Trust in Testing: Contract Labs for Safe, Compliant Supplements

Jen JohansenVice President of Quality Regulatory

& Government Affairs, CyanotechCorp.

Catherine Rimmer, Ph.D.Research Chemist,

National Institute of Standards and Technology

Sandy Almendarez Director, Content, Health & Nutrition,

Informa Markets

Tara Lynn Couch, Ph.D.Senior Director of Dietary Supplement and

Tobacco Services, EAS Consulting Group LLC

Ensuring GLPs is Key to Compliance

Jen Johansen

VP of Quality, Regulatory & Government Affairs

Cyanotech Corporation October 17, 2019

GLPs in GMPs

FDA Code of Federal Regulations 21(CFR)111

Subpart J21 CFR 111.303 – SOPs21 CFR 111.310 – Facilities 21 CFR 111.315 – Lab Control21 CFR 111.320 – Methods21 CFR 111.325 – Records

GLPs in GMPs

21 CFR 111.70 – Specifications

Identity, Purity, Strength, Composition

Specification Development

Know Your Product & It’s Unique Attributes

Origin, Processing, Use, Consumer

Use Monographs (USP, FCC)

Astaxanthin(Haematococcus pluvialis microalgae)

Whole Dried MicroalgaeIdentity – DNA or HPLC

Supercritical CO2 ExtractionResidual Solvents?

Softgel EncapsulationPurity (Micros – Allergens)Certifications – Gluten Free?

Product SpecificationsProduct Name: BioAstin® Hawaiian Astaxanthin® 12 mg Soft Gels

Item # Botanical name: Haematococcus pluvialis Country of Origin: USA

QUALITY MEASURE METHOD REFERENCE SPECIFICATION

PHYSICAL PROPERTIES:

Average Fill Weight USP <2091> 505 mg ±5%

Disintegration/Rupture USP <2040> NMT 15 minutes

IDENTITY:

Identification A, B AL-08 (HPLC)** Conforms

STRENGTH:

Astaxanthin AL-08 (HPLC)** NLT 12.00 mg/softgel

PURITY:

E.coli USP <2022> Negative/ 10g

Salmonella USP <2022> Negative/ 10g

Arsenic USP <233> NMT 0.25 mcg/cap

Lead USP <233> NMT 0.1 mcg/cap

Product SpecificationsProduct Name: BioAstin® Hawaiian Astaxanthin® 12 mg Soft Gels

Item # Botanical name: Haematococcus pluvialis Country of Origin: USA

Other Ingredients Shell Ingredients

High Oleic Safflower oil Bovine Gelatin, Glycerin, Purified Water

Packaging, Storage, and Shelf life: Soft Gels are doubled bagged in Polyethylene bag with a 30g desiccant between the inner and outer bags. Double walled cardboard box containing 10,000 gel caps. Store at room temperature. Shelf-life is three years from the date of manufacture.

Labeling Requirements: Labels must have Product Name, Statement of Identity (“Dietary Supplement”), Net Quantity, Ingredient Statement, Telephone Number, and Cyanotech Lot Number and expiration date.

Certifications: Gluten Free, USP Dietary Supplement Verified

Regulatory requirements: Non-irradiated, Non-ETO treated, Non-GMO (no ingredients were genetically modified). Free of: yeast, corn, wheat, gluten, lactose, pesticides and BSE.

Product Specification Development

Monitor Recalls &Serious Adverse Event Reports (SAER)

National Institute of HealthUpper Intake Levels (UL)

Product Specification Development

Prop 65 Limits

Consumer Product Safety Commission (CPSC)

Origin, Global & Consumer Concerns

Melamine, Irradiation, Radiation, Glyphosate

GLPs in GMPs 21 CFR 111.320 - Methods

You must verify that the laboratory test method is appropriate

Is the detection limit sufficient & is the method valid?Gluten 10ppm vs. 20ppm (FDA limit)

21 CFR 111.315 – Lab ControlsWhat tests, specifications, and methods do you use?

USP, FCC Monographs

Have you set criteria for purchasing reference standards?Is the company reputable & do they provide COAs?

GLPs in GMPs

21 CFR 111.310 - FacilitiesAre the lab facilities adequate for testing?(Component, In-process Specs, Supplement Specs)

Microbiology Laboratory

21 CFR 111.303, 111.325 - SOPs, Records

Lab Selection - SOP

Lab Accreditation Current?FDA Registered, ISO 17025, USDA

AOAC Proficiency Testing Program?Accuracy and reliability of data

Accuracy & Reproducibility of Methods?Determined per method

Based on control limits of reference material analyzed daily

Lab Selection - SOP

Calibration & Qualification Programs?Equipment validation, Calibrate per MFG recommendations

Lab Personnel Qualifications, Affiliations, Experience & Expertise?

Microbiology Degree, American Chemical Society

Botanical Reference Libraries

Familiar with product type & matrix

Contract Lab Approval & Annual Monitoring

THE ROLE OF REFERENCE MATERIALS AND QUALITY ASSURANCE PROGRAMS IN LABORATORY QUALIFICATION

KATE RIMMER

CATHERINE.RIMMER@NIST.GOV

NATIONAL INSTITUTE OF STANDARDS AND TECHNOLOGY (NIST)

• NIST is a non-regulatory bureau within the Department of Commerce

• Provide traceability infrastructure for the nation for the measurement of species in clinical, environmental, and food matrices

• Assist industry to meet measurement goals

NIST TOOLS FOR DIETARY SUPPLEMENT ANALYSIS

• Matrix Based SRMs

For method development, validation, and as a quality assurance tool.

• Quality Assurance Programs

For method validation, comparison with community and as a substitute for proficiency testing. Also a tool to learn about community needs, strengths and weaknesses.

VOCABULARY (FOR THIS PRESENTATION)

Reference Standard: measurement standard designed for calibration1

Reference Material: material sufficiently homogeneous and stable with reference to specified properties, which has been established to be fit for its intended use in measurement or in examination of nominal properties.1

Standard Reference Material: SRM is a trademark registered by the US National Institute of Standards and Technology for the certified reference materials they produce.

Certified Reference Material: a reference material accompanied by documentation providing one or more specified property values with associated uncertainties and traceabilities using valid procedures1

Measurement Uncertainty: a parameter, associated with the result of a measurement that characterizes the dispersion of values that could reasonably be attributed to the measurand. Measurement uncertainty reflects the lack of exact knowledge of the value of the measurand.1

Metrological Traceability: Property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations each contributing to measurement uncertainty.2

1

International Vocabulary of Metrology https://www.bipm.org/en/publications/guides/vim.html (accessed 10/2/2019)2 Guide to the Expression of Uncertainty in Measurement https://www.bipm.org/utils/common/documents/jcgm/JCGM_100_2008_E.pdf (accessed 10/2/2019)

QUESTIONS WHEN CONSIDERING RESULTS

Is the lab using a compendial or “official” method?

Has a method extension or verification been performed for a new matrix

If a new method has been developed, has it been validated?

How are calibrants selected and made?

Purity analysis

Number of calibrants

Internal standard, external standard, standard addition?

Use of RMs or CRMs

Participation in Proficiency testing or round robin testing

SCIENTIFICALLY VALID METHODS

A scientifically valid method is:

Accurate

Precise

Specific for intended purpose

Consistently does what it is intended to do

From Tara Lin Couch webinar https://easconsultinggroup.com/what-is-a-scientifically-valid-method/

ACCURACY AND PRECISION

Neither Accurate nor Precise

Accurate but not Precise

Precise but not Precise

Accurate and Precise

ACCURACY AND PRECISION

Increasing Precision

Incr

easi

ng T

ruen

ess

SELECTION AND USE OF A CRM

Milk thistle capsules, need to determine Cadmium

https://www.enerhealthbotanicals.com/milk-thistle-tincture.html Test contents only or full capsule?

SELECTION AND USE OF A CRM

SRM 3256Green Tea Tablets

Cd = 25 ng/g

AnalyteAnalyteAnalyte

Finished ProductPlant Extract

Cd

SRM 3248Ginkgo TabletsCd = 1.56 ng/g

SRM 3280MultivitaminCd = 80 ng/g

AnalyteAnalyte

SRM 3248Ginkgo TabletsCd = 1.56 ng/g

SRM 3280MultivitaminCd = 80 ng/g

Material Type(Plant, Extract, Finished Product)

30 ng/g

SELECTION AND USE OF A CRM

NIST Certified Value25 ± 2 ng/g

Lab Result29.9 ± 2 ng/g

Moisture = 2.36 %

22

24

26

28

30

32

34

NIST Lab

Mas

s Fr

actio

n (n

g/g)

Cd in SRM 3256 Green-Tea Containing Tablets

SELECTION AND USE OF A CRM

Cd in SRM 3256 Green-Tea Containing Tablets

22

24

26

28

30

32

34

NIST Lab

Mas

s Fr

actio

n (n

g/g)

NIST Certified Value25 ± 2 ng/g

Moisture = 2.36 %

Lab Moisture-Corrected Result30.6 ± 2 ng/g

SELECTION AND USE OF A CRMIs 30.6 ng/g ± 2 ng/g equivalent to 25 ng/g ± 2 ng/g?

∆m = Cm − Ccrm u∆= u2

m + u2crm

𝑈𝑈∆= 2 ∗ u

∆

∆m absolute difference between mean measured value and certificate value

cm mean measured valueccrm certified value

u∆ combined uncertainty of result and certified value (uncertainty of ∆m)

um uncertainty of the measurement resultucrm uncertainty of the certified value

U∆ expanded uncertainty of difference between result and certified value

If ∆m ≤ U∆ then there is no significant difference between the measurement result and the certified value.

30.7 − 2 = 5.6 22 + 22= 2.8

2 ∗ 2.8 = 5.6

5.6 ≤ 5.6

Difference between Mean and Certified Value Combined Uncertainty

Compare ResultsExpanded Uncertainty

ROLE OF PROFICIENCY TESTING AND ROUND ROBIN

Sign up for exercise

Receive Samples

Test Samples

Report Results

Review Data Tables

Receive Report

Maybe Pay

In-house methodOrMandated Method

Note condition and storage instructions.

PT=reviewRR=maybe review and change

How do different methods compare?

WHAT WE WANT TO TEST: TYPES OF SAMPLES

https://www.mountainpanoramas.com/__magazine/_articles/everest-2014.html

https://littlechefbigappetite.com/chia-seed-and-turmeric-smoothie-recipe/

https://www.irishtimes.com/life-and-style/food-and-drink/what-s-really-in-protein-bars-and-are-they-healthy-1.3610375

https://www.sciencedirect.com/science/article/pii/S0378874111003035

WHAT WE WANT TO TEST: METHOD CHARACTERISTICS

Sample Preparation Instrumental MethodsCalibration

https://www.calpaclab.com/soxhlet-extraction-workstation-with-heating-mantle-stirrer-250ml-flask/un-hmsox-250#

https://www.pce-instruments.com/english/weighing-equipment/scales-and-balances/analytical-balance-pce-instruments-analytical-balance-pce-bt-200-det_61986.htm

https://www.srainstruments.com/p/gc-ms-5977b-agilent-technologies/

LESSONS: CONCENTRATION DEPENDENCE

LESSONS: METHOD BIAS

LESSONS: METHOD BIAS

WHAT CAN WE USE A QAP FOR: COLLABORATIVE STUDY

Stakeholder Panel Identifies

Needs

Working Group Establishes

Performance Requirements

Experts Review Submitted

Methods with Single Lab Validation

Information

First Action Method

Method Tested Further in

Collaborative Study

Recommendation to OMB for Final

Action or Withdraw

WHAT CAN WE USE A QAP FOR: IDENTITY

WHAT TO THINK ABOUT

How do you validate your methods?

Do you evaluate performance with new samples?

Is your method an “official method”?

Do you use reference materials?

Where are they from?

Do they have qualitative or quantitative values?

Are you getting the “right” results?

Do you participate in a QAP or PT?

How do your results compare with other labs and with the “right” results?

How often do you participate?

SUMMARY OF TOOLS FOR LABORATORY EVALUATION

Reference Materials

Quality Assurance Programs

Method Validation X X

Quality Control X X

Analyst Training X X

Preparation of In-House RMs X X

Document fit-for purpose performance X X

Improve measurement comparability X X

Rapid Response to Emergent Needs X

THANK YOU

Thank you to the Office of Dietary Supplements at the National Institutes of Health for Funding

Questions?

Catherine.Rimmer@nist.gov

Produced by

Auditing Your Contract Laboratory to Ensure “Trust in Testing”Tara Lin Couch, Ph.D.Senior Director of Dietary Supplement and Tobacco ServicesEAS Consulting Group

Specializing in FDA Regulatory Matters

FDA Enforcement• Nine years after full FDA enforcement of Good Manufacturing Practices

(GMPs) for dietary supplements the greatest challenge to the dietary supplement industry continues to be the establishment of specifications and testing in accordance to those specifications.TOP FDA Observations: 2010 - 2017

2010 2011 2012 2013 2014 2015 2016 2017 2010-20171 21 CFR 111.75 Testing 54 111 226 287 188 144 195 216 14212 21 CFR 111.70 Specifications 32 104 176 234 204 154 214 251 13693 21 CFR 111.205 MMRs 28 53 94 117 82 67 87 94 6224 21 CFR 111.255 BPRs 18 52 74 93 71 71 72 87 5385 21 CFR 111.103 QU Operations 18 43 47 66 47 45 55 76 3976 21 CFR 111.553 Product Complaints 15 34 42 70 36 28 31 63 3197 21 CFR 111.453 Holding & Distribution 6 18 29 47 32 27 30 46 235

631 1328 1964 2211 1549 1294 1625 1842 12444Total Observations

DescriptionCitationRank Number of Times Cited

FDA Enforcement• 21 CFR 111.70 - Specifications for raw

materials (components), in-process materials, and products must be developed and used to verify that the finished dietary supplement product consistently meets its quality expectations.

• 21 CFR 111.73 and 111.75 – Testing of all materials and products is required to verify that the specification is met.

Regulations• 21 CFR 111, Current Good Manufacturing Practices (cGMP) in

Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements.

• To ensure the quality of a dietary supplement specifications must be established by the brand owner and manufacturer to ensure production and process control.

• 21 CFR 111.70: You must establish specifications to ensure the quality of the dietary supplement

(b): Raw Materials – Components and Dietary Ingredients(c): In-process Materials(d): Labels and Packaging Components(e): Finished Products(f): Finished Products – Received from a Contract Manufacturer(g): Finished Products – Packaged and Labeled

Regulations• 21 CFR 111.73: You must determine whether the specifications you establish under

111.70 are met.• 21 CFR 111.75: What must you do to determine whether specifications are met?

(a)(1)(i): Conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient (a)(2)(i): Conduct other appropriate component tests or examinations(b): Monitor the in-process points, steps, or stages where control is necessary(c): Verify that your finished batch of the dietary supplement meets product specifications via tests and examinations(e): Visually examine product received from a Contract Manufacturer (f): Conduct visual examinations and documentation review from suppliers of packaging components and labels(g): Conduct a visual examination of the finished packaged and labeled dietary supplement

Required Specifications

• Raw Materials• In-Process Materials• Finished Products

• Packaging Components

• Labels - Comply with 21 CFR 101.9, Nutrition Labeling of Food

IdentityPurityStrengthCompositionLack of Potential Contaminants

SafeSuitable for Intended UseNot Reactive or Absorptive

Establishing Specifications• Finished Product Specifications must be established as a coordinated effect with all

contracting partners including the dietary supplement brand owner or Own Label Distributor (OLD), Contract Manufacturer, and Contract Laboratory to ensure that all the necessary information is taken into account.

• Product Label Claims• Supplement Facts Panel (SFP)• Front panel • “Romance” panel• Other labeling such as pamphlets, flyers, advertisements, and other media

information provided to the consumer

Establishing Specifications• Product Formulation

• Components: Dietary ingredients and other ingredients - Characteristics, ingredient form, manufacturing processes, origins, and concentration in the formulation

• Intended Overages• Manufacturing Process

• Special processing steps or processing aids – Potential contaminants introduced• Manufacturing variability• Dietary ingredient interactions

• Test Methods• Clearly defined, written test method assigned• Scientifically Valid: Experimentally documented• Test method variability

• Dietary Ingredient Stability

Contract Laboratory

• Contract Laboratory – External, third-party laboratory that provides analytical, microbiological, and/or physical testing of raw materials, in-process samples, finished products, stability time-point samples, and environmental samples.

• Other services may include:• Analytical method development, verification, and validation.• Microbiological preservative effectiveness and preparatory testing.• Storage of stability samples.• Clinical studies to support NDI notifications

• A Contract Laboratory is an extension of the Quality Unit for companies such as dietary supplement manufacturers and product Own Label Distributors (OLDs) using their services.

“So, how does a dietary supplement brand owner or Own Label Distributor (OLD) know that the contract laboratory sought out for technical expertise can be trusted?”

Qualification• Qualification – A pass of an examination or an official completion of a course, especially

one conferring status as a recognized practitioner of a profession or activity. A condition that must be fulfilled before a right can be acquired; an official requirement.

• A Contract Laboratory qualification process is designed to ensure that the Contract Laboratories has:

• Technical expertise necessary to perform testing services;• A quality system that has been established to support substantial compliance with 21

CFR 111; and• Procedures related to the appropriate development and use of scientifically valid test

methods in place.

Laboratory Qualification• Contract Laboratory Qualification

• Documentation (Paper) Audit• On-Site Laboratory Facility Audit• Challenge Testing• Risk Assessment• Periodic Re-Qualification

Qualification Status

• Qualified - Laboratory who has been deemed acceptable for testing service use based on approval of the Contract Laboratory Questionnaire, risk assessment, on-site audit, and/or challenge testing results.

• Provisionally Qualified - Laboratory who has been deemed temporarily acceptable for testing service use based on current corrective and preventative actions for all non-critical compliance issues.

• Not Qualified - Laboratory who has been deemed unacceptable for testing service use based on the rejection of Contract Laboratory Questionnaire responses, identification as high risk via the risk assessment, unacceptable on-site audit report findings, and/or challenge testing results

Documentation Audit• Each proposed laboratory is sent a Contract Laboratory Qualification Questionnaire for

completion and return to the manufacturer or OLD Quality Unit.• The questionnaire will include information about the laboratory personnel, facility,

equipment, laboratory processes, documentation, test methodologies, and quality system.

• Any regulatory history of the laboratory will also be requested.• Completed questionnaires will be reviewed by the Quality Unit.• Responses must be thorough and detailed.

• Incomplete or unreturned questionnaires ⇒ Not Qualified• Unsatisfactory responses ⇒ Not Qualified

On-Site Laboratory Audit• On-Site laboratory audits are ESSENTIAL to verify that the information provided on the

questionnaire for the documentation audit are accurate and that the systems, policies, processes, and test methods provided are being followed in practice.

• The use of a Laboratory Qualification Questionnaire, often referred to as the paper audit, alone is NOT sufficient.

• An on-site audit must be performed to determine if Good Manufacturing Practices, Good Laboratory Practices, and Good Documentation Practices; processes; and test methods indicated are being followed as documented.

• A true evaluation of a laboratory facility and personnel can only be accomplished on-site.

• Contract Laboratory Audits should be completed prior to testing!⇒ Data generated at the laboratory is used to ascertain if the dietary supplement product has met specifications and can be released and distributed to the consumer.

Audit• The audit should be scheduled for 1 – 2 Days, depending on the scope of the work being

conducted at the laboratory.• Opening Meeting (No more than 30 minutes)

• Personnel introductions• Discussion of purpose and scope of audit• Laboratory operations overview – verbal or presentation

• Facility “Tour”• Escorted walkthrough of all laboratory facilities• Questions and Answers on all laboratory operations• Discussions regarding observed regulatory issues• Documentation requests

Audit• Documentation Review

• Extensive records review• Additional documentation requests, as necessary• Copious notes made of laboratory operations, procedures, and records.

• Emphasis on regulatory observations • Continued during working lunches

• Close-Out Meeting • Verbal summary of audit findings presented by auditor

Auditor• It is imperative that the auditor has expertise in laboratory operations, and especially the

type(s) of testing being performed at the contract laboratory. • Hire an appropriate Subject Matter Expert (SME) or use a laboratory

consultant if an appropriate auditor is not available at the OLD or manufacturer.

• Auditor MUST have expertise in the area of work that the Contract Laboratory will be performing.

• Audit also serves as the beginning of the business relationship with the laboratory.• OLD or manufacturer should be present during the audit even if outside auditor is

utilized.

On-Site Audit Categories• Personnel• Facility• Equipment• Laboratory Processes• Documentation• Test Methods• Quality Systems

Personnel• A variety of scientific expertise among the

laboratory personnel will be available depending on the testing that is performed.

• All personnel must possess the education, training, or experience needed to perform their job function in accordance to 21 CFR 111.12(c).

• Assigned Supervisors must also have the education, training, or experience to supervise laboratory operation per 21 CFR 111.13(b).

Laboratory Personnel• Personnel will include:

• Educated Scientists: Chemistry, Microbiology, and other scientific disciplines.• Bachelor of Science (B.S.)• Master of Science (M.S.)• Doctor of Philosophy (Ph.D.)

• Laboratory experience• Safe use of chemicals, bacteria (particularly pathogens), yeasts and molds• Knowledge of laboratory processes

• Subject Matter Experts (SMEs)• Specific analytical and/or microbiological techniques

Training Documentation• Job Description (JD) – Description of the required education, training, and experience;

and responsibilities for each assigned job function or title.• A Training Record is used to document that each individual possesses the requirements

indicated in the JD. This will include both on-the-job training as well as prior education and experience.

• Education and Experience• Resume, Curriculum Vitae (CV), Job Application, Biography

• Training• On-the-Job training: Read and Understand versus Proficiency Testing • Course attendance• Certifications

Laboratory Facility• 21 CFR 111.310: Must use adequate laboratory facilities to perform testing and

examinations• 21 CFR 111.20(a): Suitable in size, construction, and design to facilitate maintenance,

cleaning, and sanitizing operations• 21 CFR 111.20(b): Have adequate space to prevent contamination and mix-ups

• Microbial - Microbiology testing must be conducted using the aseptic technique to prevent cross contamination of bacteria, yeasts, or molds.

• Some dietary supplement materials and products, such as probiotics and botanicals, contain high amounts of bacteria.

• Microbiology laboratories will have live organisms • Growth promotion studies to demonstrate a

test method is scientifically valid• Positive controls during testing

Listeria monocytogenes

Laboratory Facility• Allergens – Food allergies are triggered by an abnormal immune response and can

cause severe reactions, and may even be life-threatening. • Eight major food allergens are Milk, Eggs, Fish, Crustacean shellfish, Tree nuts,

Peanuts, Wheat, and Soybeans.• Many material and product samples being tested will contain one or more of these

eight food allergens.• Allergen cross-contamination is a major topic of the 21 CFR 117, HARPC

Laboratory Facility

• Chemical Hygiene Plan (CHP): Safe operating conditions

• CHP is a written program that describes the procedures, equipment, personal protective equipment (PPE), and work practices that protect personnel from potential health hazards presented by hazardous chemicals, carcinogens, or toxins that may be present or in use.

• Hazardous Waste Control: • Identification, storage, and disposal in accordance to

local, state, and federal regulations• Chemical waste streams• Biohazardous waste

Laboratory Facility• Water:

• Water used as an ingredient or supportive operations during dietary supplement product manufacture must meet the National Primary Drinking Water Regulations(NPDWRs) dictated in 40 CFR part 141 ⇒ Minimum requirement.

• Test Methods may dictate different, more stringent water standards:• Distilled – Water with impurities removed through distillation.• De-ionized - Water passed through cation and anion exchange resins, mixed-bed

filters, to remove dissolved salts.• Ultrapure – NPDWR water that is carbon filtered, de-ionized, treated by reverse

osmosis, exposed to ultraviolet oxidations, and finally microfiltered.• United Stated Pharmacopeia (USP) Water with requirements dictated in chapter

<1231>, Water for Pharmaceutical Purposes

Equipment Qualification• In accordance to 21 CFR 111.27 of Subpart D – Equipment and Utensils:

• (a): All equipment must be of appropriate design, construction, and workmanship to enable them to be suitable for their intended use

• An equipment qualification is conducted to demonstrate and document that the equipment is of appropriate design, construction, workmanship, and is suitable for its intended use as required in 21 CFR 111.27.

• Design Qualification (DQ)• Installation Qualification (IQ)• Operational Qualification (OQ)• Performance Qualification (PQ)

• Equipment Qualification Protocol developed for each step; and then executed and documented at the time of performance.

• Process of equipment qualification is described in a Standard Operating Procedure (SOP).

DQ/IQ/OQ/PQ

Equipment Calibration• 21 CFR 111.27(b): All equipment must be calibrated before its first use and at a frequency

dictated by the manufacturer to maintain accuracy and precision• Equipment that is calibrated for all direct and indirect measurements needed to obtain

an analytical result prior to each use does NOT require an equipment Qualification.• This includes general and physical Equipment without sophisticated computer

software that incorporates authorization controls, audit trails documentation, and mathematical operations.

• Calibration activities must be documented per 21 CFR 111.35(b)(3).• A calibration sticker is usually applied to note the calibration status, date of the

calibration, the person performing the calibration, and the next calibration due date.

Equipment Maintenance• 21 CFR 111.27(c): Equipment or the

controls thereof must be repaired or replaced if they cannot be adjusted to agree with the reference standard

• 21 CFR 111.27(d) states that all equipment must be maintained, cleaned, and sanitized as necessary.

• 21 CFR 111.35(b)(2) also requires that equipment logbooks be used to document all maintenance, cleaning, and sanitizing activities of equipment.

Laboratory Processes• 21 CFR 111.315: Laboratory control processes must be reviewed and approved by quality

control personnel.• Vital laboratory control processes include:

• Sample Management• Receipt, Identification, Chain of Custody (COC), Retention, Disposal

• Chemical Inventory• Receipt, Identification, Tracking, Handling, Expiration Dating, Storage, Proper

Disposal• Chemical Preparations

• Lot number assignment, Tracking, Expiration Dating, Usage, Storage• Pipetting / Dilution Technique

• Media Preparations• Lot number assignment, Tracking, Expiration Dating, Usage, Storage• Aseptic Technique• Sterility and Growth Promotion Testing

Laboratory Processes• Chemical and Biological Standards Management

• Lot number assignment, Tracking, Expiration Dating, Usage, Storage• 21 CFR 111.315(d): Use of criteria for selecting standard reference materials used

in performing tests and examinations• Quality Controls

• Microbiological• Analytical

• Data Review• Analyst, Peer, Supervisory, QA

• Data Management • Reporting, Tracking, Archival

Documentation• Subpart J – Laboratory Operations

• 21 CFR 111.325 (2)(i)(ii): Must document testing and examinations at the time of performance and include all test results.

• Subpart P – Records and Recordkeeping• 21 CFR 111.605(a): You must keep written records required for 1 year past the shelf

life date, or if no shelf life date used, 2 years beyond the date of distribution of the last batch associated with those records.

• 21 CFR 111.605(b): Records must be kept as original records, as true copies (such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records), or as electronic records

• 21 CFR 111.605(c): All electronic records must comply with 21 CFR 11, Electronic Records, Electronic Signatures.

• Dietary Supplement and Nonprescription Drug Consumer Protection Act: Serious Adverse Event documents must be kept for 6 years

Test Methods• 21 CFR 111.303: Must establish and follow written procedures for laboratory operations,

including written procedures for the tests and examinations conducted.• Test methods used for the determination of whether a dietary supplement material or

product has been met must be scientifically valid as required in 21 CFR 111.75(h)(1) and 111.320(b).

• The FDA described a scientifically valid test method in the Preamble to the 21 CFR 111 regulation as:

• Accurate• Precise• Specific for its intended purpose • Consistently does what it is intended to do: Rugged

• Documentation that a method meets these criteria is accomplished from studies for the particular sample matrix via experimentation, peer-reviewed literature, or compendial sources.

Quality Systems - OOS• Out of Specification (OOS) Investigations

• Purpose of OOS investigation is to determine if the original result is Valid.• To be meaningful, the investigation should be thorough, timely, unbiased, well-

documented, and scientifically sound.• FDA, Center for Drug Evaluation and Research (CDER), Guidance for Industry: Out

of Specification (OOS) Test Results for Pharmaceutical Production, October, 2006. • Phase I

• Documentation review• Historical Review

• Phase I – Experimental• Re-Analyses of Sample• Re-Testing of Sample

Quality Systems - OOS• Phase II

• Additional testing• Resampling• Method modifications

• CANNOT “Test into compliance”• CANNOT average failing results with passing results to produce a passing result

• U.S. v Barr Laboratories, 812 F. Supp. 458, 03/30/93.

Quality Systems• Deviations

• Planned versus Unplanned deviations from controlled processes or test methodologies• Thorough evaluation to ensure that sample and date integrity have not been

compromised• Change Control

• Tracking and monitoring system for creation and modification of control processes• Corrective and Preventative Actions (CAPAs)

⇒ Used to address Observations found during Contract Laboratory Audit and listed in Audit Summary Report!

Audit Report• A thorough and detailed written summary of observations noted during the audit will then

be prepared by the auditor. This is the document that will be used to assign necessary CAPAs and demonstrate laboratory compliance.

• Audit Observations should be categorized as critical, major, or minor depending on severity of expected FDA action.

• Critical – Systematic issue, Observation routinely cited in FDA Warning Letters• Major – Clear regulatory violation but not necessarily systematic, Observation noted

in FDA 483 List of Observations Forms• Minor – Opportunity for improvement, potential FDA 483 Form observation

• List of necessary Corrective and Preventative Actions (CAPAs).• May include recommendations for improvements

Challenge Testing• Challenge Testing may be conducted to evaluate the overall performance of the Contract

Laboratory, verify the appropriate application of GMP quality systems, and the use of scientifically valid test methodologies.

• Indirect assessment of the accuracy, precision, specificity, and ruggedness of the test methods ⇒ Scientifically Valid Test Method

• Performed with or without contract laboratory knowledge• Tool to avoid “dry-labbing” or the falsification of testing

and/or test results. • Types of challenge testing:

• Inter-laboratory Testing• Replicate Testing• Use of Fortification (spiked) Samples• Blind Testing

A good Contract Laboratory will NOT be offended by the use of challenge testing.

Me

Risk Assessment• Completed Contractor Laboratory Questionnaires are used to conduct an initial Risk

Assessment but this should be continually monitored and modified based upon all of the following Risk Factors:

• Laboratory regulatory history;• Quality System;• Personnel and technical expertise;• Criticality of tests performed;• Volume of tests performed;• On-Site Audit Report and outcome; • Challenge testing results;• Quality of service and communication with laboratory; and• Frequency, root cause(s), thoroughness, and timeliness of

Out of Specification (OOS) investigations

Re-Qualification• Questionnaires will be resent to Qualified or Provisionally Qualified Contract

Laboratories annually to capture any major facility, personnel, equipment, test availability, or quality system changes.⇒Re-Qualification

• Follow-Up On-Site Audit Frequency will be determined by:• Annual Questionnaire update• Previous On-site Audit Report• Results of Challenge Testing• Other issues or situations with Contract Laboratory

Tara Lin Couch, Ph.D.Senior Director of Dietary Supplement and Tobacco Servicestcouch@easconsultinggroup.com571-447-5500 571-447-5510 (Direct)www.easconsultinggroup.com

Specializing in FDA Regulatory Matters