In-Process Testing - 2005 PQRI

IBC Found Course in Pharma Analysis In-Process Sampling 1

Joint CVG/Therapeutic Products Directorate Convention Risk Based Decision Making in

Pharmaceutical Validation

Geoff Carr

Oct 06, 2005

Doubletree International Plaza Hotel, Toronto, Canada

http://www.patheon.com [email protected]

Applications of Stratified Sampling to In-Process Controls and Blend Uniformity

Testing for Solid Oral Dosage Forms


Introduction Very important to have good assurances that manufacture

processes are performing satisfactorily during pharmaceutical production

Process Validation is conducted to ensure that a particular process is inherently sound

In-process controls are designed to challenge the process on a batch by batch basis and demonstrate that each batch manufactureran satisfactorily

Analogous to conducting validation studies on analytical procedures and then applying system suitability tests each time the method is applied to demonstrate that it performed correctlyand results are valid


Introduction In-process controls represent a good example of practical

applications of analytical science This topic will be concerned with the demonstration of the

adequacy of powder mixing as an in-process control Important in the manufacture of solid oral dosage forms eg tablets

and capsules Requirement during development, CTM manufacture, registration

batches, process validation and commercial manufacture Specific FDA requirement that we can demonstrate adequate

mixing of powder blends during manufacture This presentation will deal with issues associated with Blend

Uniformity (BU) testing


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IntroductionBackground to Blend Uniformity TestingWhat is PQRIFDA Guidance on Stratified SamplingCase StudyConclusions


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IntroductionIntroductionIntroductionBackground to Blend Uniformity TestingWhat is PQRIWhat is PQRIWhat is PQRIFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingCase StudyCase StudyCase StudyConclusionsConclusionsConclusions


Background Blend uniformity testing has been considered the most

appropriate way of demonstrating that powders were adequately mixed prior to compression into tablets or filling of capsules

Logically this would seem to be a very appropriate approach FDA issued a DRAFT Guidance in Aug 1999 FDA Guidance proposed that the mean value for BU samples

should be within 90.0 to 110.0% label claim and RSD 5.0% Limits may seem to be very tight in view of typical 85.0 to

115.0% Stage 1 limits for Content Uniformity (CU) but note that CU limits are designed to cope with additional tablet compression or capsule fill variabilities


Background BU testing typically conducted on sample sizes equivalent to 2 to

3 dosage units Samples taken from blender as Top, Middle, Bottom samples

using a sample thief Generally about 12 locations sampled in a blender Our Manufacturing Batch Records (MBRs) include a sampling

plan for the blender being used This all looks very straightforward and should not create any

issues

BUT


Background When sample thief is inserted into blend it can be very disruptive

Local segregation Selective adsorption Electrostatic effects etc

To get samples from 12 locations requires x4 insertions of thief into blend and MBR Sampling Plan indicates locations

We then typically take 2 or even 3 sets of samples Set 1 - For analysis Set 2 - Spare set Set 3 - QC retain set


Background We have had clients that insisted on BU testing with even very

small batches Under these circumstances we get occasional rogue results that

then can create big problems You cannot conduct a complete Out of Specification (OOS)

investigation so difficult to confirm/overcome OOS value Sampling artefacts are well known with standard thieves and so

alternative designs are available to offer alternatives eg compaction thieves Very thin thieves

Even so, problems still continue which led to so much negative response from industry to the FDA DRAFT Guidance that they withdrew it in May 2002


Background You cant overcome a blend uniformity failure by just meeting

Content Uniformity (CU) Test requirements A typical commercial scale batch could consist of 1 million

tablet/capsule units CU testing requires that just 10 units be tested at Stage 1

Could increase to 30 units if Stage 2 testing required Either way, sample size is extremely small and it is dubious

whether this could be considered representative Therefore not surprising that Reg Agencies such as FDA insist

that we apply in-process controls and in this case can demonstrate satisfactory blend uniformity


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IntroductionIntroductionIntroductionBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingWhat is PQRIFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingCase StudyCase StudyCase StudyConclusionsConclusionsConclusions


What is PQRI? PQRI is the Product Quality Research Institute Created in Jan 1996 Collaborative body that involves FDA Centre for Drug

EvaluationResearch (CDER) , N American Pharmaceutical Institutes and academia

Mission To generate scientific information in support of regulatory policies through research

For more info, visit www.pqri.org


What is PQRI? PQRI Member Organisations include:

AAPS = American Association of Pharmaceutical Scientists CHPA = Consumer Healthcare Products Association PDA = Parenteral Drug Association USP = United States Pharmacopeia PhRMA = Pharmaceutical Research and Manufacturers of

America


What is PQRI? PQRI sets up Working Groups to deal with various subject areas Blend Uniformity Working Group (BUWG) was actioned to

propose suitable in-process control systems for powder blends PQRI proposal was issued in March 2002

The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends

Much of the content of this paper has then been taken into a newFDA DRAFT Guidance for Industry

Powder Blends and Finished Dosage Units Stratified In-Process Dosage Unit Sampling and Assessment


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IntroductionIntroductionIntroductionBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingWhat is PQRIWhat is PQRIWhat is PQRIFDA Guidance on Stratified SamplingCase StudyCase StudyCase StudyConclusionsConclusionsConclusions


FDA Guidance Essentially based on principles of stratified sampling as described

in PQRI recommendations but more details of how to apply them


FDA Guidance Scope Stratified Sampling

Process by which samples of dosage units are taken at predefined intervals and collecting samples from specifically targeted locations during compression/filling operation

Targeted locations supposed to have the greatest potential of demonstrating extreme high or low results

Guidance does not restrict us to this procedure and recognises that traditional BU/CU sampling are still acceptable


FDA Guidance Applications Guidance recognises different phases of applications and

generally as: Process Development Phase Exhibit/Validation Batch Phase Verification of Manufacturing Criteria Phase Routine Manufacturing Phase


FDA Guidance Applications Process Development Phase

Correlation of In-Process Stratified Sampling with Powder Mix and Finished Product

Document recommends that procedures recommended in this section be completed if intended to apply stratified sampling atlater stages of development etc

3 phases to this section:




A. Assessment of Powder Mix Uniformity Conduct blend analysis by extensively sampling from blender

and/or intermediate bulk containers (IBCs) Identify

Optimum processing conditions Blending time Speed range

Dead spots in blenders Locations for segregations in IBCs Sampling errors




A. Assessment of Powder Mix Uniformity contd Define sample sizes and develop a reliable method for measuring

true uniformity of the blend Recognises sample sizes could be from 1 to 10x dosage unit

but requires justifications for sample sizes greater than 3x dosage units

Design blend sampling plan and evaluate by appropriate statistical analysis




A. Assessment of Powder Mix Uniformity contd Investigate any variabilities within sample sets ie is it attributable to

Lack of blend uniformity? Sampling error?

Within location variability could be Inadequacy of mixing Sampling error Agglomeration 1 or more of the above

Between location variability could be: Inadequate blending operation




B Correlation of Powder Mix Uniformity with Stratified In-Process Dosage Unit Data

Conduct periodic sampling and testing of dosage units at definedintervals/locations during compression/filling

Minimum of 20 appropriately spaced sampling points At least 7 units at each point Total minimum of 140 samples

Take additional samples of 7s from additional locations to assess significant events

Filling/emptying hoppers/IBCs Start/end of compression/filling Equipment shutdown





Recommended that summary of this data will be required in NDA submission!!!





Compare BU with CU values Investigate discrepancies Plenty of literature references provided that may help Suggests correction of discrepancies could involve

Back to drawing board on product development Process optimisation Sampling issues to be corrected using state-of-the-art methods for

real time sampling and analysis




C. Correlation of Stratified In-Process Samples with Finished Product

Conduct CU test on finished product Compare results with those obtained from stratified in-process

dosage units without weight correction Prepare Table to show that data demonstrates that stratified in-

process sampling provides assurances of CU in finished product Recommends that this is included in NDA


FDA Guidance Applications Exhibit/Validation Batch Phase Phase

Note that Exhibit Batch means any batch submitted in support of an NDA or ANDA

Includes bioequivalence, test and commercial production batches!!!!

Recommends independent assessment of Uniformity of powder blend In-process dosage unit content uniformity Finished product content uniformity


FDA Guidance Applications Exhibit/Validation Batch Phase

Powder Mix Homogeneity Identify at least 10 sampling locations in blender Should represent potential areas of poor blending

For tumbling blenders eg V-blenders, take samples from at least 2 depths along the axis of the blender

For convective blenders eg ribbon blender concentrate on oncorners and discharge areas

Recommends at least 20 locations for convective blenders Take at least 3 replicate samples from each selected location



Powder Mix Homogeneity The following criteria proposed:

Assay 1 sample per location ie n 10 for tumbler blenders n 20 for covective blenders

RSD of all individual results 5.0% All individual results 10.0% (absolute) of mean value ie if mean = 95.0%, 10.0% (absolute) of mean value = 85.0

to 105.0% and not 9.5% If criteria satisfied, proceed to next phase

If criteria not satisfied, investigate (as shown later) and do not proceed further



Powder Mix Homogeneity Guidance recognises that sampling errors can occur Recommends use of in-process dosage unit data in conjunction

with blend sample data to evaluate blend uniformity This is in effect exactly the recommendation that originally came

from PQRI



Stratified In-Process Dosage Unit Sampling Using the stratified sampling approach previously developed,

determine RSD values (Assess normality)

Test results then classified according to RSD as follows: Readily passes RSD 4.0% Marginally passes RSD 6.0% Inappropriate (to demonstrate batch homogeneity) > 6.0%

So thats the objective, this is how we are recommended to proceed:



A Sampling and Analysis Select locations during compression/filling for taking samples Include significant process event locations as previously defined Specifically tells us to take beginning and end samples from units

that would normally be included in the batch Take from at least 20 locations with 7 units each to give a

minimum total of 140 units Assay at least 3 units from the sets of 7 and weight correct the

values



A Sampling and Analysis contd Analyse the data to demonstrate

Normal distribution of API content Investigate any trends

Bimodal distributions Any distribution other than normal

Prepare a summary report and include in NDA



B Criteria for Readily Pass Category RSD of individual results 4.0% (n 60) Each location mean is 90.0 to 110.0% of label claim (n 3) Each individual value is 75.0 to 125.0% of label claim If all criteria satisfied, we are ready to go to routine batch testing



C Criteria for Marginally Pass Category Assay the remaining units from the sets of 7 Check results against following criteria:

RSD of individual results 6.0% (n 140) Each location mean is 90.0 to 110% of label claim (n = 7) Each individual value is 75.0 to 125.0% of label claim

Guidance not clear on how to proceed if we satisfy these criteria. I assume we just proceed as for Readily Pass If we dont satisfy 1 or more of the above, investigate, establish

cause(s), take corrective actions and repeat



D Sample Locations for Routine Manufacture Using data collected above, select stratified sampling locations Take into account significant process events Identify at least 10 sampling locations


FDA Guidance Applications Routine Manufacture Phase

Recommends evaluation against the following criteria: Standard Criteria Method (SCM) Marginal Criteria Method (MCM)

Depending on data obtained from validation batch stage Decision tree provided to show how criteria can switch between

SCM and MCM


FDA Guidance Reporting Use of Stratified Sampling

New Applications Recommends the following information be provided in

Manufacturing Process and Process Controls section (CTD 3.2.P.3.3)

Statements that this Guidance was used or description of alternative methods

Summary of data analysis from powder mix assessment and stratified sample testing

Summary of In-Process dosage unit stratified sampling data that shows normal distribution of API in product

Summary of powder mix sampling data analysis demonstrating it meets acceptance criteria for validation and establishing initial criteria



New Applications contd Product specification (CTD 3.2.P.4.1) should include statement

that methods of this Guidance were used to demonstrate finished product content uniformity or a description of alternative methods

Recommends that information provided in Pharmaceutical Development Information section (CTD 3.2.P.2.2)

Summary of data analysis that correlates in-process dosage unit stratified sampling with finished product content uniformity

Summary of data analysis for correlation of blend uniformity with in-process dosage unit stratified sampling



Post Approval Changes To change from an existing approach to the procedures in this

Guidance, considered a minor change that should be noted in the next annual report together with the information as defined for NDA above


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IntroductionIntroductionIntroductionBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingWhat is PQRIWhat is PQRIWhat is PQRIFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingCase StudyConclusionsConclusionsConclusions


Case Study Dosage form tablets in 2 strengths

0.5mg 1mg

Stage of development Phase II Case involves the first batches of each strength for an early

Phase II study Scale of manufacture about 100,000 tablets of each strength

Equivalent to about 26Kg of blend BU problems had been observed in a feasibility batch of the

0.5mg strength but the 1mg strength seemed to be OK For the Phase II CTM batch we encountered problems with 1mg

tablets


Case Study In-process results for blend uniformity:


Case Study To summarise BU results

Acceptance criteria: Mean value 90.0 to 110.0% label claim RSD 5.0%

Results obtained Mean value 94.8% of lc Max 103.6% Min 85.2% RSD 6.6%


Case Study An OOS investigation was initiated and as part of this Sample

Sets 2 and 3 were tested and previous results were supported Powder blend was held in a single drum and so this was also

sampled with following results


Case Study Mean value (n = 9) 97.3% lc Max 115.8% Min 75.4% RSD 12.2%


Case Study Blend batch was given Conditional Release to compression and

stratified sampling conducted during compression with following results


Case Study In-process results for weight corrected content uniformity:


Case Study To summarise CU results with weight correction Overall mean value (n=154) 96.3% of lc Max 110.9% Min 91.4% Overall RSD 3.0%


Case Study In-process results for content uniformity without weight

correction:


Case Study To summarise CU results without weight correction Overall mean value (n=154) 96.3% of lc Max 111.4% Min 90.5% Overall RSD 3.3%


Case Study Other analytical data for this batch

Content uniformity (n=10) Mean 97.9% of lc Max 100.4% Min 94.6% RSD 2.2%

Potency assay 99.1% 100.9%

Dissolution (n = 6) Mean 100% Max 101% Min 98% RSD 1.4%


Case Study Stratified sample data quite clearly indicated that the blend

homogeneity data was misleading Content uniformity, potency assay and dissolution data showed

reasonable agreements with the stratified sample data


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IntroductionIntroductionIntroductionBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingBackground to Blend Uniformity TestingWhat is PQRIWhat is PQRIWhat is PQRIFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingFDA Guidance on Stratified SamplingCase StudyCase StudyCase StudyConclusions


Conclusions Stratified sampling is an FDA recommended approach of

overcoming difficulties of in-process blend homogeneity testing To follow these principles will generate a considerable amount of

analytical samples Interpretation of results will require very close collaborations

between Analytical and Manufacturing Groups It may be acceptable to FDA but how will other ICH territories

react to this?


Conclusions More details of PQRI and FDA Guidance documents are

available from their respective websites which are available at: PQRI - http://www.pqri.org/ FDA - http://www.fda.gov/ - Section, CGMPs DRAFT

IntroductionIntroductionMenuMenuBackgroundBackgroundBackgroundBackgroundBackgroundMenuWhat is PQRI?What is PQRI?What is PQRI?MenuFDA GuidanceFDA Guidance ScopeFDA Guidance ApplicationsFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Process Development PhaseFDA Guidance Applications Exhibit/Validation Batch Phase PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Exhibit/Validation Batch PhaseFDA Guidance Applications Routine Manufacture PhaseFDA Guidance Reporting Use of Stratified SamplingFDA Guidance Reporting Use of Stratified SamplingFDA Guidance Reporting Use of Stratified SamplingMenuCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyCase StudyMenuConclusionsConclusions

In-Process Testing - 2005 PQRI

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