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THE ROLE OF CURRENT GOOD MANUFACTURING PRACTICES (cGMPS)
IN REGULATORY DRUG QUALITY
Korea-Maryland, USA Bio Expo 2013
November 8, 2013
Charles J. Raubicheck, Partner
([email protected]) and
Brian J. Malkin, Partner ([email protected])
Frommer Lawrence & Haug LLP
FDA Lawyers Blog
(http://www.fdalawyersblog.com)
OVERVIEW
 Guidelines for Manufacturing and Quality Control
• Charles J. Raubicheck
 Generic Pharmaceutical Manufacturing
• Brian J. Malkin
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Guidelines for Manufacturing and
Quality Control
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Regulatory Authority
 1) Drug Adulterated Unless It Complies With Current
Good Manufacturing Practices (cGMPs) to Assure
Identity, Strength, Quality, and Purity
• [Federal Food, Drug, and Cosmetic Act, Section 501]
 2) FDA GMP Regulations for Finished
Pharmaceuticals
• [21 CFR Part 210]
 3) Courts Upheld cGMP Regulations as Sufficiently
Specific
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FDA’S DRUG cGMP REGULATIONS
 1) Control of Drug Components
• Sampling and Testing of Incoming Raw Materials
(Specifications)
• Retesting
• Rejections
 2) Control of Containers and Closures (Specifications,
Physical Examination)
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FDA’S DRUG cGMP REGULATIONS (cont’d)
3) Records
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Equipment Cleaning and Use Log
Components, Container/Closures and Labeling
Master Production Records
Batch Production Records
Laboratory Records
Distribution Records
Complaint Files
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FDA’S DRUG cGMP REGULATIONS (cont’d)
4) Production and Process Controls
• Written Procedures for Manufacturing
• Sampling and Testing of In-Process Materials and
Finished Products
• Control of Microbiological Contamination
• Reprocessing to Meet Specifications
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FDA’S DRUG cGMP REGULATIONS (cont’d)
5) Laboratory Controls

Incoming Raw Materials
6) Stability (Potency)
7) Reserve Samples
8) Finished Product Release
9) Distribution Procedures
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FDA’S DRUG cGMP REGULATIONS (cont’d)
MANUFACTURING PROCESS VALIDATION
─ 3 Production Batches
─ FDA: Prior to Shipment
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cGMP COMPLIANCE
 FDA Pre-Approval Inspection
 Post-Approval Inspection Every 2 Years
 Court Injunctions
 Criminal Prosecutions (Park case)
 Product Seizures
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Generic Pharmaceutical
Development Manufacturing
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Purpose of cGMPs
Quality is a centerpiece of FDA’s cGMP
regulations (effective March 28, 1979):
• Under the Federal Food, Drug, and Cosmetic Act, a drug is
deemed to be adulterated unless the methods used in its
manufacture, processing, packing, and holding, and the
facilities and controls used therefore, conform to current
good manufacturing practice so the drug meets the safety
requirements of the act and has the identity and strength
and meets the quality and purity characteristics that is
represented to have.
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Purpose of cGMPs
Identity is the identification specification.
Strength is the potency specification.
Purity includes the impurity specifications.
Quality is more than just conformance to
specifications
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Means it is what it says it is, not adulterated
Means it does what it supposed to do
Means it is made under cGMP
Means it is pure and not contaminated.
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Quality under FDASIA
Quality is everything under FDASIA:
• Section 501 (21 U.S.C. 351) amended to add:
“For the purposes of paragraph (a)(2)(B), the
term ‘current good manufacturing practice’
includes the implementation of oversight and
controls over the manufacture of drugs to
ensure quality, including managing the risk and
establishing the safety of raw materials,
materials used in the manufacturing of drugs,
and finished drug products.”
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Quality Documents
Shift towards innovation and continuous
improvement
Guidance includes:
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ICH Q1 through Q11
Q8(R2) Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System.
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Quality Documents
Concept of quality includes
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Robust quality system
Quality risk management
Corrective and Preventive Actions (CAPA)
Change control
Separate quality management of product, system, and
process quality
• Leadership needs to be committed to quality.
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Generic Drugs
Account for 70-75% U.S. Prescriptions
Therapeutically Equivalent means:
• Has the same clinical effect and safety
profile when administered to patients
under the labeled conditions
• Pharmaceutically Equivalent +
Bioequivalent.
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Generic Drugs (cont’d)
Pharmaceutical equivalence means:
• Same active ingredient
• Same dosage form
• Same route of administration
• Identical in strength or concentration
• Meet compendial or applicable standards of
strength, quality, purity, and identity
• May differ in shape, excipients, packaging.
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Generic Drugs (cont’d)
Bioequivalence
• Generally demonstrated by in vivo blood plasma levels
(90% confidence interval, log transformed to 80-125%
parameters compared to innovator’s product).
• In vitro dissolution is often a quality measure but may also
be required for more complex dosage forms (e.g.,
simulated gastrointestinal tract pH levels).
• May involve multiple active ingredients or prodrug and
metabolite.
• All bioequivalence studies must be included in an ANDA.
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Generic cGMP Toolbox
Quality by Design (QbD) initiatives
Question-Based Review (QbR) and FDA MaPPs
Auditing and due diligence controls
Remaining current with GMPs
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Industry meetings and seminars
Monitor trends via FDA 483s and Warning Letters
Industry publications
External consulting
Delivery of quality message
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Quality by Design (QbD)
Common to innovator and generic products
• “[M]eans that product and process performance
characteristics are scientifically designed to meet specific
objectives . . . To achieve QbD objectives, product and
process characteristics important to desired performance
must be derived from a combination of prior knowledge
and experimental assessment during product
development.”
• Function of drug substance, excipients, manufacturing,
and packaging
• Goal to develop a Quality Target Product Profile (QTPP)
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Quality Metrics
 Metrics must be quantitative and objective.
 Metrics must be clinically relevant to patient safety and health.
 Main metrics (consensus development)
• Batch/lot failure rate (rejected, reworked)
• Right first time
• Laboratory failure investigation rates
Standards for sampling/acceptance plans.
 For generics, sponsors must explain how they systematically
arrived at a bioequivalent drug product (not just passed
bioequivalence studies) & demonstrate stability and other
critical metrics for a consistent drug product.
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Examples of Generic Drug Quality Metrics
 Efforts to optimize formulation for “stability by design”
 Demonstrate active pharmaceutical ingredient/excipient
compatibility
 Demonstrate stability of dispersion (API/binder) on
pharmaceutical core (i.e., compare different binders and relative
amounts on final product)
 Consider plasticizers/coatings to minimize curing and consistent
coating issues (i.e., to prevent changes in drug release by the
curing process)
 Consider effect of compression on coatings (cushioning
excipients needed?)
 Scale-up issues addressed prior to approval.
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Audits and Due Diligence
 Dive deep into ALL systems for baseline.
 Understand site processes and people.
 Harmonize gaps between sites.
 Regularly assess cGMP compliance and measure
progress toward harmonization goals.
 Train stakeholders to develop workflows to
constantly assess programs and improve based on
experiences and regulatory requirements.
 Consider post-approval changes (lifecycle).
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Quality Deficiencies Lead to …
Increased regulatory oversight
Inspections for cause
Warning Letters
Recalls and field alerts
Shortages
Reduced acceptance of generic drugs.
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Perception of Generic Drugs
 Immediate release/solutions generally viewed as good.
 Complex dosage forms potentially problematic:
• Modified release drugs may have different release
mechanisms but bioequivalent blood levels
• Greater chance for chemistry, manufacturing, and control
issues, particularly with selection of API and excipients.
 More modified release generic products are leading to more
consumer complaints – actual or real problems?
 Complexities or variability of innovator drug may be missed in
rush to be first-to-file generic (180-day exclusivity).
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New Contract Manufacturing Draft Guidance
 Quality agreements define role of product owners and
contract facilities in terms of responsibilities, cGMPs, and
ability for product owners to evaluate contracted facilities as
well as mechanisms for timely notifications and
communications.
 Owners have ultimate responsibility for final product
including rejected lots/batches.
 Contracted facility has responsibility for meeting cGMPS
including identification and responses to quality issues.
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GDUFA Considerations
 Fees to pay for backlog review (3000 unapproved ANDAs; trend
was 1000 new ANDAs/year with 600 approvals/year), permit
hiring additional review employees, and implement efficiency
improvements.
 Fee structure for ANDAs, DMFs / Facility self-identification.
 ANDA Complete Response Letters (except easily correctible).
 Focus on drug supply chain including active pharmaceutical
ingredients AND excipients.
 Requires maintaining records for inspections (prioritized).
 ANDA median review times up (35 months) during new staff
training and efficacy changes – will FDA meet 10-month ANDA
reviews (2-month controlled correspondence)?
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QUESTIONS?
Charles J. Raubicheck
Partner, Frommer Lawrence & Haug LLP
212-588-0800 [email protected]
Brian J. Malkin
Partner, Frommer Lawrence & Haug LLP
Editor, FDA Lawyers Blog
202-292-1530 [email protected]
http://www.fdalawyersblog.com
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