L2 - Assessing Manufacturer's Compliance to Product Quality

Question 1

What does QbD include?

Answer 1

• Product design/ formulation of dosage form
• Control of starting materials
• GMP Compliance
• Contamination control, process validation & stability testing
• Use of innovative technologies & approaches (eg. parametric release)

Question 2

Why is parametric release > batch sterility testing

Answer 2

Parametric release: Release of a batch of injectable products that has been terminally sterilised, based on “key parameters” of validated sterilisation process instead of results
- Temperature, pressure, sterilisation time/cycle, bio-burden of pre-sterilised parenteral product

Limitations of Sterility Testing:

• High statistical probability of passing sterility test, even when contamination level is relatively high
• not cheap
• 2 weeks incubation period
• sterilised pdct cannot be released in real time

Question 3

Objective & components of Quality Risk Management (Annex 20)

Answer 3

Objective: Assess risks to product quality/pt, manage
these risks to an acceptable level
Components: Risk identification, analysis, reduction,
communication

Question 4

Who’s responsibility is it to assure quality medications?

Answer 4

1) Manufacturer

2) Regulator (HSA)

Question 5

What constitutes a good quality medicinal product?

Answer 5

• Identity
• Potency
• Purity (Absence of contaminants/undesirable foreign matters)
• Pharmaceutical quality attributes (of final dosage form)
• -> Stability
• -> Homogenity

Note: Cross contamination control is critical in QA of product!

Question 6

What is a contaminated medicinal product?

Answer 6

A product that contains undesirable foreign matter

• introduced during manufacturing
• chemical/microbiological in nature
• may be present in starting pdct, intermediate, bulk pdct

Question 7

Type of contaminants

Answer 7

1) Intrinsic
- present inherently in API/excipients/packaging materials
- referred to as Impurities: often SPECIFIC in nature

2) Extrinsic
- originate externally from production personnel/ processing equipment/ packaging equipment/ manufacturing premises (envt)
- often NON-SPECIFIC in nature

Question 8

Why is there a need to control impurities?

Answer 8

• Can be toxic
• Affects overall therapeutic effect of medicinal product (not only dependent on pharmacological properties of API)
• Important part of drug development, manufacturing, GMP compliance & regulatory assessment for marketing approval

Question 9

Type of impurities

Answer 9

1) Process-related impurities
2) Drug-related impurities
- degradation product (after API formed)
3) Polymorphs
4) Stereoisomers
5) Impurities from container-closure system & labels
- from primary containers
- from labels

Question 10

How are intrinsic contaminants (impurities) controlled?

Answer 10

Sources of impurities coming from starting materials:

• closure (type of rubber, plastics)
• container (types of glass, plastics)
• API
• Excipients

Controlled by:

• QC testing of materials & finished products
• assessment of impurity profile
• GMP compliance by manufacturer
• Periodic GMP audits by HSA inspectors

Question 11

How are extrinsic contaminants controlled?

Answer 11

Source (Non-specific) :

• personnel
• equipment
• premises (envt)

Controlled by:

• Manufacturer’s compliance to GMP is critical
• Periodic audits by GMP inspectors to verify compliance

Question 12

How is product stability demonstrated?

Answer 12

Stability testing program

Question 13

What does Stability testing program constitute of?

Answer 13

Takes into consideration both product-related & environmental factors:

• real time studies (6 mths under appropriate storage conditions)
• accelerated studies (to proj shelf life beyond 6mths)
• continual stability testing

Question 14

Why is proper storage, distribution & handling of product important?

Answer 14

1) Elevated temperature result in…
- loss of potency (via degradation)
- loss of vehicle (via evaporation)
- hardening of tablets (via loss of moisture content)

2) Elevated RH/Moisture content result in…
- formation of toxic degradation products
- loss of package integrity & label clarity
- loss of adhesion of transdermal patch

3) Increased agitation & vibration during transportation can result in…
- intro of micro-organisms into product

4) Poor handling of product during in-use
- contamination of product

Question 15

How is homogenity demonstrated?

Answer 15

Process validation

Question 16

What is Process validation?

Answer 16

• Means of ensuring & providing documentary evidence
  that the manufacturing processes are capable of consistently producing a finished product of required quality
• > Identifies CQA
• > Extensive process design & process qualification
• > Monitoring of CPP

Continued process VERIFICATION beyond 3 production batches!!!

Question 17

What does Process validation constitute of?

Answer 17

1) Establishing CQA
2) Identifying CPP (critical process parameters)
- blending, milling, compression
3) Design sampling plan
4) Design testing plan
5) Set acceptance criteria

6) Perform statistical analysis
i) Intra-batch Analysis - consistency
- Cp >= 1.3 (Outliers <= 63ppm)
ii) Inter-batch Analysis - equivalency
- CV among 3 validation batches & pilot batch should be statistically similar i.e. CV (or RSD) <= 5%

7) Documentation
i) Validation protocol
ii) Validation report (impt to ensure manufacturer has carried out process validation)