Finished Pharmaceutical Products (FPPs) (special reference to TB and HIV/AIDS)

1
Finished Pharmaceutical Products (FPPs)(special
reference to TB and HIV/AIDS)

• World Health Organization
• Training Workshop on Pharmaceutical Quality, GMP
  and Bioequivalence
• Kiev - Ukraine
• 3 to 7 October 2005

Theo Dekker, D.Sc., consultant to WHO Research
Institute for Industrial Pharmacy North-West
University, Potchefstroom, South
Africa iiftgd_at_puk.ac.za
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What is an FPP?

• Pharmaceutical Product
• Any preparation for human or veterinary use that
  is intended to modify or explore physiological
  systems or pathological states for the benefit of
  the recipient
• Finished Pharmaceutical Product (FPP)
• A product that has undergone all stages of
  production, including packaging in its final
  container and labelling
• Marketing Authorization of Pharmaceutical
  Products with special Reference to Multisource
  (Generic) Products a Manual for a Drug
  Regulatory Authority(WHO, Blue Book)

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Section 3. Dossier requirements for a Finished
Pharmaceutical Product (FPP)

• Guideline
• Guideline on Submission of Documentationfor
  Prequalification of Multi-source (Generic)
  Finished Pharmaceutical Products (FPPs)used in
  the Treatment of HIV/AIDS, Malaria and
  Tuberculosis
• (Main guideline, PQ website, hand-out)

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Section 3. FPPs content of dossier 10/50

• 3.1 Manufacturing and marketing authorization
  10/50
• 3.2 Pharmaceutical development 10/50
• 3.3 Formulation 11/50
• 3.4 Sites of manufacturing 12/5
• 3.5 Manufacturing process 12/5
• 3.6 Process controls, critical steps
  intermediates 12/5
• 3.7 Process validation and evaluation 13/5
• 3.8 Specifications for excipients 15/50
• 3.9 Control of the FPP (specifications) 16/50
• 3.10 Container closure system other packaging
  17/50
• 3.11 Stability testing (shelf-life) 17/50
  (separate topic)
• 3.12, 3.13, 3.14 Labelling/SmPC/PIL 23/50
• Not discussed in session

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3.2 Pharmaceutical development 10/50

• The aim of pharmaceutical development is
• to design a quality product and
• the manufacturing process to deliver the product
  in a reproducible manner.
• Quality is built in by design, not tested in
• ICH Q8

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3.2 Pharmaceutical developmentDesk research

• Learn about FPP before development, through
• Standard works / series / books such as
• (Analytical) Profiles of Drug Substances and
  Excipients eds Florey / Brittain 31 volumes
• Especially for older products, such as TB
• Journals through search facilities such as
• International Pharmaceutical Abstracts, Chemical
  Abstracts, Analytical Abstracts internet
• Public assessment reports
• EPAR WHOPAR
• Particularly important for ARVs

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3.2 Pharmaceutical developmentDesk research TB
4FDC tablets (1)

• This is a problem combination
• Composition in current Essential Drug List
• Rifampicin 150 mg
• Isoniazid 75 mg
• Pyrazinamide 400 mg
• Ethambutol 2HCl 275 mg
• Total API weight 900 mg
• Typical tablet weight 1.3 g

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3.2 Pharmaceutical developmentTB 4FDC tablets
a problem mix (2)

• Rifampicin
• Oxidation (quinone N-oxide)
• Protect from air exposure
• Hydrolysis (3-formylrifamycin 25-desacetyl)
• Wet granulation / drying a potential problem?
• Reaction with Isoniazid
• produces 3-(isonicotinylhydrazinomethyl)rifamycin
  or more commonly known as isonicotinyl hydrazone
• isonicotinyl hydrazone major decomposition
  product
• Light sensitive
• Product to be protected from light exposure

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3.2 Pharmaceutical developmentTB 4FDC tablets
a problem mix (3)

• Isoniazid
• Reacts with aldehydes/reducing sugars
• Sugar lactose to be avoided in formulation !!
• 3-Formylrifamycin (from rifampicin)
• Ethambutol hydrochloride (2HCl)
• Hygroscopic
• Absorbs water for reaction in tablets
• Creates slightly acidic conditions
• pH of 2 w/v solution 3.7-4.0 (BP)
• The acidic conditions enhance reaction between
  rifampicin and isoniazid reaction (isonicotinyl
  hydrazone formation)

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3.2 Pharmaceutical developmentTB 4FDC tablets
a problem mix (4)

• Isonicotinyl hydrazone (3-(isonicotinylhydrazinome
  thyl)rifamycin)
• This is major decomposition product in tablets
  containing rifampicin and isoniazid
• Series of articles by dr. S. Singh et al.
  (NIPER), e.g.
• S. Singh, T. T. Mariappan, N. Sharda, S. Kumar
  A. K. Chakraborti. The reason for an increase in
  decomposition of rifampicin in the presence of
  isoniazid under acid conditions. Pharm.
  Pharmacol. Commun., 6, 405-410 (2000)
• The pathway for the formulation of the hydrazone
  is discussed in the above publication

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4FDC-TB tabletsexposed to 40C/75RH for one week

• Two products. Bleeding may start after more
  exposure (in-house) ethambutol hygroscopic
• Indicates problem of moisture
• Control on left Control on left

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4FDC-TB tabletspreventative/protective measures

• Formulation - no sugar/lactose (isoniazid)
• Separate granulation of rifampicin isoniazid
  (limit contact)
• Rifampicin as powder (not granulate)?
• Prevent oxidation hydrolysis
• Low water content of tablet (USP 3.0)
• Protect product from moisture and oxygen
• Film coating
• Non-permeable packaging
• Do not remove from primary packaging
• Avoid repackaging
• Light protection
• Enteric coated tablets (delayed release)?
  clinical studies
• Differential formulation, e.g. delayed release
  immediate release in one tablet ?? clinical
  studies

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3.2. Dossier requirementsPharmaceutical
development

• Section 3.2 should contain information on the
  development studies conducted to establish that
• the dosage form,
• the formulation,
• manufacturing process,
• container closure system,
• microbiological attributes and
• storage and usage instructions
• are appropriate for the purpose specified in the
  application.
• Also consult ICH Q8 Pharmaceutical Development

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3.2.1 Company research and development (RD) 10/50

• Aspects important for development of tablets
• a) Properties of the API of importance to the for
  FPP manufacturing and performance to be
  discussed, supported by data, such as
• Stability for instance against
• heat, oxidation by air and hydrolysis
• Solubility
• Hygroscopicity
• Crystal form and particle size
• especially for practically insoluble APIs

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3.2.1 Company RD (cont.)

• Choice of excipients, e.g.
• Compatibility with API(s)
• Intended functions and concentrations in product
• Safety aspects, e.g. TSE risk, to be addressed
• For fixed-dose combination (FDC) products
• Compatibility of APIs with each other
• Consult the FDC guidelines of WHO and Botswana
  Principles on website

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3.2.1 Company RD (cont.)

• Comparative dissolution testing (separate topic)
• Assist in selection of the formulation
• Compare formulation(s) with innovator product
• This should be a basic strategy in development to
  maximize the chances of bioequivalence
• Comparison of pivotal batches
• Setting of dissolution specifications
• e) Explain
• selection and
• optimisation
• of manufacturing process critical aspects

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3.2.1 Company RD (cont.)

• f) Overages should be justified
• Packaging should ensure stability of FPP
• Prospective validation at development phase
• critical situations
• unsatisfactory processes to be rectified
• See also ICH Q8 guideline

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3.2.1 Company RD (cont.)

• i) Comparison of formulas (tabulated form) of
• bio-batche(s) (clinical / bioequivalence)
• development batches
• stability batches
• batches for validation / production
• Provide brief summary of development of the FPP
  from pre-formulation to production scale

strict requirement
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3.2.1 Information from literature 11/50

• Supportive data from literature can be included
• Strongly recommended
• Scientifically sound do not reinvent the wheel
• Examples
• Examples given at this workshop in other
  presentations
• 4FDC TB tablets incompatibilities (earlier)
• Indinavir sulfate
• Excellent analysis of published data for
  development purposes Dr. J. Pogány Research
  Development, WHO workshop, 28 February 2005,
  Shanghai (PQ website)
• Solid state properties of rifampicin (next slides)

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3.2.1 Information from literatureRifampicin
solid state properties (1)

• Rifampicin exist is 3 solid state forms
• Polymorph I
• Polymorph II
• Amorphous form
• Commercial material contains
• Polymorph II (predominantly)
• Mixture of polymorph II and amorphous form
• Five commercial samples (A to E) tested
• Sample A Form II
• Sample B Form II
• Sample C Form II amorph
• Sample D Form II amorph
• Sample E Form II

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3.2.1 Information from literature Rifampicin -
SEM photos

• Sample A Sample D
• Form II Form II amorph

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3.2.1 Information from literatureRifampicin
-XRPDs

• Top Sample A (Form II) sharp signals
• Middle Sample C (Form II amorph) intensity
  drop
• Bottom Amorphous form - no pattern

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3.2.1 Information from literatureRifampicin
powder dissolution (1)

• Medium 0.1 M hydrochloric acid
• Profiles of all samples are similar
• Dissolves immediately in 0.1 M hydrochloric acid

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3.2.1 Information from literatureRifampicin
powder dissolution (2)

• Medium Phosphate buffer pH 7.4
• Profiles A, B E are similar (f2 50)
• Profiles C D are similar (f2 50) -
  dissolution incomplete
• Profiles A, B, E dissimilar from profiles C,D (f2
  lt 50)

A, B, E(form II)
C, DForm II Amorph
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3.2.1 Information from literatureRifampicin
powder dissolution (3)

• Medium Water
• Profiles A, B E are similar (f2 50)
• Profiles C D are similar (f2 50) -
  dissolution incomplete
• Profiles A, B, E dissimilar from profiles C,D (f2
  lt 50)

A, B, E(form II)
C, D(form II amorph)
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3.2.1 Information from literatureRifampicin -
solid state conclusions

• Solid state forms can be identified with XRPD
  SEM
• Presence of amorphous form slows down dissolution
  of raw material powder at higher pH (f2 test)
• Incomplete dissolution after 65 minutes !!
• Product may fail USP tolerance at pH 6.8 (75 in
  45 min.)
• Reason Agglomeration / wettability
• Comparative powder dissolution powerful tool for
• selection of API manufacturer and
• even in-house specification
• Reference
• S. Q. Henwood et al. Solubility and dissolution
  properties of generic rifampicin raw materials.
  Drug Dev. Ind. Pharm. 26, 403-408 (2000) (RIIP)

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3.3 Formulation 11/50

• Formula in tabulated form for
• Administration unit (e.g. one tablet)
• Typical batch
• Excipients
• State function (e.g. lubricant, disintegrant)
• Technical grade (e.g. micronised, purified water)
• Also those removed during process (e.g. water)
• Also those not always added (e.g. acid alkali)
• Capsule shells, inked imprints on dosage form
• Justify any overages

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3.3 FormulationExample

• ? Removed during process (not in total mass)

Ingredient Quantity per tablet (mg) Quantity per batch (kg) Purpose
Isoniazid 300.00 600.00 Active
---------------- ------(90.00) ------(180.00) --------------
Mg Stearate 2.00 4.00 Lubricant
Pur. Water? 60.0 120.00 Solvent
Total 450.00 900.00
2 000 000 tablets 2 000 000 tablets
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3.5 Manufacturing process 12/50

• Flow diagram
• Indicate critical steps in-process controls
• Description of manufacturing/packaging, including
• Scale
• Equipment by type (e.g. tumble blender) working
  capacity
• Process parameters for steps, e.g. time, temp, pH
• Environmental conditions, e.g. rel. humidity for
  hygroscopic FPPs.

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3.5 Manufacturing process (cont.)

1. Proposal for reprocessing justified with data
2. Copy of master formula
3. Batch manufacturing record real batch
4. Sterile products sterilisation steps /or
   aseptic procedures
5. Description of in-process tests
6. Data for 3 full scale batches to support
   achievement of predetermined specifications

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3.6 Manufacturing process controls ofcritical
steps and intermediates 12/50

• Critical steps
• Acceptance criteria (justified)
• Test methods (cross reference acceptable)
• Intermediates isolated during process,
• for instance tablets cores in film-coated tablet
  production
• Acceptance criteria (justified if not compendial)
• Test methods (cross reference acceptable)

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3.7 Process validation evaluation 13/50

• Differentiate between the following generics
• 3.7.1 New FPPs (new for manufacturer, not
  market)
• FPPs that have been newly developed by the
  manufacturer, though it will be a generic
• Full validation required
• 3.7.2 Established FPPs
• The manufacturer has manufactured marketed this
  FPP for quite some time and now wishes to
  prequalify the FPP
• 10 recent consecutive batches
• result/trend/statistical analysis discussion
• Rejected batches excluded - submit failure
  investigation

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3.7.1 Validation new product 13/50

• Purpose To demonstrate validity of process
• Submit concurrent validation
• If not yet available
• Submit validation protocol (details in dossier)
• Commitment that once data has been generated on
  production scale batches
• the data will be available for verification
  during inspection
• the validation report will be submitted for
  evaluation
• WHO will be informed of any significant
  deviations from the expected and proposed changes
  need prior approval by WHO by way of variation

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3.7.1 Validation new productConcurrent /
prospective validation (1)

• Concurrent validation
• Carried out during normal production
• First 3 production batches (prospective
  validation)
• In-process controls are set on outcome
• Extensive sampling and testing during process,
  for example (tablets)
• planned sampling on mixing / granulation stages
  for content uniformity (low-dose FPPs FDCs !)
• A large number tablets for mass and/or content
  uniformity, hardness, friability and even
  dissolution
• Sampled according to plan during process
• Statistical analysis of results with conclusions
• To be within acceptance criteria

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3.7.1 Validation new productConcurrent /
prospective validation (2)

• Parenteral products, aseptically filled (if
  terminal sterilization is not possible)
• Filling ampoules with culture media, then
• Incubation and control of microbial growth
• Level of contamination 0.1 (previously
  0.3)
• Challenge experiments to determine
• robustness of process
• affect of material variations, such as particle
  size
• Can be carried out on experimental batches
• For instance stability of granulate over time
• Effect in case of unplanned stoppage

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3.7.1 Validation new productConcurrent /
prospective validation (4)

• Laboratory scale batches (small size),
• To support e.g. formulation and packaging
  development
• Pilot batches
• Used e.g. in stability and safety/efficacy
  studies
• Size for oral solid dosage forms the largest of
• 10 of production scale or 100,000 units
• Productions scale
• For full validation and stability studies
• Scale-up / scale down after prequalification
• Up to10-fold compared to the original batch size
  (minor)
• Consult guideline on variations revalidation
  required

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3.9 Control of FPP 16/50

• Four subsections
• 3.9.1 Specifications
• 3.9.2 Analytical procedures
• 3.9.3 Validation of analytical procedures
• 3.9.4 Batch analysis (against full set of
  specifications)
• Three or more batches
• Full information on the batches, e.g.
• Batch number and size
• Date/place of manufacture and QC testing
• Purpose of batches
• Batch number of API
• QA certified

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3.9.1 Specifications for the FPP 16/50

• Specifications are one part of a total control
  strategy for the FPP designed to ensure product
  quality and consistency (ICH Q6A).
• Others include sound development studies and
  adherence to GMP e.g., suitable facilities, a
  validated manufacturing process, in-process
  testing, stability testing, API testing, etc.
• Product specifications (as in pharmacopoeia) or
  split into
• Release specifications and
• Shelf-life specifications (may differ if
  justified)

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3.9.1 FPP specifications (cont.)

• Important reading for setting specifications
• ICH guideline Q6A (also good for generics)
• Specifications Test Procedures and Acceptance
  Criteria for New Drug Substances and New Drug
  Products Chemical Substances.
• Specifications based on compendial monographs
• Additional product related specifications, e.g.
• Those standard for the type of dosage form (e.g.
  friability, tablet hardness, mass uniformity,
  viscosity)
• ID of colorants (skip testing?)
• microbial limits (skip testing?)
• ID and assay of preservatives
• Limits may be tighter than in monograph

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3.9.1 FPP specificationsTypical parameters (2)

• Appearance
• Identification of the following in FPP
• APIs
• Colorants (skip testing possible)
• Preservatives
• Physical tests appropriate to dosage form e.g.
• LOD, friability, hardness (tabs), relative
  density
• Uniformity of dosage units (mass / content)
• Pharmaceutical tests, e.g.
• dissolution
• Each API in FDC products

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3.9.1 FPP specificationsTypical parameters (2)

• Purity tests
• Degradation products (related substances)
• Special attention to API-API degradation products
• Residual solvents (solvents used in process)
• Microbial count / sterility / bacterial
  endotoxins
• Content of APIs in FPP (assay)
• Limits 95.0 105.0, unless justified
• Content of preservatives
• Limits 90.0 110.0, generally acceptable

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3.9.1 FPP specificationsExample for uncoated
tablets (1)
Attribute Release limits Stability limits
Appearance Full description Same as release
Identification At least 1 method Not required for stability studies. Not regarded as variables for product.
Dimensions Diameter, etc Not required for stability studies. Not regarded as variables for product.
Average mass w.r.t. theoretical Not required for stability studies. Not regarded as variables for product.
Mass uniformity Ph.Eur/USP/Int.Ph Not required for stability studies. Not regarded as variables for product.
Tablet hardness product specific Same as release
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3.9.1 FPP specificationsExample for uncoated
tablets (cont.)
Attribute Release limits Stability limits
Friability 1 (normally) Same as release
Dissolution Set per product Same as release
Disintegration Not required if dissolution is done Not required if dissolution is done
Rel. substances (degradants) Only if formed during production Required. Limits to one decimal
Assay (content) 95.0-105.0, unless justified May be 90.0-105.0, if justified
Microbial limits Skip-testing end of shelf
Tests not necessary at release if done in-process Tests not necessary at release if done in-process Tests not necessary at release if done in-process
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3.9.3 Validation analytical methods 17/50

• Non-pharmacopoeial methods
• All methods should be validated
• Validation reports, including data conclusions
• Stability of sample/standard solutions
• Pharmacopoeial methods
• Full or partial validation / verification of
  suitability
• show validity for this formulation specificity
  important
• Validation study - ICH guidelines
• Q2A Q2B

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3.9.3 Validation analytical methodsICH (Q2A)
table - validation parameters
Type of analytical procedure Type of analytical procedure Type of analytical procedure Type of analytical procedure
Characteristics ID impurities impurities Assay Incl. diss.
Characteristics ID quantitative limit Assay Incl. diss.
Accuracy
Precision
Repeatability
Iterm. precision
Specificity
Limit of detection ?
Limit of quantitation
Linearity
Range
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3.10 Packaging 17/50

• Container/closure system (immediate container)
• Suitability for storage, transport, compatibility
• protection against moisture, air, light if
  required
• Detailed description, including liner/wadding
• Specifications of parts in contact with product
• Description
• Identification (Typical IR - specific)
• Drawings and critical dimensions
• Outer packaging
• Description, type of material

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3.11 Stability testing 17/50 separate topic

• One comment here
• The purpose of stability testing is to provide
  evidence on how the quality of a FPP varies with
  time under the influence of a variety of
  environmental conditions such as temperature,
  humidity and light and to establish a shelf-life
  for the FPP
• from EMEA guidance CPMP/QWP/122/02

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3.12 Container labelling 23/50

• Outer packaging
• where no outer packaging, on immediate packaging,
  e.g. HDPE bottle
• Blisters and strips
• All the elements as listed on page 23/50

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3.13 SmPC 3.14 PIL 23/50

• 3.13 Summary of product characteristics (SmPC)
• To appear in WHOPAR
• Changes to SmPC to be approved by WHO
• See Annex 5 of guideline
• 3.14 Patient information leaflet (PIL)
• To appear in WHOPAR
• In conformance with SmPC
• See Annex 6 of guideline
• From quality side, include (where appropriate)
• Identification of dosage form in detail
• Container description in detail
• Storage requirements and approved shelf-life

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Closing remarks

• The joint efforts of manufacturers WHO
• should cover all activities aimed at ensuring
  that the patient receives a product that meets
  established specifications and standards of
  quality, safety and efficacy
• It concerns both
• the quality of the products themselves and
• anything that might affect quality,
• including information supplied with the product
• (derived from Health Action International
  (Africa) definition for QA)
• Quality is built in by design, not tested in