Transcript No Slide Title

Drug Manufacture,
Quality Assurance,
and Regulation
Tom Layloff
Quality Assurance Advisor
Supply Chain Management System –
Providing Quality Medicines for People Living With and
Affected by HIV and AIDS
www.scms.pfscm.org [email protected]
The views expressed here are those of the author and
may not be those of USAID, SCMS, FDA, or MSH.
www.layloff.net [email protected]
Objectives
By the end of this session, you should be able to—
• Describe the difference between Active Pharmaceutical Ingredients
and Dosage Forms
• Differentiate between brand vs. generic products and the conditions
for interchange
• Be familiar with drug manufacturing requirements and Good
Manufacturing Practices (GMP)
• Explain the concept of and issues relating to drug product quality
assurance
• Identify risks associated with substandard and counterfeit drug
products
• Understand the extent of the problem of substandard and
counterfeit drug products in developing countries
• List and describe the components of a quality assurance system
• List criteria for quality testing
• Outline an approach for quality testing in resource-limited settings
The Drug Universe
• Begins with the Active Pharmaceutical Ingredient (API).
• APIs are chemicals that have been shown through clinical studies or
long history of safe use to have desirable therapeutic properties when
used appropriately.
• APIs are extracts from natural products or are chemically or biologically
synthesized.
• The safety and efficacy (S&E) of APIs are established almost
universally through the guidelines developed by the International
Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH), www.ich.org.
• The ICH guidelines are adopted into the laws and regulations of the
ICH countries (European Union, Japan, and USA) where essentially
100% of the drug research is conducted and which constitute over 85%
of the world drug market.
• WHO has observer status and represents interests of other countries.
Global Pharmaceutical Sales by Region, 2005
2005 Sales
(US$B)
% Global Sales
% Growth
Year-over-Year
(Constant $)
North America
$265.7
47.0%
5.2%
Europe
169.5
30.0
7.1
Japan
60.3
10.7
6.8
Asia, Africa and Australia
46.4
8.2
11.0
World Audited Market
(China)
Latin America
Total IMS Audited*
(11.4)
(20.4)
24.0
4.2
18.5
$565.9
100%
6.9%
*Source: IMS MIDAS®, MAT Dec 2005. All information current as of February 27
Sales in ICH countries (No. America, Europe, Japan) totals 87.7%
More on APIs
• Chemically synthesized APIs (fine chemicals) are
produced primarily in the China/India economic block,
Korea, and Italy (near Milan).
• Biotechnologically derived APIs are almost all
manufactured in the ICH regions.
• The clinical studies—Phase III—define the therapeutic
window for a specific drug—too much may be toxic and
too little may be ineffective.
• Summary: Clinical studies are used to define the safety
and efficacy of a drug product containing the API and the
therapeutic window in which the drug is effective.
The Nomenclature of APIs
• International Non-proprietary Names (INN) for APIs are
assigned by the WHO or in the USA by United States
Adopted Names (USAN) Council established by the AMA,
USP, and APhA. The INN and USAN names are generally
the same but some are not—e.g., acetaminophen (USAN)
and paracetamol (INN).
• Single source (new) and generic drug products frequently
are given proprietary trade names by the manufacturer for
market leverage—e.g., Tylenol brand acetaminophen and
Bayer brand aspirin. In Namibia, a pharmaceutical
distributor carried 28 trade name amoxicillin products.
• A MESS.
New Drug Development
Generic Drugs
• A generic drug product is bioequivalent to an “innovator”
(new) drug product with respect to pharmacokinetic and
pharmacodynamic properties.
• Generic drugs must
– Contain the same active ingredient at the same strength as the
"innovator" product
– Be bioequivalent
– Meet the same pharmacopoeial standards as applicable
– Be identical in dose, strength, route of administration, safety,
efficacy, and intended use
Therapeutic Window – Bioequivalence
New vs. Generic Review Processes
New Drug (ICH)
Requirements
1.
2.
3.
4.
5.
6.
7.
8.
Chemistry
Manufacturing
Controls
Labeling
Testing
Animal studies
Clinical studies
Bioavailability
Generic Drug
Requirements
1.
2.
3.
4.
5.
Chemistry
Manufacturing
Controls
Labeling
Testing
6. Bioequivalence
Preparing an API for Patient Use
• To serve the patient’s needs an API must be provided in
the right amount using an appropriate delivery
mechanism (i.e., a drug product or dosage form).
• Excipients are used to make the drug more convenient,
palatable, or effective.
– 325 mg Tylenol tablet excipients include cellulose, corn starch,
magnesium stearate, sodium starch glycolate.
• Some common dosage forms include –
Capsules
Tablets
Chewable tablets
Granules
Creams
Gels
Ointments
Injections
Powder for injection
Oral solutions
Suspensions
Syrups
Powder for suspension
Rectal suppositories
Vaginal suppositories
Inhalers
Powder for inhalation
Transdermal patches
Creating a Drug Product
• Extemporaneous compounding:
– Part of the practice of medicine and pharmacy.
– Governed by Good Compounding Practices.
– In the US, the practice of medicine and pharmacy is regulated by
state professional practice boards.
• Manufacturing:
– Governed by current Good Manufacturing Practices.
– API and drug product manufacturing are regulated by national drug
regulatory bodies (FDA in the US).
Drug Product Manufacturing
• Manufacturing involves the production, propagation,
conversion, or processing of a drug or device, either
directly or indirectly, by extraction of the drug from
substances of natural origin or by means of chemical or
biological synthesis.
• Manufacturing also includes:
(1) Packaging or repackaging of the substance(s)
(2) Labeling or relabeling of containers
(3) Any preparation of a drug or device that is given or sold for resale
by pharmacies, practitioners, or other persons
(4) Distribution of inordinate amounts of compounded preparations or
the copying of commercially available drug products
(5) Preparation of any quantity of a drug product without a licensed
prescriber/licensed pharmacist/patient relationship
Good Manufacturing Practices (GMP)
• GMPs are intended to assure the production of a uniform,
consistent product. The WHO and US have published the
flagship guidance. The manufacturing processes must be
well-defined, documented and in demonstrated control.
• The GMP process starts with the quarantine of all received
goods that are released to production after verification.
• The GMP process ends with the review of the finished
product to assure that it complies with the stated
requirements.
• It is estimated that the meeting of GMP requirements costs
25-35% of sales revenue.
Determinants of Drug Product Quality
• Drug production
– Equipment and
maintenance
• Drug formulation
– Active ingredients
– Inactive ingredients
– Plant environment
– Drug product
manufacturing process
• Quality control
• Packaging—both
immediate and external
• Handling and storage
conditions
Substandard Medicines in Developing
Countries (1)
Out of 325 Cases of Substandard Drugs, Including
Antibiotics, Antimalarials, and Antituberculosis Drugs
Reported to WHO
Incorrect
ingredient
16%
60% No active ingredient +
16% Incorrect ingredient =
76% Would fail ID/TLC test
Incorrect
amount
17%
Other errors
7%
17% Fail assay
93% of these substandard
drugs might be detected by
ID and TLC testing
60%
No active
ingredient
Substandard Medicines in Developing
Countries (2)
Vietnam
Thailand
Tanzania
Nigeria
Myanmar
Laos
India
Ghana
El Salvador
Cambodia
Brazil
Therapeutic groups
• Analgesics
• Antihypertensives
• Antimicrobials
• Antimalarials
0
10
20
30
40
50
Percentage of Samples Found to Be Substandard
Rägo, L. 2002. Ensuring Access to Drug Products That Are of Acceptable Quality.
PowerPoint presentation, WHO/EDM Technical Briefing, October 2, Geneva.
Quality of Antimalarial Products:
Both Content and Dissolution Are Problems
Chloroquine
% failure*
Sulfadoxine/pyrimethamine
% failure*
100
100
80
80
60
60
Dissolution
* Sam ples were judged to have “failed” if
content was <93% or >107%, and
dissolution <80% in 45 minutes.
Content
Ma
Mo
li
zam
b iq
ue
Su
da
n
Zim
ba
bw
e
a
Ke
ny
an
Gh
n
bo
Ga
Ke
ny
an
Gh
bo
Ga
Content
Ma
li
0
a
0
a
20
n
20
a
40
40
Dissolution
* Samples were judged to have “failed” if
content was <90% or >110%, and
dissolution <65% in 30 minutes.
Reasons for Poor Quality
Pharmaceuticals
• Gaps in regulatory capacity—Improper requirements
and no capacity for implementation of requirements.
• Failure to apply global standards for generics—WHO
has guidelines, but country implementation varies.
• Different quality requirements for export—Very few
countries effectively control quality of pharmaceuticals
for export; certificates for export are issued more easily
than are certificates for domestic markets.
• Lack of financial incentives—Local manufacturers do
not have sufficient incentives to meet international
standards
• No enforcement actions.
Definitions of Quality Control and
Quality Assurance
• Quality control: The testing of pharmaceutical samples
against specific standards of quality.
• Quality assurance: The management of activities required
to ensure that the pharmaceuticals that reach the patient
are safe, effective, and acceptable to the patient.
Source: Management Sciences for Health and World Health Organization.1997.
Managing Drug Supply, p. 182.
Current Testing Methods
•
•
•
•
•
•
Color reactions
Spectrophotometry
Thin-layer chromatography (TLC)
Gas chromatography
High-performance liquid chromatography (HPLC)
Others
Testing Standards and Methods
• Public vs. private standards
(i.e., pharmacopoeia vs.
manufacturer/registration)
• Legal vs. credentialed
methods (i.e., pharmacopoeia
vs. AOAC International)
Pharmacopoeial Assessments
• Rooted in the analytical methods developed in the drug
discovery process—technology dependent
• Discovery technologies are very focused on API and
impurity characterization (high-resolution systems)
• Relatively expensive systems:
–
–
–
–
Analytical equipment
Maintenance and other consumables
Reference materials
Personnel training
Critical Attributes for Testing Dosage
Forms
• Identity
• Assay (amount of active ingredient)
• Disintegration (prerequisite for bioavailability)
• Dissolution (higher level of assurance of bioavailability)
• Impurities (generally related to active pharmaceutical
ingredient, similar toxicities)
Implications for Resource-Limited
Settings (1)
• Being largely import-dependent, developing countries
need to develop and maintain an effective product testing
program.
• Major hurdles are:
– Newer essential therapeutic drugs for which public
standards/monographs are not available.
– Multi-source essential therapeutic drug products for which the legal
reference methods require high-technology support.
– Lack of resources to effectively mount an effective product testing
program.
Implications for Resource-Limited
Settings (2)
• Difficult to implement and sustain effective
high-technology testing programs
– Complexity of equipment and maintenance needs
– Access to reference materials, reagents, and other
consumables
– Need for highly trained technical staff
– High cost to launch and maintain effective program
Suriname Case Study
Percentage of Submitted Samples That Were Tested
Percentage of Tested Samples That Were Rejected
1.2%
84
82
1.0%
80
0.8%
78
76
0.6%
74
0.4%
72
70
0.2%
68
0.0%
66
2000
2001
2002
2000
2001
2002
• 75% of samples could not be analyzed using pharmacopoeial
methods
• Spectrophotometer and high-performance liquid chromatographer
not operational at time of study (for 9 and 2 months, respectively)
• No regular equipment maintenance due to cost
• Shortage of reference standards and mobile phase for HPLC tests
Assuring Pharmaceutical Product
Quality
Stakeholders
•
•
•
•
•
•
•
•
•
Drug regulatory authority
Quality control laboratory
Procurement agencies
Local manufacturers
Pharmaceutical importers
Port of entry officials
Pharmaceutical distributors
Providers
Patients
Documentation
Monitoring
Analysis/
Evaluation for
DecisionMaking and
Enforcement
Testing
Inspection
Quality Assurance: Documentation
• Country product registration and
procurement
• Prequalification of suppliers
– Product technical file
– Certification
•
•
•
•
•
GMP compliant
Monitoring
Certificate of free sale
Certificate of analysis
Certificate of origin
WHO certification (Certification Scheme
for Pharmaceutical Products Moving in
International Commerce)
• Supply chain management
– Distributor invoices or bills of lading
– Records of purchases/invoices
Documentation
Analysis/
Evaluation for
DecisionMaking and
Enforcement
Testing
Inspection
Quality Assurance: Inspection
• Manufacturing operations
– Good manufacturing practices
(GMPs)
Documentation
• Wholesalers and distributors
– Good storage practices
• Hospitals, clinics, pharmacies,
and drug sellers
Monitoring
Analysis/
Evaluation for
DecisionMaking and
Enforcement
– Good dispensing practices
• Pharmaceutical products
– Technical specifications and
organoleptic characteristics
– Sampling for testing
Testing
Inspection
Quality Assurance: Product Testing by
Resource-limited Countries
• Use of a tiered testing strategy
Documentation
– Level 1 (local) testing to
“screen” products for poor
quality using simple methods
– Level 2 (secondary) testing to
confirm screening results
– Level 3 (tertiary) testing
capacity at national level for
impurity contaminations
Monitoring
Analysis/
Evaluation for
DecisionMaking and
Enforcement
Testing
• Prioritize testing based on risk
to patients
Inspection
Determining Risk
Case # -Problem
Risk (Possible outcome)
Comments
#1 – No API or
does not
disintegrate
Safe but not effective (lack of treatment No API is most common in
and possible acerbating of resistance
counterfeit products
development)
#2 – Wrong
API
Generally unsafe (as above plus
pharmacogenic diseases and death)
#3 – Wrong
amount of API
or dissolution
failure
Variable depending on half-life and
Generally associated with poor
toxicity (low content may be below
GMPs of manufacture
therapeutic window and be ineffective;
high content may be toxic while content
uniformity variations may average out)
#4 – Presence
of impurities
Variable depending on genotoxicity and
toxicity (birth defects, long-term
carcinogenicity, illness, or death
depending on impurity)
Second in frequency; also arises
from production crosscontamination, packaging and
labeling mix-ups, and use errors
Generally associated with poor API
GMP manufacture compliance or
storage abuse; thermal, moisture
exposure, or light
Testing Level Needed to Address the Risks
Case # -- Problem
Testing
Level
#1, 2, and 3 -No API or does not
disintegrate, wrong API, or
significantly sub-standard
(too little or too much API)
Level 1
#3 – Wrong amount of API
or dissolution failure (does
not release medicine
properly)
Level 2
Testing Approach and Relative Cost
Thin Layer Chromatography (TLC); visual
disintegration test using Minilab
Inexpensive; low maintenance
Assessments per legal standard (generally
USP or BP monographs) using High
Performance Liquid Chromatography (HPLC)
in addition to other techniques
Expensive; high maintenance
#4 – Impurity
contaminations:
Precursors, by-products,
degradation products,
residual solvents
Level 3
Complex and Instruments such as Mass
Spectrometry are needed to determine
Impurities
Very expensive; high maintenance
Rationale for Testing
• New essential therapeutic drug products
– High potential for counterfeiting (and fraud-motivated
noncompliance with legal standards
• Older essential therapeutic drug products
– Mostly “off-patent,” multisource products
• Sampling
– Pharmaceutical products are presumed to be produced under
GMP so the collection of a single sample, sufficient for the
intended analyses is adequate.
• Appendix 4, WHO Expert Committee on Specifications for Pharmaceutical
Preparations, Thirty-ninth Report, Geneva 2005. See
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf#page=47
German Pharma Health Fund Minilab
www.gphf.org/web_en/projekte/minilab/index.htm
Quality Assurance: Product Testing
Malaysia: GMP Certificates vs. Testing Results
Malaysia
• Government Pharmaceutical
Laboratory purchases in 1992
– GMP certification and product
testing
100
80
– Product testing program
59%
40
20
0
Costa Rica
• Social Security Fund purchases
in 1977 vs. 1991
100%
60
% Provided GMP Certificates % Passed Tests
Costa Rica: Samples That Failed Testing
20
15
18%
10
5
1977
1%
1991
0
Quality Assurance: Monitoring
• Product problem reporting
Documentation
– Suppliers
– Health care providers
– Consumers
Monitoring
• Supplier and product database
Analysis/
Evaluation for
DecisionMaking and
Enforcement
– Supplier performance
– Product problems
• Clinical (ineffective, adverse
events)
• Pharmaceutical (physicochemical
problems)
Testing
Inspection
Quality Assurance: Evaluation and
Enforcement
Documentation
• Withdrawal of marketing
authorization (product
license)
• Delisting from prequalified status
Monitoring
Analysis/
Evaluation for
DecisionMaking and
Enforcement
• Rejection of shipment
• Product recall
Testing
Inspection
Detection of Counterfeit Medicines
• A perfect counterfeit product cannot be detected.
• A well-made and well-labeled counterfeit is very difficult to
detect even if direct comparisons between authentic and
fake products can be made.
• Testing may be the best available option.
Summary
• Many resource-limited countries are planning to purchase
generics for HIV/AIDS, TB, malaria, and other diseases,
so product quality is becoming a growing concern
• There are a number of program implications if
substandard or counterfeit products are purchased—poor
treatment outcomes, potential liabilities, loss of public trust
• More open (international) procurement can be financially
beneficial, but requires a more stringent QA system
• A three-tier testing program is a less expensive, viable
option for quality control—big laboratories are not always
necessary