate to facilitate cleaning, maintenance, operationsfacilitate cleaning, maintenance, operations

Layout and air handling designed and Layout and air handling designed and constructed to prevent crossconstructed to prevent cross--contaminationcontamination

Flow of materials & personnel designed to Flow of materials & personnel designed to prevent mixprevent mix--ups or contaminationups or contamination


Defined areas or other control systems to Defined areas or other control systems to prevent mixprevent mix--ups or contaminationups or contamination

Incoming materials (id, quarantine)Incoming materials (id, quarantine)

Sampling area (prevent contamination)Sampling area (prevent contamination)

Quarantine (intermediates, APIs)Quarantine (intermediates, APIs)

Released materialsReleased materials

RejectionRejection


EQUIPMENTEQUIPMENT

Appropriate design, size, location, nonAppropriate design, size, location, non--reactive product reactive product contact surfacescontact surfaces

Identification clearly markedIdentification clearly marked

Qualification (DQ, IQ,OQ, PQ)Qualification (DQ, IQ,OQ, PQ)

CalibrationCalibration

Preventive Maintenance schedule and proceduresPreventive Maintenance schedule and procedures

Cleaning procedures and validationCleaning procedures and validation

Records of use, cleaning, maintenanceRecords of use, cleaning, maintenance


Lubricants, heating fluids or coolants (not Lubricants, heating fluids or coolants (not contact/alter product quality)contact/alter product quality)

Closed or contained equipmentClosed or contained equipment

Inspection prior to useInspection prior to use

**********************************************************************************

Separate facilities or containment where needed Separate facilities or containment where needed ((penicillinspenicillins, highly potent compounds etc.), highly potent compounds etc.)

UtilitiesUtilitiesQualified and appropriately monitored; drawings Qualified and appropriately monitored; drawings should be availableshould be available

Designed and constructed to prevent Designed and constructed to prevent contamination or crosscontamination or cross--contaminationcontamination

RecirculatedRecirculated air to production (same concern)air to production (same concern)

Permanently installed Permanently installed pipeworkpipework should be should be appropriately identifiedappropriately identified

Drains of adequate size with air breakDrains of adequate size with air break

WaterWaterProcess water at minimum meeting WHO Process water at minimum meeting WHO guidelines for potable waterguidelines for potable water

Justify quality of water used to achieve stated Justify quality of water used to achieve stated API quality and establish specificationsAPI quality and establish specifications

Water treatment facilities validatedWater treatment facilities validated

API to be used for incorporation into sterile API to be used for incorporation into sterile dosage form dosage form –– water used in later stages should water used in later stages should be monitored and controlled for total microbial be monitored and controlled for total microbial counts, objectionable organisms and counts, objectionable organisms and endotoxinsendotoxins

Materials SystemMaterials SystemWritten procedures for receipt, identification, Written procedures for receipt, identification, quarantine, storage, handling, sampling, testing quarantine, storage, handling, sampling, testing and approval or rejection of materialsand approval or rejection of materials

System to evaluate suppliers (critical materials)System to evaluate suppliers (critical materials)

Purchased against agreed specificationPurchased against agreed specification

Change control process for changing suppliersChange control process for changing suppliers

Upon receipt check for correct labeling, sealsUpon receipt check for correct labeling, seals

Before coBefore co--mingling bulk material, id/testmingling bulk material, id/test

Assurances obtained from nonAssurances obtained from non--dedicated tankers dedicated tankers

Materials SystemMaterials SystemIdentification on large storage containers and Identification on large storage containers and associated manifolds, filling and discharge linesassociated manifolds, filling and discharge lines

Code given to received batches; status identityCode given to received batches; status identity

At minimum, a specific identity test on incoming At minimum, a specific identity test on incoming batches; COAbatches; COA

Supplier evaluation should include three fully Supplier evaluation should include three fully tested batches; one fully tested batch/yeartested batches; one fully tested batch/year

Written sampling plan with justificationWritten sampling plan with justification

Prevent contamination of sampled containersPrevent contamination of sampled containers

Materials SystemMaterials SystemStored in manner to prevent degradation, Stored in manner to prevent degradation, contamination, no adverse effect on qualitycontamination, no adverse effect on quality

Drums, bags, boxes off the floorDrums, bags, boxes off the floor

First in, first outFirst in, first out

Rejected materials identified and controlled Rejected materials identified and controlled under a quarantine systemunder a quarantine system

Established reEstablished re--test/ retest/ re--evaluation periodsevaluation periods

Packaging & Labeling SystemPackaging & Labeling SystemWritten procedures for receipt, identification, Written procedures for receipt, identification, quarantine, sampling, examination and/or quarantine, sampling, examination and/or testing P&Ltesting P&L

P&L should conform to specificationsP&L should conform to specifications

Records maintained for each shipment (showing Records maintained for each shipment (showing receipt, examination & result)receipt, examination & result)

Containers protective, clean, not alter product Containers protective, clean, not alter product quality; if requality; if re--used, cleaned & labeling defaced used, cleaned & labeling defaced

LabelingLabelingAccess to label storage area limitedAccess to label storage area limited

Written procedures for reconciliation; Written procedures for reconciliation; investigation if discrepancyinvestigation if discrepancy

All excess labels with batch #, destroyedAll excess labels with batch #, destroyed

Obsolete labels destroyedObsolete labels destroyed

Printing devices controlled to insure accuracy of Printing devices controlled to insure accuracy of label (against batch record)label (against batch record)

Print labels checked against master and a copy Print labels checked against master and a copy placed into the batch recordplaced into the batch record

Packaging/Labeling OperationsPackaging/Labeling OperationsDocumented procedures to assure correct Documented procedures to assure correct packaging materials/ labels usedpackaging materials/ labels used

Operations designed to prevent mixOperations designed to prevent mix--upsups

Labels: API name, batch #, storage conditionsLabels: API name, batch #, storage conditions

Shipped API: Name/ address manufacturer; Shipped API: Name/ address manufacturer; special transport conditions; expiry/ retest datespecial transport conditions; expiry/ retest date

Documented clearance before operationsDocumented clearance before operations

Packaged/ labeled intermediates or APIs Packaged/ labeled intermediates or APIs examined as part of packaging (documented)examined as part of packaging (documented)

Seal employed to assure package integritySeal employed to assure package integrity

APIs are Drug SubstancesAPIs are Drug SubstancesFDA Food, Drug and Cosmetic Act definition of FDA Food, Drug and Cosmetic Act definition of drug includes drug includes ““articles intended for use in the articles intended for use in the diagnosis, cure, mitigation, treatment or diagnosis, cure, mitigation, treatment or prevention of disease in man or other animalsprevention of disease in man or other animals””(no distinction between APIs & dosage forms)(no distinction between APIs & dosage forms)

Before ICH Q7A, FDA used dosage drug Before ICH Q7A, FDA used dosage drug regulations as regulations as guidanceguidance for API inspectionfor API inspection

Still true (see next slide) , however, ICH Still true (see next slide) , however, ICH Q7A Q7A provides guidance on the application of those provides guidance on the application of those cGMPscGMPs to APIsto APIs))

From current FDA Compliance Program 56002 for Drug Manufacturing Inspections:

(This is the compliance program for FDA Investigators; this revision introduced Systems Inspections)

“The cGMP regulations are not direct requirements for manufacture of APIs…….but they are guidance for cGMP in API manufacture.”

Current FDA Compliance Guide Current FDA Compliance Guide on Process validationon Process validation

From FDA Compliance Policy Guide “Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients CPG 7132c.08”; revision date 12 March 2004:

Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals, and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory cGMP provisions of the Federal Food, Drug, and Cosmetic Act”.

Differences API/ Dosage FormDifferences API/ Dosage Form

APIs involve purification stepsAPIs involve purification steps

GMP controls tighter for later API stepsGMP controls tighter for later API steps

API impurity profile is critical focus and API impurity profile is critical focus and steps which produce or remove impurities steps which produce or remove impurities require greater control and validationrequire greater control and validation

Dosage forms do not involve purification Dosage forms do not involve purification

Similarities APIs/Dosage FormsSimilarities APIs/Dosage Forms

Require demonstrated knowledge of Require demonstrated knowledge of process and application of appropriate process and application of appropriate GMP controls to assure safety, identity, GMP controls to assure safety, identity, strength, quality and purity.strength, quality and purity.

Systems in control to be in complianceSystems in control to be in compliance

Life Cycle Approach to Validation (beyond Life Cycle Approach to Validation (beyond the initial the initial ““conformance batchesconformance batches””))

Similarities includeSimilarities include……..Processes for Processes for specificspecific productsproducts vary in vary in complexity (either API or dosage can involve complexity (either API or dosage can involve complex or simple processes)complex or simple processes)

InIn--process controlsprocess controls

Finished product controlsFinished product controls

Critical steps/ critical process parametersCritical steps/ critical process parameters

Process validationProcess validation

Quality assurance for consumer is based on Quality assurance for consumer is based on understanding & control of sources of process/ understanding & control of sources of process/ product variabilityproduct variability

More SimilaritiesMore Similarities……....

Science based approach for the Science based approach for the establishment of processesestablishment of processes

Knowledge of process based on Knowledge of process based on Process Process Development work Development work

Design Of Experiments (DOE)Design Of Experiments (DOE)

Quality System (review/ trending)Quality System (review/ trending)

Continuous Improvement possible within Continuous Improvement possible within well characterized processwell characterized process

Oral Solid Dosage Forms/Michael O'Meara/ 2004

FDA CGMPChina Training Program

December 5-7, 2005Ying Jie Convention CenterBeijing University Beijing

Solid Oral Dosage FormsNicholas Buhay

Deputy DirectorDivision of Manufacturing & Product Quality

Office of Compliance, CDER, FDA


Solid Oral Dosage Forms

Discussion of Manufacturing Considerations and Current Good

Manufacturing Practice


FORMS

• Powders• Pills• Troche• Capsules• Tablets


Most Common Dosage Forms

• Convenient• Relatively Stable• Easily Administered• Palatable• Flexible


Capsules

• Hard Gelatin• Soft Gelatin


Hard Gelatin Capsules

• Empty Capsule Storage– Controlled temperature

and humidity• Too moist - capsules

become tacky• Too dry - capsules

become brittle and change dimensions

• 30 to 45% R.M. ideal


Operations

• Rectify the capsule• Separate body from cap• Fill the body• Replace the cap


Capsule Filling Machine

• Hand Operated• Semi-automatic• Fully automatic




Process Variables

• Speed• Humidity• Bulk Powder Level• Weight Variation• Gelatin Moisture Content


Compressed Tablet

• Un-coated• Immediate Release


Multiple Compressed

• Layered– Tablet Within a Tablet– Two Part– Three Layer

• Compression Coated– Function as Film/Sugar

Coated


Repeat-Action

Active ingredient in the tablet core and in the coating.


Delayed-Action/Enteric Coated

• Coating protects core in the stomach• Drug released in the upper GI tract after the

stomach


Film Coated

• Solvent Based• Aqueous Based• Alternative to Sugar Coated


INGREDIENTS

• Active– Drug Substance

• Non-Active– Diluents– Binders– Lubricants– Disintegrants– Coloring– Flavoring– Antiadherents– Glidants


Drug Substance

• Fully Characterized– Physical

Specifications (Including Particle size distribution, density, isomerism and Morphology)

– Chemical Specifications (Including Impurity and Degradation Profile)


DILUENTS

• Lactose• Starch• Mannitol• Calcium Sulfate• Sorbitol

• Dicalcium Phosphate• Kaolin• Sodium Chloride• Powdered Sugar• Microcrystalline

Cellulose


DISINTEGRANTS

• Starch• Microcrystaline Cellulose• Alginic Acid• Gums• Crospovidone


Binders

• Starch Paste• Glucose• Gelatin Solution• Acacia• Sucrose• Sodium Alginate


LUBRICANTS

• Magnesium Stearate• Calcium Stearate• Talc• Stearic Acid• Sodium Lauryl Sulfate• Sodium Acetate


Observations


-) Testing standards for raw materials used in the manufacture of ***** 40 mg tablets do not include specifications for physical characteristics.


-) ***** raw material is not sufficiently characterized to determine its suitability for the manufacturing process. Various lots have passed all acceptance criteria, but have been identified as the causative factor in granulation and tableting deviations.


-) …..The affect of particle size distribution, surface area and the particle morphology of the bulk drug substance, on the granulation process were not fully evaluated…..


There was a failure by QA to identify two separate lots of diluted Isosorbide Dinitrate bulk drug substance, received from the supplier in the same shipment...


-) The investigation into the acquisition and release of aluminum stearate of the wrong grade obtained from an unapproved source failed to identify that the wrong grade of material was ordered from the vendor.


GRANULATING

• Wet Granulation• Direct Compression• Dry Granulation

– Slugging– Roll Compaction


Wet Granulation

• Advantages– Improved

Compressibility– Improved uniformity– Decreased segregation– Flexibility

• Disadvantages– Process complexity– Cost– Possible affect on drug

substance


Wet Granulation Manufacturing Steps

Compression

Lubrication

Screening

Drying

Screening

Granulation

Mixing

Weighing


Wet Granulation

• Specific Manufacturing Instructions• Amounts, Rates and Timing of Granulating

Fluid Additions• Mixer Speeds and Configuration• Specified End Points - Motor Load,

Appearance, Texture


FDA 483 Observation...some granulation batches have required on the spot changes in established procedures for water addition and/or mix time to compensate for over and under granulation problems, the addition of a wet milling step or hand processing to break up lumps in over granulated batches, an additional drying step...


Dry Granulation

• Useful when ingredients are sensitive to moisture or heat

• Blended ingredients are either compressed into “slugs” or roll compacted into “sticks”or sheets

• Slugs or sticks are screened/milled• Granulation is blended with lubricant and

disintegrants then compressed

•


Roller Compactor


Direct Compression

• Ingredients are milled and/or screened, then mixed, then compressed into tablets.

• Few Manufacturing steps• Greater potential for segregation


Mixers & Blenders• Pony/Planetary Mixer• High Shear Mixer• Ribbon Blender• Screw Blender• Tumble Blenders

– Twin Shell– Double Cone– Drums– Other


Mixing Process Validation

• Validation of the reliability of mixing operations is a very significant control expected

• Sample from the blender (if possible)• 10 individual assays• Sample size

– Approximate unit dose


Planetary Mixer

• Good horizontal mixing• Cross contamination risk• Poor vertical mixing




Ribbon Blender

• Horizontal and vertical mixing• Dead zones• Cleaning issues





Screw Blenders

• Three Distinct Intermixing Action– Screw produces lifting action– Orbiting screw moves material from the walls

of the blender into the center of the vessel– Material lifted by the screw gravitates

downward– No picture


Tumble Blenders

• Shell blenders• Twin Shell and Double Cone

– Low energy mixing• clumping and segregation

– Working capacity– Cleaning– Liquid Dispersion Granulation






High Shear Mixers

• Very efficient• Ideal for wet

granulation• Amount and addition

rate of granulating fluid must be strictly controlled

• End points can be measured

• Single pot production• Heat• Cleaning




OTHER BLENDERS

• Drum• Bags


Inspection Observations


there were no blend time studies conducted to assure uniformity of granulation for the pre-blend or final blend steps…In addition, production batch records do not specify a finite time for blend steps.


one of six granulation samples obtained from the blender, at final blend step, assayed below specification.


- Content uniformity of the preservative was not included in the validation study for ***.


- During the processing of *** 500mg tablet batch ***, an operator was observed inverting a drum of granulation several times prior to placing it above the tablet press granulation hopper. This step is not part of the established process, but is reportedly common practice.


- ******* 40 mg tablets are not manufactured in accordance with the approved filed process. The current manufacturing process includes an additional 5 minutes of blending with intensifier bar prior to the granulation step, an additional 3 minute blending step (drum mix) during the tableting operation, and pre-compression and dissolution evaluation steps, none of which are represented in the filed process.


DRYING

• Fluid Bed• Tray• Vacuum


Fluid Bed Drying

• Efficient• Uniform drying• Process Variables

– Temperature– Air velocity– Filter pore size


Fluid Bed Granulating

• Process Variables– Droplet size and spray

rate– Inlet air temperature,

humidity and velocity– Location of spay

nozzle


Oven/Tray Drying

• Drying is less uniform than with fluid bed

• End point determination

• Cross contamination issues

• Cleaning


Vacuum Drying

• Jacketed tumble dryer• Heat applied to vessel walls• Vacuum draws off moisture/solvent




Milling

• Process Variables– Feed rate– Inlet feed throat design– Blade type– Rotor speed– Screen type– (Overhead)


Transfer & Storage

• Post blending segregation• Floor vibration• Chutes and collars• Equipment Vibration• Segregation ????


Compression

• Start up tablets• In process testing

– hardness– friability– size– shape– disintegration– thickness


Tablet Presses

• Single Punch• Rotary Press• High Speed Rotary Press• Multi-layer Rotary Press



Tooling

• Quality Control• Accountability

– unique identifier– security




Problems

• Sticking and Picking– granulation moisture– lubricant– punch face

• Capping– Fines– Air– punch-die clearance


Problems

• Lamination– Tooling– granulation procedure– formulation

• increase binder• lubricant

• Chipping & Cracking– tooling– granulation

• fines• granule size


Common controls

• Hardness– Force required to break

a tablet

• Friability– Ability to withstand

abrasion and trauma without crumbling


Common controls

• Disintegration– The time it takes for a

tablet to disintegrate in an aqueous medium

• Dissolution– How the formulation

releases the drug


Inspection Observations


The investigations into a capping problem associated with seven production batches of XXX Tablets identified by MDIR's for one year are incomplete, in that; there was no evaluation of the granulation nor of the raw materials used.


The manufacturing process for XXX Extended Release Tablets is not validated in that :a) the 45 station Stokes BB2 rotary tablet press (firm's ID # xxx ) was not qualified to assure the capability and controls for this piece of equipment were suitable to meet requirements established for manufacture of this product.


MDIR's were not generated, nor investigations conducted to determine cause, identity of content, and quantity of "chunks" of granulation which had to be occasionally removed from the tablet press screen during compression of xxx, batch xxx, nor of "lumpy" granulation observed in the hopper of the press during granulation of xxx, batch xxx.


- Development history supports an in-process disintegration limit lower than the current value of < 15 min. An unusual dissolution profile in a development batch was associated with in-process disintegration times > 9min.


- The ***** 40mg tablet manufacturing process is not validated in that:

a) Tableting parameters are set batch to batch based on pre-compression dissolution test results.


b) Critical physical characteristics of raw materials have not been identified.c) Validation lots did not include specifications for the physical characteristics of blends and granulations.


d) Final blend samples taken for physical characteristics analysis were composite.


- The agency was not notified, in accordance with NDA Field Alert reporting requirements, when it was determined that lot **** failed dissolution testing at the 1 month stability station.


- The operating speed for the Perry Powder Filler when filling XXX is listed as 95 bottles per minute (BPM) in the Line Set-up Standard Sheet, which is outside the 80 to 90 BPM range used in the validation batches.


COATING

• Protect drug from the environment• Mask taste• Improve appearance• Separate ingredients• Provide multiple release profiles


Equipment

• Standard coating pan• Perforated coating pan• Fluidized bed


Standard Pans



Perforated Pans


Fluid Bed


Types

• Film• Enteric• Sugar


Film Coating Materials

• Polymers - Hydroxypropyl methylcellulos Povidone Polyethyleneglycol

• Enteric Materials - Cellulose acetate phthalate


Sugar Coating Materials

• Sealant - Shellac• Sugar - Syrup and color


Process Variables

• Pan design• Pan speed & load• Air quality• Temperature

• Airflow rate• Spray rate• Spray pattern• Nozzle to bed distance


There are no written SOP's for conducting batch record reviews to

assure consistency and completeness of those reviews...


A sticky note, attached to the official lab report, both dated with the same day, contained unacceptable test results of an individual tablet relative to a dissolution profile test conducted during the initial validation batch xxx, for product XXX. The values for this tablet were not included on the final lab report.


- 80% of the Aluminum Stearate used in the formula for ***** lot ***** was an unapproved grade obtained from an unapproved source. This lot has been distributed. The following two lots, ***** & *****, which were manufactured using 100% of the unapproved material were rejected for failing to meet specification.


- There was no investigation conducted following the rejection of86 kg of XXX 40mg tablets from lot ***** (a post validation lot) when the 2 hour compression trial sample failed dissolution testing; there was also no QA Management evaluation of the incident or its impact on the validation status of the process.


The local Quality Unit review has failed to assure the accuracy and completeness of validation reports, manufacturing documents, and analytical reports. For example:...


The local QA unit failed to follow the procedure (***.*) to notify senior corporate officials of significant quality issues so that resources could be allocated to resolve problems...


Laboratory procedures do not provide for the expeditious analysis of stability samples that require multi stage testing. For example, stage one dissolution testing for stability sample *** was initiated on August 9, but stage three testing, indicating a stability failure, was not completed until October 5.


Specifically, the manufacturing process for lots of *** mg tablets manufactured between *** and *** was not validated in that approximately 9 of 39 lots were rejected due to dissolution failures. Changes made to the manufacturing process during this time did not resolve the dissolution failures. Approximately 21 lots manufactured during this time were released for commercial distribution.


Summary

• Process Analysis• Process Variables• Process Controls


Summary• Evaluate material• Evaluation of site for cross-contamination• Consider operations (steps) in process• Consider equipment for operations• Determine process controls• Demonstrate process reliability (validation)• Commit to continuous monitoring of

manufacturing experience


Inspection References


GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG

MANUFACTURER'S - CGMP'SOctober, 1993


GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE

FORMS PRE/POST APPROVAL ISSUES FOR

DEVELOPMENT AND VALIDATIONJanuary, 1994


GUIDE TO INSPECTIONS VALIDATION OF CLEANING

PROCESSES

May 1987


GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL

LABORATORIESJuly, 1993


EXPIRATION DATING AND STABILITY TESTING FOR HUMAN DRUG PRODUCTS

Inspection Technical guide 41

(http://www.fda.gov/ora/inspect_ref/itg/itg41.html)


CGMP Guidance: Answers to Frequently Asked Questions

NotesHuman Drug CGMP Notes (3/1995-7/2000) • Human Drug CGMP Notes (1/1993-12/1994)

– [CNOTES vol. 1 no. 1 Feb 1993]– [CNOTES vol. 1 no. 2 May 1993]– [CNOTES vol.1 no. 3 Sept 1993]– [CNOTES vol.1 no. 4 Dec 1993]– [CNOTES vol. 2 no. 1 Mar 1994]– [CNOTES vol. 2 no. 2 Jun 1994]– [CNOTES vol. 2 no. 3 Sep 1994]– [CNOTES vol. 2 no. 4 Dec 1994]

►TO FIND, GO TO WEBSITE: http://www.fda.gov/cder/dmpq/index.htm

Other Resources• Guidance for Industry: CGMPs (Pharmaceutical CGMPs for the 21st Century)

– Questions and Answers on Current Good Manufacturing Practices (cGMP) for Drugs (Posted 8/4/2004)

►TO FIND, GO TO WEBSITE: http://www.fda.gov/cder/guidance/cGMPs/default.htm


Good Luck!!

• Think soundly• Operate under control

FDA API InspectionsFDA API Inspections

Robert C. Horan, PhDRobert C. Horan, PhDFDA Pharmaceutical InspectorateFDA Pharmaceutical Inspectorate

New York DistrictNew York District

Quality System observationsQuality System observations

FDA 483 Observations for Product QualityFDA 483 Observations for Product Quality

Reviews range Reviews range fromfrom::No SOP for Product Quality ReviewsNo SOP for Product Quality Reviews

No Product Quality Reviews conducted No Product Quality Reviews conducted toto: : various components of the reviews not donevarious components of the reviews not done

inadequate investigationsinadequate investigations

no corrective actions or other conclusionsno corrective actions or other conclusions

Quality System observationsQuality System observationsRegarding the annual product reviews:Regarding the annual product reviews:

The reports do not identify the specific batches The reports do not identify the specific batches which were covered by the review period and there which were covered by the review period and there is no evaluation of specific data from the batches is no evaluation of specific data from the batches covered.covered.

The annual report from 200X was found to contain The annual report from 200X was found to contain some conclusions regarding out of specification data some conclusions regarding out of specification data and corrective actions without providing specific and corrective actions without providing specific information such as batch numbers, actual events, information such as batch numbers, actual events, specific data, conclusions and any specific specific data, conclusions and any specific corrections made.corrections made.


An example is on page 3 which states:An example is on page 3 which states:

““The main unqualified item in 200X is the The main unqualified item in 200X is the XXX content out of the specific range. We XXX content out of the specific range. We take relative measures to strengthen the take relative measures to strengthen the control of manufacturing process, training control of manufacturing process, training the workers, strengthening the workersthe workers, strengthening the workers’’quality sensequality sense””. .

Quality System observationsQuality System observationsMany of the firmMany of the firm’’s written procedures (SOPs) have not s written procedures (SOPs) have not been periodically reviewed and revised where needed to been periodically reviewed and revised where needed to ensure that they accurately describe current procedures ensure that they accurately describe current procedures at the firm and are in compliance with at the firm and are in compliance with cGMPscGMPs. Some of . Some of the SOPs were found to have approval dates as far back the SOPs were found to have approval dates as far back as 1994. Examples include but not limited to:as 1994. Examples include but not limited to:a)a) **********, revision 1, approved 10 Jan 1994**********, revision 1, approved 10 Jan 1994

b)b) XXXXXXXXX, revision 1, approved 23 March 1998XXXXXXXXX, revision 1, approved 23 March 1998

Further, review of SOP XX found that it describes Further, review of SOP XX found that it describes equipment which had been removed two years ago and equipment which had been removed two years ago and the attachments the attachments ““CC”” and and ““DD”” are no longer used for are no longer used for documentation and were replaced by other forms which documentation and were replaced by other forms which were not attached to the SOP.were not attached to the SOP.


From a Warning Letter:From a Warning Letter:““Failure to establish corrective and preventive Failure to establish corrective and preventive actions (CAPA) procedures for investigating the actions (CAPA) procedures for investigating the cause of noncause of non--conformities relating to product, conformities relating to product, processes and the quality system.processes and the quality system.

Specifically, the firm received Specifically, the firm received –– complaints complaints related torelated to…………. You failed to follow SOP # . You failed to follow SOP # ---- in in that investigations were inadequate and no that investigations were inadequate and no CAPAsCAPAs were implemented.were implemented.


Change control forms for changes in Change control forms for changes in Master Batch Production records fail to Master Batch Production records fail to identify specific changes made.identify specific changes made.

Further, there is no written evaluation of Further, there is no written evaluation of the significance of the change, need for the significance of the change, need for rere--validation etc.validation etc.


Software change control reports were Software change control reports were found to have multiple text changes made found to have multiple text changes made by means of by means of ““whitewhite--outout”” rather than by rather than by following the firmfollowing the firm’’s written procedure of s written procedure of crossing out the original text and initialing crossing out the original text and initialing (stamp) the correction. Further, there (stamp) the correction. Further, there were no written explanations given for the were no written explanations given for the specific changes made.specific changes made.


There is no control over the use of There is no control over the use of signature stamps by production and signature stamps by production and quality control personnel used in the quality control personnel used in the signing of documents.signing of documents.

Quality System observationsQuality System observationsProcess validation reports for API *** did not Process validation reports for API *** did not have criteria for acceptable reduction of the two have criteria for acceptable reduction of the two specified impurities specified impurities ““eimpeimp”” and and ““fimpfimp””. Batch . Batch record review (20 consecutive batches) found record review (20 consecutive batches) found that postthat post--validation batches showed typical levels validation batches showed typical levels of both impurities were much higher than in the of both impurities were much higher than in the validation batches. A number of batches validation batches. A number of batches exhibited exhibited ““eimpeimp”” values that were more than values that were more than double that in validation batches and approached double that in validation batches and approached the limit of 1.0%.the limit of 1.0%.


SOP SOP ““QA Inspector in the WorkshopQA Inspector in the Workshop””describes a twice daily check of describes a twice daily check of equipment readings versus data recorded equipment readings versus data recorded in batch records. Examination of several in batch records. Examination of several entries in the QA inspectorentries in the QA inspector’’s log and s log and corresponding batch records from those corresponding batch records from those same dates/times found discrepancies same dates/times found discrepancies between the QA inspectorbetween the QA inspector’’s record and s record and batch record data.batch record data.

Quality System observationsQuality System observationsFurther, on (date), the QA inspector recorded a Further, on (date), the QA inspector recorded a temperature of 0 C for the critical **** reaction temperature of 0 C for the critical **** reaction step step ------------ for batch ***, however, my for batch ***, however, my examination of the batch record found that for examination of the batch record found that for that step which lasts 5 hours, the temperature that step which lasts 5 hours, the temperature never reached 0 C. In fact, the critical never reached 0 C. In fact, the critical temperature range is 12 to 20 C and examination temperature range is 12 to 20 C and examination of 25 batch records close to dates for batch *** of 25 batch records close to dates for batch *** found found

1) Examples of temperature exceed upper limit 1) Examples of temperature exceed upper limit

2) No batches recorded a temperature of 0C.2) No batches recorded a temperature of 0C.

Cited on warning letterCited on warning letter

The firmThe firm’’s procedures for identifying and s procedures for identifying and documenting problems that occur in documenting problems that occur in manufacturing are deficient. For example, 235 manufacturing are deficient. For example, 235 ““minorminor”” deviations were logged yeardeviations were logged year--toto--date, of date, of which only one was fully documented as a which only one was fully documented as a deviation investigation. Minor deviations that deviation investigation. Minor deviations that were not fully investigated and documented were not fully investigated and documented included:included:

Quality System observationsQuality System observations1)1) API ^^^ production lot *** failed to form final API ^^^ production lot *** failed to form final

product crystals. The cause was attributed to an product crystals. The cause was attributed to an operator error and the charging of excess operator error and the charging of excess solvent. Nonsolvent. Non--validated measures were used to validated measures were used to attempt to force the formation of crystals. The attempt to force the formation of crystals. The inin--process lot was subsequently divided into process lot was subsequently divided into thirds and blended into three other production thirds and blended into three other production lots that became finished API ^^^ lots ***, *** lots that became finished API ^^^ lots ***, *** and ***. This was listed as a minor deviation and ***. This was listed as a minor deviation and a full investigation was not performed.and a full investigation was not performed.

continuedcontinued

2)2) API ^^^ production lot *** yielded only 57%. API ^^^ production lot *** yielded only 57%. The yield was approximately 30% below The yield was approximately 30% below average. The cause was attributed to an initial average. The cause was attributed to an initial high processing temperature caused by the high processing temperature caused by the computer system. No additional information or computer system. No additional information or justification was provided; this was listed as a justification was provided; this was listed as a minor deviation and a full investigation was not minor deviation and a full investigation was not performed.performed.

Quality System observationsQuality System observationsReview of a number of Review of a number of ““oosoos”” for potency in API ***, for potency in API ***, it was found that this was attributed to failure of it was found that this was attributed to failure of temperature sensors on manufacturing equipment temperature sensors on manufacturing equipment XXX and that the temperature had been out of the XXX and that the temperature had been out of the critical control range. In reviewing other deviation critical control range. In reviewing other deviation reports, it was found that following earlier episodes reports, it was found that following earlier episodes of of ““oosoos”” potency values, there were corrective potency values, there were corrective actions recommended including one to increase the actions recommended including one to increase the frequency of calibrations of the sensing devices. frequency of calibrations of the sensing devices. Examination of the applicable SOPs found these Examination of the applicable SOPs found these recommended had not been implemented and no recommended had not been implemented and no other corrective action taken.other corrective action taken.

Quality System observationsQuality System observationsAction limits for testing of Purified Water have been Action limits for testing of Purified Water have been exceeded several times without any investigations exceeded several times without any investigations or completion of nonor completion of non--conformance reports. The test conformance reports. The test results were included in the Purified Water System results were included in the Purified Water System Qualification report dated (date). For example, Use Qualification report dated (date). For example, Use Point XX sampled on (date), results were Point XX sampled on (date), results were ““UnsatisfactoryUnsatisfactory”” for absence of clinically significant for absence of clinically significant organisms (pathogens), User Point YY sampled on organisms (pathogens), User Point YY sampled on (date, three months earlier) had Total Viable Counts (date, three months earlier) had Total Viable Counts which were more than 10 times the action limit of X which were more than 10 times the action limit of X cfu/mLcfu/mL. This data was recorded in the final report . This data was recorded in the final report signed by quality management.signed by quality management.

Quality System observationsQuality System observationsThe written procedure (SOP XXThe written procedure (SOP XX--Y) for training of Y) for training of employees does not address the conduct of job employees does not address the conduct of job specific, performance based training and there is no specific, performance based training and there is no documented record of such training for quality documented record of such training for quality control laboratory and production personnel. control laboratory and production personnel.

Inspection found many production deviations where Inspection found many production deviations where the cause was reported to be operator error and the cause was reported to be operator error and retraining was conducted. SOP XXretraining was conducted. SOP XX--Y does not Y does not address the retraining of personnel and there is no address the retraining of personnel and there is no documentation of retraining.documentation of retraining.

There are no individual training records for There are no individual training records for personnel.personnel.

Laboratory observationsLaboratory observationsCalibration of pH meter #__ is done using Calibration of pH meter #__ is done using buffers at pH 4.0, 7.0 and 9.0, however, it is buffers at pH 4.0, 7.0 and 9.0, however, it is used to measure the pH of *** which has an used to measure the pH of *** which has an expected pH around 12.expected pH around 12.

Balance # ___ used in the testing of *** is Balance # ___ used in the testing of *** is calibrated at ___ intervals using weights in the calibrated at ___ intervals using weights in the range *range *--*, however, sample weights as per the *, however, sample weights as per the method for testing of *** are considerably method for testing of *** are considerably below the lower end of the calibration.below the lower end of the calibration.

Laboratory observationsLaboratory observationsThe identification test used for XX@The identification test used for XX@--Na by FTIR Na by FTIR compared the spectrum of XX@compared the spectrum of XX@--Na against the Na against the spectrum for USP XX@. These spectra are not spectrum for USP XX@. These spectra are not equivalent and are in fact quite different.equivalent and are in fact quite different.

Identification testing of API *** Identification testing of API *** batches batches ……,,……,,……,,……,,…… using IR was not actually using IR was not actually done. The analyst simply used a previous done. The analyst simply used a previous spectrum and changed the batch number each spectrum and changed the batch number each time.time.

Laboratory observationsLaboratory observationsRegarding the computerized and paper systems Regarding the computerized and paper systems used in the recording of quality control testing used in the recording of quality control testing data for chemistry, microbiology and indata for chemistry, microbiology and in--process process production testing the following was observed:production testing the following was observed:a)a) The computerized (LIMS) system is not secure in that The computerized (LIMS) system is not secure in that

it is possible for data to be changed. This was it is possible for data to be changed. This was observed following a request during inspection for a observed following a request during inspection for a challenge to be performed. In performing the challenge to be performed. In performing the requested challenge, the analyst was able to change requested challenge, the analyst was able to change previously recorded input including sample gross and previously recorded input including sample gross and net weights resulting in changed assay results.net weights resulting in changed assay results.

Laboratory observationsLaboratory observations

b)b) There is no system such as the use of There is no system such as the use of prepre--coded sheets, signed and distributed coded sheets, signed and distributed by a responsible quality employee for by a responsible quality employee for assuring the integrity of loose paper data assuring the integrity of loose paper data sheets used in the recording of test sheets used in the recording of test resultsresults

Laboratory observationsLaboratory observationsInspection of the QC and Microbiology laboratories Inspection of the QC and Microbiology laboratories found that analysts use loose printed sheets for found that analysts use loose printed sheets for recording raw data, there were stacks or pads of recording raw data, there were stacks or pads of blank pages readily available. blank pages readily available.

In the microbiology laboratory, in response to a In the microbiology laboratory, in response to a question about how the name of the product is question about how the name of the product is stamped on the data page, an analyst took out a stamped on the data page, an analyst took out a stamp and ink pad and demonstrated how it would stamp and ink pad and demonstrated how it would be done. There is no procedure in place to insure be done. There is no procedure in place to insure the integrity of data sheets used in the QC the integrity of data sheets used in the QC laboratory.laboratory.


Examination of the HPLC systems in the API Examination of the HPLC systems in the API testing laboratory found that for the *** testing laboratory found that for the *** systems, the audit trail function was not enabled.systems, the audit trail function was not enabled.

For the *** For the *** HPLCsHPLCs, the audit trail function was , the audit trail function was enabled, however, the laboratory management enabled, however, the laboratory management has never conducted an examination of the has never conducted an examination of the audit trail on any of these instruments.audit trail on any of these instruments.

No training of analysts regarding audit trail.No training of analysts regarding audit trail.


Generic Statement Generic Statement –– details withhelddetails withheld

FDA inspections sometimes find evidence FDA inspections sometimes find evidence of data in computer files which is not of data in computer files which is not recorded in laboratory notebooks, lab recorded in laboratory notebooks, lab worksheets or final written reports. worksheets or final written reports.


The firmThe firm’’s QC chemistry laboratory has s QC chemistry laboratory has three HPLC systems and reportedly tests three HPLC systems and reportedly tests about 2000 samples per year, however, about 2000 samples per year, however, the calibration is done only once every the calibration is done only once every two years (by government agency).two years (by government agency).

There is no established basis for not There is no established basis for not conducting more frequent full equipment conducting more frequent full equipment calibration related to the high equipment calibration related to the high equipment usage.usage.


NoteNote::At least several FDA 483s have cited At least several FDA 483s have cited observations regarding incomplete information observations regarding incomplete information provided on certificates following their provided on certificates following their calibrations. It has also been cited several times calibrations. It has also been cited several times that the factories receive no other information that the factories receive no other information and that it is not possible for an adequate and that it is not possible for an adequate review to be done of the instrument calibration review to be done of the instrument calibration ––either by the factory or outside auditor either by the factory or outside auditor -- such as such as FDA). FDA).


Calibration of HPLC is inadequate in that Calibration of HPLC is inadequate in that the lamp energy was not determined to the lamp energy was not determined to assure that it is capable of detecting low assure that it is capable of detecting low concentration of impurities during impurity concentration of impurities during impurity determination.determination.


System suitability is not performed each System suitability is not performed each time the HPLC assay method is run.time the HPLC assay method is run.

The firm has conducted system suitability The firm has conducted system suitability only once in the history of testing API***.only once in the history of testing API***.

The firm does no conduct system The firm does no conduct system suitability each time testing is done as per suitability each time testing is done as per USP.USP.


The firm has not demonstrated that the The firm has not demonstrated that the assay method used for stability testing of assay method used for stability testing of API *** is stability indicating.API *** is stability indicating.

Laboratory observationsLaboratory observationsThere is no data available from the forced There is no data available from the forced degradation studies which serve as the basis for degradation studies which serve as the basis for demonstrating that the stability test method for demonstrating that the stability test method for testing of API stability samples is stabilitytesting of API stability samples is stability--indicating. indicating.

The management stated that at the time the The management stated that at the time the studies were conducted in 200X, the factory was studies were conducted in 200X, the factory was not retaining raw data.not retaining raw data.

(continued)(continued)


Further, there is no record of preparation Further, there is no record of preparation of samples, sample stress treatments or of samples, sample stress treatments or the actual testing. the actual testing.

Finally, there is no record of the subFinally, there is no record of the sub--dividing of stressed samples to prepare a dividing of stressed samples to prepare a subsub--sample to be sent to a contract sample to be sent to a contract laboratory for the peak purity studies.laboratory for the peak purity studies.

Laboratory observationsLaboratory observationsFor the related compounds methods for *** API, For the related compounds methods for *** API, the procedure states to run the chromatogram the procedure states to run the chromatogram for NLT 2.5 times the retention time of the API. for NLT 2.5 times the retention time of the API. Review of earlier test data shows that a Review of earlier test data shows that a significant recurring impurity elutes at significant recurring impurity elutes at approximately five times the retention time of approximately five times the retention time of the API, which could go undetected when the API, which could go undetected when following the instructions for chromatographic following the instructions for chromatographic run time.run time.

Laboratory observationsLaboratory observationsFor several tests from the USP monograph for For several tests from the USP monograph for API ^^^, USP, the firm either did not perform API ^^^, USP, the firm either did not perform the test or did not conduct it as per USP. For the test or did not conduct it as per USP. For example, the UV identity test was not done and example, the UV identity test was not done and the IR identity scan in the batch records was the IR identity scan in the batch records was simply a copy of a simply a copy of a ““representativerepresentative”” batch run batch run previously; previously; ““the test for the specified impurity 4the test for the specified impurity 4--XXXXX was not conducted for any of the batches XXXXX was not conducted for any of the batches examined (batches ***, *** and ***) and the examined (batches ***, *** and ***) and the ““CrystallinityCrystallinity”” test was not done.test was not done.

Laboratory observationsLaboratory observationsThe firmThe firm’’s s ““out of trendout of trend”” ((““OOTOOT””) investigation for stability ) investigation for stability testing on three consecutive validation batches ****1, testing on three consecutive validation batches ****1, ****2 and ****3 concluded that the ****2 and ****3 concluded that the ““OOTOOT”” result was due result was due to analyses being conducted by different analysts on to analyses being conducted by different analysts on different instruments. The following is noted:different instruments. The following is noted:

The analysts were also reportedly trained and the The analysts were also reportedly trained and the instruments calibrated and deemed acceptable for the instruments calibrated and deemed acceptable for the testingtesting

There is no documented basis for the investigation There is no documented basis for the investigation conclusionconclusion

The conclusion suggests the method is not robust, however, The conclusion suggests the method is not robust, however, the investigation did not address the significance for all the investigation did not address the significance for all other previous testingother previous testing


For the related compounds method for For the related compounds method for ***, several errors exist in the procedure ***, several errors exist in the procedure that were not detected during the review that were not detected during the review process. These include the incorrect process. These include the incorrect concentration listed for the stock standard concentration listed for the stock standard and the incorrect dilution for the low level and the incorrect dilution for the low level standard preparation.standard preparation.


Following an out of specification result for Following an out of specification result for *** in the 6 month stability sample of ***, *** in the 6 month stability sample of ***, lot ***, the analyst reported that the lot ***, the analyst reported that the "Test FAILED" on the report sheet and "Test FAILED" on the report sheet and forwarded this to the group leader, forwarded this to the group leader, however, no action was taken. According however, no action was taken. According to the laboratory manager, the sheet must to the laboratory manager, the sheet must have been missed and was not discovered have been missed and was not discovered for more than two months.for more than two months.

Laboratory observationsLaboratory observationsThere is no written procedure which requires the There is no written procedure which requires the investigation, review and trending of laboratory investigation, review and trending of laboratory deviations not covered by deviations not covered by ““oosoos”” investigations.investigations.

Inspection of product *** found that there were Inspection of product *** found that there were HPLC assays discontinued when an outdated HPLC assays discontinued when an outdated reference standard solution introduced unknown reference standard solution introduced unknown peaks. The firm has stability data for 15 days peaks. The firm has stability data for 15 days use of *** reference standard solution and use of *** reference standard solution and supervisor stated supervisor stated ““We would not normally use We would not normally use such an old solution. It was done because such an old solution. It was done because standard is expensivestandard is expensive””. .

““oosoos””The firmThe firm’’s investigation of s investigation of ““oosoos’’ test results for test results for assay,, related substances and residual solvents assay,, related substances and residual solvents for the two consecutive batches *** and *** of for the two consecutive batches *** and *** of API ^^^ was limited to verifying that there was API ^^^ was limited to verifying that there was no laboratory error and the results were valid. no laboratory error and the results were valid.

There was no evaluation to determine the root There was no evaluation to determine the root cause of the multiple critical specification failure, cause of the multiple critical specification failure, no extension of the investigation to consider the no extension of the investigation to consider the potential significance for other batches. The potential significance for other batches. The only further action taken was to reprocess the only further action taken was to reprocess the batches and sell them to the local market batches and sell them to the local market instead of U.S.instead of U.S.

““oosoos””The firm received complaint of batches **** and The firm received complaint of batches **** and *** of the API product ^^^ failing the related *** of the API product ^^^ failing the related substances test for the single largest related substances test for the single largest related substance. The API manufacturer investigated the substance. The API manufacturer investigated the original test records from (date) and found that the original test records from (date) and found that the analyst had selected the wrong peak as the largest analyst had selected the wrong peak as the largest related substance peak.related substance peak.

The investigation was not extended to other batches. The investigation was not extended to other batches. Review during the current inspection of test results Review during the current inspection of test results from other batches found that the same analyst from other batches found that the same analyst made the same mistake for several other batches. made the same mistake for several other batches. This had not been discovered by the API This had not been discovered by the API manufactuermanufactuer’’ss investigation.investigation.

““oosoos””Inspection found that an Inspection found that an ““oosoos”” for potency of for potency of API ^^^, lot *** was invalidated based solely API ^^^, lot *** was invalidated based solely on the testing of a new sample. Examination on the testing of a new sample. Examination of the firmof the firm’’s SOP PPs SOP PP--T, found the following T, found the following regarding the procedure for regarding the procedure for ““oosoos””investigations:investigations:

a)a) If an identified cause for the If an identified cause for the ““oosoos”” is not is not determined or not confirmed, then a second analyst determined or not confirmed, then a second analyst will test a new sample.will test a new sample.

b)b) If the second sample meets specification, the If the second sample meets specification, the conclusion is made that the original sampling was conclusion is made that the original sampling was flawed. (continued next slide)flawed. (continued next slide)

““oosoos””

c)c) If the new sample failed, only then would If the new sample failed, only then would the lab supervisor prepare an the lab supervisor prepare an ““oosoos””reporting form which would be copied to reporting form which would be copied to production, QC and QA.production, QC and QA.

d)d) The SOP does not address retesting the The SOP does not address retesting the original sample.original sample.

““oosoos””

Regarding the firmRegarding the firm’’s procedure for s procedure for investigation of investigation of ““oosoos”” test results:test results:

a)a) There is no log, file or other cumulative There is no log, file or other cumulative record of the firmrecord of the firm’’s s ““oosoos”” investigations.investigations.

b)b) The annual product reviews do not include The annual product reviews do not include review of these investigations.review of these investigations.

c)c) There is no time frame identified in the SOP There is no time frame identified in the SOP for completion of for completion of ““oosoos”” investigations.investigations.

““oosoos””(From an FDA letter sent to factory to indicate inadequate (From an FDA letter sent to factory to indicate inadequate written response to FDA 483):written response to FDA 483):

Specifically, we remain concerned regarding the Specifically, we remain concerned regarding the consistency of the manufacturing process and/or consistency of the manufacturing process and/or analytical procedures. analytical procedures.

The inspection revealed numerous The inspection revealed numerous ““oosoos”” assay results in assay results in different samples from batch *** as well as different samples from batch *** as well as ““oosoos”” for for two other batches within the same campaign. Some of two other batches within the same campaign. Some of the the ““oosoos”” values were attributed to analytical error but values were attributed to analytical error but the cause of others remain undetermined. (continued the cause of others remain undetermined. (continued next slide)next slide)

““oosoos””Your written response indicates that the Your written response indicates that the ““oosoos””investigations will be closed out within 30 days investigations will be closed out within 30 days and that new laboratory SOPs have been written, and that new laboratory SOPs have been written, training has been provided to laboratory training has been provided to laboratory personnel, and additional laboratory personnel personnel, and additional laboratory personnel have been recruited.have been recruited.

Please provide the documentation that the Please provide the documentation that the ““oosoos””investigations have been completed and that the investigations have been completed and that the cause of the cause of the ““oosoos”” assay results have been assay results have been identified as either process related or analysis identified as either process related or analysis related. (continued next slide)related. (continued next slide)

““oosoos””

Please address any process or analytical Please address any process or analytical changes which may have been necessary changes which may have been necessary to address this issue.to address this issue.

FacilitesFacilites & Equipment& Equipment

The firmThe firm’’s written procedures for preventive s written procedures for preventive maintenance (PM) do not include examination maintenance (PM) do not include examination and evaluation of all equipment components or and evaluation of all equipment components or schedule for replacement of parts. In this schedule for replacement of parts. In this regard, there were three batches (***, *** and regard, there were three batches (***, *** and ***) which were reported in the annual product ***) which were reported in the annual product review to be contaminated with particles from a review to be contaminated with particles from a shredded Teflon gasket associated with the shredded Teflon gasket associated with the ------mixer. Inspection found: (continuedmixer. Inspection found: (continued……..)..)

FacilitesFacilites & Equipment& Equipmenta)a) There was no extension of the investigation to There was no extension of the investigation to

determine if previous batches may have been determine if previous batches may have been contaminated. In addition, the investigation contaminated. In addition, the investigation does not document the identification of the does not document the identification of the contamination being consistent with Teflon contamination being consistent with Teflon particles.particles.

b)b) The engineering management stated that while The engineering management stated that while they are responsible for equipment they are responsible for equipment maintenance, they have no PM procedures and maintenance, they have no PM procedures and stated PM should be the responsibility of stated PM should be the responsibility of production.production.


c)c) There are no PM SOPs in the production There are no PM SOPs in the production department.department.

d)d) The production department has a The production department has a machine log for each piece of equipment, machine log for each piece of equipment, however, review of the machine log for however, review of the machine log for the mixer found no record of the Teflon the mixer found no record of the Teflon gasket replacement in the period gasket replacement in the period following the reported contamination.following the reported contamination.


The investigation into lots of API ^^^ The investigation into lots of API ^^^ returned due to the presence of metallic returned due to the presence of metallic particles does not include a measure to particles does not include a measure to prevent future recurrence.prevent future recurrence.

Please notePlease note: : The following two slides list other The following two slides list other observations on that same FDA 483.observations on that same FDA 483.


Facilities & equipment in which crude APIs Facilities & equipment in which crude APIs are exposed during processing are not are exposed during processing are not maintained in a clean and sanitary manner maintained in a clean and sanitary manner andand are not designed to prevent are not designed to prevent contamination of the crude APIs from contamination of the crude APIs from foreign particles like dirt, rust, dust, paint foreign particles like dirt, rust, dust, paint chips and metal. chips and metal.

FacilitesFacilites & Equipment& EquipmentThen 483 lists a number of examplesThen 483 lists a number of examples……..transfer ..transfer of crude API from of crude API from ---------- reactor to centrifuge is reactor to centrifuge is performed underneath a metal platform in a performed underneath a metal platform in a building which is open to the outside; transfer building which is open to the outside; transfer to the to the multimillmultimill is performed in a room with is performed in a room with peeling and flaking paint on walls/ ceiling; peeling and flaking paint on walls/ ceiling; inside of the inside of the multimillmultimill granulator is corroded granulator is corroded toward the bottom of the chute and was missing toward the bottom of the chute and was missing knives; interior of the vacuum dryer for crude knives; interior of the vacuum dryer for crude API is rusted; transfer room of API to drums has API is rusted; transfer room of API to drums has peeling/ flaking paint on wall/ceilings.peeling/ flaking paint on wall/ceilings.


In the warehouse for storage of In the warehouse for storage of replacement parts such as valves for the replacement parts such as valves for the process water system and reverse osmosis process water system and reverse osmosis membranes, there were numerous membranes, there were numerous pigeons observed flying above the pigeons observed flying above the equipment parts and evidence of bird equipment parts and evidence of bird droppings. This included in the locked droppings. This included in the locked cage which contained the stored reverse cage which contained the stored reverse osmosis membranes.osmosis membranes.


There are no piping or instrument There are no piping or instrument drawings of the incoming source water, drawings of the incoming source water, deionizeddeionized water or water or UltrafiltrationUltrafiltration Water Water systems to show current systems to show current ““asas--builtbuilt””components, treatment or distribution components, treatment or distribution systems of water, for the purpose of systems of water, for the purpose of system maintenance, monitoring and system maintenance, monitoring and operation. operation.


Welds used in the initial installation or Welds used in the initial installation or replacement of critical equipment replacement of critical equipment components are not examined, not components are not examined, not electropolishedelectropolished or in any other manner or in any other manner evaluated against acceptance criteria. evaluated against acceptance criteria.

Several investigations of microbial Several investigations of microbial contamination implicated residual weld contamination implicated residual weld material as a principal contributing factor.material as a principal contributing factor.


There is a dead leg of at least 1 foot in There is a dead leg of at least 1 foot in length between the crystallization vessel length between the crystallization vessel XX (for purified API) and the centrifuge.XX (for purified API) and the centrifuge.

((NoteNote: This was from a previously used : This was from a previously used connection to another piece of equipment connection to another piece of equipment –– no longer is use no longer is use –– now capped)now capped)


The firm recently introduced and qualified The firm recently introduced and qualified a new delivery system for nitrogen a new delivery system for nitrogen blanketing of a critical step in the *** blanketing of a critical step in the *** process. process.

The system including new valves and flow The system including new valves and flow meters was qualified as reported in IQ, meters was qualified as reported in IQ, OQ reports. OQ reports.

FacilitesFacilites & Equipment& EquipmentInspection on (date) found that although the Inspection on (date) found that although the replacement valves associated with lines X and Y replacement valves associated with lines X and Y were closed, the nitrogen flow meter display were closed, the nitrogen flow meter display indicated a significant nitrogen flow to line X. indicated a significant nitrogen flow to line X.

(NOTE: The initial change was made to deal (NOTE: The initial change was made to deal with intermittent flow problem. Following the with intermittent flow problem. Following the inspection, the firm determined that the new inspection, the firm determined that the new valve design was faulty/ not appropriate for the valve design was faulty/ not appropriate for the intended use and replaced all of the valves). intended use and replaced all of the valves).


Equipment cleaning deficiencies Equipment cleaning deficiencies include:include:

a)a) Product residues were visible in numerous Product residues were visible in numerous pieces of equipment labeled as clean pieces of equipment labeled as clean (including fluid bed dryers, centrifuges; one (including fluid bed dryers, centrifuges; one vessel which was stated to have not been vessel which was stated to have not been used in several weeks had yellowused in several weeks had yellow--brown brown residue, no status label)residue, no status label)


b)b) Tape on discharge chutes of centrifuges and Tape on discharge chutes of centrifuges and other surfaces with potential for product other surfaces with potential for product contact.contact.

c)c) There were rough welds on the product There were rough welds on the product contact surface of the hopper used to contact surface of the hopper used to charge purified product to the dryer.charge purified product to the dryer.

(Risk for next batch ? (Risk for next batch ? DegradantsDegradants ?) ?)


According to the firmAccording to the firm’’s written procedure s written procedure (SOP XX(SOP XX--Y), the cleaning of Sparkler filters Y), the cleaning of Sparkler filters requires that at the completion of a requires that at the completion of a campaign, the equipment is dismantled campaign, the equipment is dismantled and all components thoroughly cleaned. and all components thoroughly cleaned. Examination of Sparkler filters #s *** and Examination of Sparkler filters #s *** and *** found the bolts to be worn/ stripped. *** found the bolts to be worn/ stripped.


The firmThe firm’’s maintenance employees in the s maintenance employees in the presence of the plant manager and the presence of the plant manager and the FDA investigator were unable to remove FDA investigator were unable to remove the bolts using dedicated tools. The firm the bolts using dedicated tools. The firm has no individual equipment cleaning has no individual equipment cleaning record and the batch documentation record and the batch documentation records only that all equipment in the records only that all equipment in the ““traintrain”” was cleaned.was cleaned.


The UltraThe Ultra--Filtered (UF) Water system which Filtered (UF) Water system which produces water used in the critical steps of API produces water used in the critical steps of API production was observed to have ballproduction was observed to have ball--type type valves at numerous locations including in the valves at numerous locations including in the finishing area for the final API ******. These finishing area for the final API ******. These valves are potential valves are potential ““deaddead--legslegs”” in the UF Water in the UF Water system. (API ****** is intended to further system. (API ****** is intended to further processing to manufacture sterile products for processing to manufacture sterile products for injection.)injection.)

FacilitesFacilites & Equipment& EquipmentThe piping throughout the purified/UF water The piping throughout the purified/UF water system is ABS plastic pipe and elbows and the system is ABS plastic pipe and elbows and the line leading to the stainless steel holding tank line leading to the stainless steel holding tank (ABS) attaches to a stainless steel line by means (ABS) attaches to a stainless steel line by means of a flange. It was stated that the water in the of a flange. It was stated that the water in the line before the storage tank is drained at times line before the storage tank is drained at times when the system is not producing water, when the system is not producing water, however, it was noted that the ABS line to the however, it was noted that the ABS line to the flange slopes in a manner which would not flange slopes in a manner which would not promote adequate drainage and, therefore, promote adequate drainage and, therefore, could promote could promote biofilmbiofilm production.production.

Production observationsProduction observations

The firmThe firm’’s SOP XX states that batch production s SOP XX states that batch production records for use in production are photocopied records for use in production are photocopied from the master record, however, examination from the master record, however, examination of executed batches found that:of executed batches found that:•• Batch production records are not an accurate Batch production records are not an accurate

reproduction of the master.reproduction of the master.

•• The following steps lacked instruction details given in The following steps lacked instruction details given in the master records:the master records:

(6 examples listed on FDA 483)(6 examples listed on FDA 483)


This observation was on FDA 483 and This observation was on FDA 483 and then cited in a letter from FDQ CDER to then cited in a letter from FDQ CDER to firm:firm:

““The master production and batch production The master production and batch production records for APIs ***, ^^^ and +++ are records for APIs ***, ^^^ and +++ are deficient in that they do not require deficient in that they do not require documentation of all significant steps and in documentation of all significant steps and in many cases are unclear. (Ten examples given many cases are unclear. (Ten examples given on FDA 483).on FDA 483).””


From an FDA 483From an FDA 483::Stage IV master production record does Stage IV master production record does not specify the mill speed nor the screen not specify the mill speed nor the screen to be used during milling and this to be used during milling and this information is not recorded in the batch information is not recorded in the batch record. Additionally, the master record record. Additionally, the master record does not specify the screen to be used does not specify the screen to be used during during seivingseiving..

Production observationsProduction observationsFrom Regulatory LetterFrom Regulatory Letter::

We also have concerns regarding particle size We also have concerns regarding particle size specifications in which all four prospective validation specifications in which all four prospective validation batches failed to meet the release specification.batches failed to meet the release specification.

NoteNote::The letter then reports the fact that inspection found The letter then reports the fact that inspection found that firm actually used different equipment from that that firm actually used different equipment from that described in manufacturing instructions and validation described in manufacturing instructions and validation protocol.protocol.

Production observationsProduction observationsIn the crystallization step to obtain crude ***, In the crystallization step to obtain crude ***, the manufacturing instructions state to add 100 the manufacturing instructions state to add 100 Liters of xxx Liters of xxx dropwisedropwise within 5 to 10 minutes. within 5 to 10 minutes. When it was pointed out that this would be more When it was pointed out that this would be more than 3000 drops per second (in 10 minutes) and than 3000 drops per second (in 10 minutes) and that the same instruction is given in the (original that the same instruction is given in the (original language version), the firmlanguage version), the firm’’s (management title) s (management title) stated that discussion with the production stated that discussion with the production personnel found that this is accomplished personnel found that this is accomplished ““roughlyroughly”” in the time period mentioned in the in the time period mentioned in the batch record by means of a valve.batch record by means of a valve.

Production observationsProduction observationsIt was noted that, in contrast to other It was noted that, in contrast to other manufacturing steps which provide details, there manufacturing steps which provide details, there is no instruction regarding use of valves or other is no instruction regarding use of valves or other means of controlling the flow. means of controlling the flow.

((NoteNote: There was suggestion at one point that : There was suggestion at one point that the word the word ““dropwisedropwise”” came from pilot scale came from pilot scale batches but no documented evaluation of the batches but no documented evaluation of the criticality of the rate of addition and how criticality of the rate of addition and how ““dropwisedropwise”” should have been converted to an should have been converted to an accurate instruction for the scaledaccurate instruction for the scaled--up batches).up batches).


Inspection of first batches of new product Inspection of first batches of new product *** found that the first batch failed *** found that the first batch failed specification for specification for ------ and this was related to and this was related to a critical step. Batch rejected. Corrective a critical step. Batch rejected. Corrective action, change critical process step time action, change critical process step time from 20 minutes to 30 minutes.from 20 minutes to 30 minutes.

(see next slide) (see next slide)

Production observationsProduction observationsExamination of batch records for product +++ Examination of batch records for product +++ which has similar critical step states in the which has similar critical step states in the manufacturing instruction:manufacturing instruction:

““ Perform operation Perform operation ------ for twenty (30) minutesfor twenty (30) minutes””..There is no record of the actual time it took for There is no record of the actual time it took for the operation, yet every batch record has the operation, yet every batch record has twotwosignaturessignatures verifying step done as described.verifying step done as described.


From Warning LetterFrom Warning Letter ((““******”” from FDA not by RCH)from FDA not by RCH)

Several batches of API are *** in a *** to produce Several batches of API are *** in a *** to produce one large batch. The individual batches are not one large batch. The individual batches are not tested for residual solvents and found to meet tested for residual solvents and found to meet appropriate specifications prior to ***. This process appropriate specifications prior to ***. This process has not been validated for *** of the combined has not been validated for *** of the combined batch. The *** is tested for residual solvents, but batch. The *** is tested for residual solvents, but the sampling method, one composite sample, does the sampling method, one composite sample, does not provide evidence of ***.not provide evidence of ***.


Inspection of the manufacturing facility on (date) Inspection of the manufacturing facility on (date) at (time) found that while the two batches of at (time) found that while the two batches of ***, lots ***, lots ---------- and and ---------- had just begun the had just begun the XXXXX step, the XXXXX step, the BPRsBPRs were signed by two were signed by two operators verifying that the 9 step process had operators verifying that the 9 step process had been completed.been completed.

Further, the production QA employee signed the Further, the production QA employee signed the sheet stating that the above was reviewed and sheet stating that the above was reviewed and approved.approved.

Production observationsProduction observationsExamination of reactor GLR # XXX in use for Examination of reactor GLR # XXX in use for the ****** step (critical step) for batch $$$$$ the ****** step (critical step) for batch $$$$$ of the API ***** found that the thermometer of the API ***** found that the thermometer which extends into the reaction mass could not which extends into the reaction mass could not be read. The QA Manager who was be read. The QA Manager who was accompanying the inspection examined the accompanying the inspection examined the batch record for that batch, then leaned forward, batch record for that batch, then leaned forward, examined the thermometer and stated that the examined the thermometer and stated that the temperature was XX C which she stated was temperature was XX C which she stated was ““right on targetright on target””. (continued). (continued)


I asked for the production manager to I asked for the production manager to examine the thermometer and it was examine the thermometer and it was determined that not only could it not be determined that not only could it not be read, the thermometer bulb was broken read, the thermometer bulb was broken and the fluid had emptied. It could not be and the fluid had emptied. It could not be determined when the thermometer had determined when the thermometer had broken nor where the contents of the broken nor where the contents of the thermometer had gone.thermometer had gone.

Production observationsProduction observationsInspection found that the initial production Inspection found that the initial production deviation report # Ddeviation report # D--XX stated that batches XX stated that batches ##### and +++++ of the product *** from a ##### and +++++ of the product *** from a campaign in (time period) were rejected due to campaign in (time period) were rejected due to failing potency results. An amended deviation failing potency results. An amended deviation report prepared just the week before the current report prepared just the week before the current inspection reported that operators admitted to inspection reported that operators admitted to not adequately monitoring the critical step X.00Y not adequately monitoring the critical step X.00Y and simply recorded results typical of previous and simply recorded results typical of previous batches. (continued)batches. (continued)


The amended deviation report:The amended deviation report:

a) Failed to explain how the workshop supervisor a) Failed to explain how the workshop supervisor was able to sign the batch record stating that he was able to sign the batch record stating that he had observed the monitoring of the batches and had observed the monitoring of the batches and that it had been done as per written instructionsthat it had been done as per written instructions

b) Failed to document an extension of the b) Failed to document an extension of the investigation to determine if there were other investigation to determine if there were other batches for which the operators had not batches for which the operators had not properly monitored and documented the properly monitored and documented the reaction progress.reaction progress.

Production observationsProduction observationsRelated to the previous observation, a production Related to the previous observation, a production employee from that shift who was reprimanded employee from that shift who was reprimanded reported that for a previous batch ***, there was a reported that for a previous batch ***, there was a spill of the final product blend from the blender onto spill of the final product blend from the blender onto the floor of production room XX and the employees the floor of production room XX and the employees swept the batch with broom and with scoops and swept the batch with broom and with scoops and reloaded the material back into the blender. reloaded the material back into the blender. According to the investigation report written five According to the investigation report written five months after the event, the team leader was months after the event, the team leader was confronted and acknowledged this had happened. confronted and acknowledged this had happened. This incident had not been documented or reported This incident had not been documented or reported at the time it occurred.at the time it occurred.


NoteNote: : A deviation report examined at another A deviation report examined at another factory stated that certain deviations and factory stated that certain deviations and batch rejections were related to batch rejections were related to ““More More experienced workers know what to do but experienced workers know what to do but take short cuts and do not follow take short cuts and do not follow procedures.procedures.””

Materials observationsMaterials observationsFrom a Warning LetterFrom a Warning Letter

Sampling and Testing of incoming xxx used in Sampling and Testing of incoming xxx used in the manufacture of API *** were inadequate:the manufacture of API *** were inadequate:

At least one specific identity test to verify the identity At least one specific identity test to verify the identity of the incoming material was not conducted.of the incoming material was not conducted.

The reliability of the supplierThe reliability of the supplier’’s certificate of analysis s certificate of analysis (COA) was not established in that a complete analysis (COA) was not established in that a complete analysis was not performed and compared with the COA at was not performed and compared with the COA at appropriate intervals.appropriate intervals.

Materials observationsMaterials observations

From a Warning LetterFrom a Warning LetterProcedures for the recovery of solvents were Procedures for the recovery of solvents were inadequate:inadequate:Procedures for solvent recovery had not been Procedures for solvent recovery had not been established to ensure that solvents are controlled and established to ensure that solvents are controlled and monitored to assure they meet appropriate standards monitored to assure they meet appropriate standards before reuse or commingling with other approved before reuse or commingling with other approved materials. (FDA 483 observation concerned comaterials. (FDA 483 observation concerned co--mingling mingling recovered solvent with fresh solvent before testing of recovered solvent with fresh solvent before testing of the recovered solvent).the recovered solvent).


Recovered solvents were not adequately Recovered solvents were not adequately controlled in that a drum of recovered controlled in that a drum of recovered chloroform was observed stored in the chloroform was observed stored in the area identified for storage of recovered area identified for storage of recovered ethyl acetate. ethyl acetate.

((From a Warning LetterFrom a Warning Letter; the actual FDA 483 ; the actual FDA 483 observation also pointed out that the observation also pointed out that the recovered chloroform was in the middle of recovered chloroform was in the middle of several drums of the other solvent).several drums of the other solvent).


Raw material sampling was not Raw material sampling was not performed in an appropriately performed in an appropriately controlled area and foreign material controlled area and foreign material was noted on the surface of bags of was noted on the surface of bags of approved materials.approved materials.

Materials observationsMaterials observationsSterile PE film used during production to form Sterile PE film used during production to form sterile bags for the finished product is gamma sterile bags for the finished product is gamma irradiated in a validated sterilization at another irradiated in a validated sterilization at another firm, however, the integrity of this film may firm, however, the integrity of this film may potentially be compromised prior to use due to potentially be compromised prior to use due to the practice employed in sampling for release for the practice employed in sampling for release for production. The PE film is transferred to the production. The PE film is transferred to the production area (class 100), sampled, resealed production area (class 100), sampled, resealed and transferred back to the warehouse with and transferred back to the warehouse with ““ReleaseRelease”” stickers place of the original cardboard stickers place of the original cardboard boxes in which the rolls of PE film are stored.boxes in which the rolls of PE film are stored.

Materials observationsMaterials observationsThe firm has outThe firm has out--sourced the testing of API sourced the testing of API ^^^ for residual solvents and does not request ^^^ for residual solvents and does not request testing of residual solvent for every batch of testing of residual solvent for every batch of product manufactured. In addition, review of product manufactured. In addition, review of two test reports from the contract laboratory, two test reports from the contract laboratory, selected at random, found that despite the fact selected at random, found that despite the fact that the firmthat the firm’’s batch records and the DMF show s batch records and the DMF show ethanol to be the only solvent used in the ethanol to be the only solvent used in the process, the test results showed benzene to be process, the test results showed benzene to be present at levels more than 20 PPM. (continued)present at levels more than 20 PPM. (continued)


Finally, the firm reportedly sends Finally, the firm reportedly sends recovered solvent to a contract firm which recovered solvent to a contract firm which performs further purification, however, performs further purification, however, there were no records present to support there were no records present to support this arrangement and in response to my this arrangement and in response to my inquiry, it was stated the factory has never inquiry, it was stated the factory has never audited the contract firm which purifies audited the contract firm which purifies the solvents.the solvents.


The computer software designed by The computer software designed by the firmthe firm’’s IT department for raw s IT department for raw material inventory control has not material inventory control has not been validated and has no user been validated and has no user controls. controls.


There is no password security for the two There is no password security for the two computer terminals (Materials Section and computer terminals (Materials Section and Synthesis Section) which are used for Synthesis Section) which are used for entering and monitoring information entering and monitoring information regarding the receipt, use and inventory regarding the receipt, use and inventory records for raw materials and records for raw materials and intermediates.intermediates.

Packaging & Labeling Packaging & Labeling observationsobservations

Failure to have a written procedure for receipt, Failure to have a written procedure for receipt, identification, quarantine, sampling, release identification, quarantine, sampling, release and handling of labelsand handling of labels

Incoming labels are not proofed against a Incoming labels are not proofed against a master label.master label.

There is no specimen labels placed in the There is no specimen labels placed in the executed batch records.executed batch records.


There is no procedure to reconcile the quantities There is no procedure to reconcile the quantities of labels issued and returned or destroyed.of labels issued and returned or destroyed.

Final product labeling for API *** lacks retest Final product labeling for API *** lacks retest date and storage temperature.date and storage temperature.

Labels on drums of finished API not sticking. Labels on drums of finished API not sticking. ((NoteNote: Inspection found solution employed was : Inspection found solution employed was use two labels use two labels –– hope one sticks).hope one sticks).


The written procedure (SOP) covering labeling of The written procedure (SOP) covering labeling of finished product, i.e., printed bags stamped with finished product, i.e., printed bags stamped with lot number does not address the details of label lot number does not address the details of label issuance or reconciliation following the labeling issuance or reconciliation following the labeling operation.operation.(Inspection found printed bags with two API batch (Inspection found printed bags with two API batch numbers in packaging staged for use in packaging of numbers in packaging staged for use in packaging of those batches. The accompanying paperwork recorded those batches. The accompanying paperwork recorded numbers of bags issued and returned even though numbers of bags issued and returned even though operation not yet started.)operation not yet started.)