lOMoAR cPSD| 6860957
CASE 9 – MANUFACTURE OF MEDICINES
LECTURE 1 – MANUFACTURE OF MEDICINES INTRO
• The lectures relate to the case of a defect being found as part of a manufacturing and
distribution process, for example a “product recall” as part of the routine manufacture of a
medicine.
• A defective product is surprisingly common but should not be considered as a regular or
routine occurrence.
• Experience shows that it can be difficult to differentiate between defects, errors and adverse
drug reactions
• Defect – Not conforming to specification. *A shortcoming.
• Error - A wrong action by a person.
• ADR - Any untoward and unintended response in a subject to whom a medicinal product has
been administered, including occurrences which are not necessarily caused by or related to
that product
Drug recalls: What are they?
• The Medicines and Healthcare Products Regulatory Agency (MHRA) makes sure the
medicines we take are safe.
• There are around 20,000 different medicines available in the UK. Once a medicine is on the
market, the MHRA and the drug manufacturers continue to monitor it for any unforeseen
problems.
• Should an issue develop, or the safety of a medication come into question, the agency has
the power to withdraw a product from the market, a recall, and to suspend production.
• The MHRA works closely with the European regulator, the European Medicines Agency
(EMA), which licences medicines and medical devices across Europe.
When is a drug recall announced?
• A drug recall occurs when a prescription or over-the-counter medicine is removed from the
market because it is found to be either defective or potentially harmful.
• The MHRA’s Defective Medicines Report Centre (DMRC) issues alerts to healthcare
professionals, hospitals, GP surgeries and wholesalers to tell them when a medicine is being
recalled or when there are concerns about the quality that will affect its safety or
effectiveness.
Alerts are graded according to the seriousness of the threat to the public’s health:
• Class 1 requires immediate recall because the product poses a serious or life-threatening risk
to health.
• Class 2 specifies a recall within 48 hours because the defect could harm the patient but is
not life-threatening.
• Class 3 requires action to be taken within five days because the defect is unlikely to harm
patients and is being carried out for reasons other than patient safety.
• Class 4 advises caution to be exercised when using the product but indicates the product
poses no threat to patient safety.
Most recalls fall into classes 2 or 3
Page 1 of 59
, lOMoAR cPSD| 6860957
Why are drugs recalled?
Several factors can cause a drug to be recalled. A recall may be issued if a medicine is:
• A health hazard. Unfortunately, some health risks associated with certain medications are
not realised until after they become widely used. For example, Vioxx in September 2004.
• Mislabelled or packaged poorly. Sometimes it is recalled because of confusing dosing
• Potentially contaminated. With either a harmful or non-harmful substance
• Not what is says. Different formulation
• Poorly manufactured. Manufacture defect related to the quality of a product, purity or
potency.
How might these issues come to light?
• A health hazard. - Yellow Card Scheme.
• Mislabelled or packaged poorly, potentially contaminated, not what is says, Poorly
manufactured. – reported by patients, healthcare professionals etc.
• An electronic Defect Reporting Form is available on the MHRA website. Or
verbal if the report involves a critical major defect
• the DMRC of the MHRA will carry out a further assessment and, if
necessary, an investigation-Will be informed with the outcome
• Only defects can be reported in line with the guidance
An example of a recall:
• ViroPharma SPRL is recalling specific batches of Buccolam Oromucosal Solution.
• Following a routine inspection of the company’s contract manufacturing site in the UK. The inspection
identified the possibility for chemical contamination.
• No evidence of contamination has been identified within Buccolam Oromucosal Solution on the
market.
Recalls – Healthcare Professionals’ Responsibilities
The Drug Alert will contain an outline of what actions should be taken; this may also be followed up
with further details from the licence holder in a subsequent communication.
Action to be taken by the pharmacist on receipt of product recall alert:
1 2 3 4
Check that no stock has Follow alert cascade Sign the recall notice, Retain these records for
been sold (by checking guidance. Communicate add the date checked at least five years
invoices, shelves, effectively with other and scan/file it
quarantine, return to clinical staff responsible
wholesaler for areas with defective
product
FORMATIVE SAQ
• Suppose you are the manufacturer and therefore supplier of packaged medicines for
distribution in community pharmacies and hospital pharmacies and an array of suitable
clinics, is there any part of the mass manufacturing process that is less significant than
others? Explain your answer briefly. (5 Marks, Integrated)
Page 2 of 59
, lOMoAR cPSD| 6860957
LECTURE 2 – MANUFACTURING OF MEDICINES CONSIDERATIONS
- Active ingredient
- Diluent
- Excipients
- Premises
- Personnel
- Equipment/Process
- Equipment/Packaging
- Transport
- Storage
- Final Product
Top 5 Reasons for a Class I Product Recall
1) Super or sub-potent formulations
2) Particulate contamination
3) Contamination of APIs (Active pharmaceutical ingredient)
4) Sterility failure in injectable products
5) Contamination with TBA
LECTURE 3 & 4 – GOOD OVERALL PRACTICE (GXP) AND
QUALITY BY DESIGN (QbD)
Page 3 of 59
, lOMoAR cPSD| 6860957
Three recalled products might include:
• Severe discoloration and loss of potency of the active pharmaceutical ingredient (active; API)
thyroxine, this has initially been ascribed to increased water content issues, leading to drug
hydrolysis and / or process issues affecting granulation inconsistency and therefore uniformity
problems (uniformity of content) in the finished tablets.
• Photo-catalytic degradation of anti-acne drug (isotretinoin) filled soft gelatin capsules as
samples were stored near a UV lamp / intense sunlight in the warehouse. This lead to
hypodosed capsules and a multitude of breakdown substances picked up by HPLC and TLC
testing in-house, when stability testing of longer-term stored product was undertaken.
• Precipitation of an ampoule based product an antibody-based drug – gemtuzumab ozogamicin
(chemotherapeutic and leukaemia drug in sterile vial) protein based injection product based on a
failure to store the sterilised vials under refrigeration temperature leading to large-scale
flocculation by buffer salts and excipients and finally precipitation. Injection of such a poor-
quality product poses a serious threat to patient health. The customer/patients and the general
practitioners involved issued complaints to the company.
The Process Manufacturing Chronology involved in manufacturing a product (quality aspects).
Emphasis on QA (Quality Assurance) and QC (Quality Control):
Important awareness:
1. Quality by design (QbD), “Right-First-Time” and MII/MI2
2. GMP and ‘three golden rules’
3. Quality Gurus, “Fit-for–Purpose”, “Zero-tolerance” and Deming
4. Quality: basic definitions and TQMS
5. Shewhart’s Cycle of effective validation
Making novel compounds into real drugs:
Development Phase…
- Discovery & screening
- “Lead” selection
- Pre-clinical
- New drug entry
- Proof of principle
- Development review decision
- Pre-NDA
- New drug application filed
- Post-NDA
…Routine use.
GMP (Good Manufacturing Practice):
Page 4 of 59
CASE 9 – MANUFACTURE OF MEDICINES
LECTURE 1 – MANUFACTURE OF MEDICINES INTRO
• The lectures relate to the case of a defect being found as part of a manufacturing and
distribution process, for example a “product recall” as part of the routine manufacture of a
medicine.
• A defective product is surprisingly common but should not be considered as a regular or
routine occurrence.
• Experience shows that it can be difficult to differentiate between defects, errors and adverse
drug reactions
• Defect – Not conforming to specification. *A shortcoming.
• Error - A wrong action by a person.
• ADR - Any untoward and unintended response in a subject to whom a medicinal product has
been administered, including occurrences which are not necessarily caused by or related to
that product
Drug recalls: What are they?
• The Medicines and Healthcare Products Regulatory Agency (MHRA) makes sure the
medicines we take are safe.
• There are around 20,000 different medicines available in the UK. Once a medicine is on the
market, the MHRA and the drug manufacturers continue to monitor it for any unforeseen
problems.
• Should an issue develop, or the safety of a medication come into question, the agency has
the power to withdraw a product from the market, a recall, and to suspend production.
• The MHRA works closely with the European regulator, the European Medicines Agency
(EMA), which licences medicines and medical devices across Europe.
When is a drug recall announced?
• A drug recall occurs when a prescription or over-the-counter medicine is removed from the
market because it is found to be either defective or potentially harmful.
• The MHRA’s Defective Medicines Report Centre (DMRC) issues alerts to healthcare
professionals, hospitals, GP surgeries and wholesalers to tell them when a medicine is being
recalled or when there are concerns about the quality that will affect its safety or
effectiveness.
Alerts are graded according to the seriousness of the threat to the public’s health:
• Class 1 requires immediate recall because the product poses a serious or life-threatening risk
to health.
• Class 2 specifies a recall within 48 hours because the defect could harm the patient but is
not life-threatening.
• Class 3 requires action to be taken within five days because the defect is unlikely to harm
patients and is being carried out for reasons other than patient safety.
• Class 4 advises caution to be exercised when using the product but indicates the product
poses no threat to patient safety.
Most recalls fall into classes 2 or 3
Page 1 of 59
, lOMoAR cPSD| 6860957
Why are drugs recalled?
Several factors can cause a drug to be recalled. A recall may be issued if a medicine is:
• A health hazard. Unfortunately, some health risks associated with certain medications are
not realised until after they become widely used. For example, Vioxx in September 2004.
• Mislabelled or packaged poorly. Sometimes it is recalled because of confusing dosing
• Potentially contaminated. With either a harmful or non-harmful substance
• Not what is says. Different formulation
• Poorly manufactured. Manufacture defect related to the quality of a product, purity or
potency.
How might these issues come to light?
• A health hazard. - Yellow Card Scheme.
• Mislabelled or packaged poorly, potentially contaminated, not what is says, Poorly
manufactured. – reported by patients, healthcare professionals etc.
• An electronic Defect Reporting Form is available on the MHRA website. Or
verbal if the report involves a critical major defect
• the DMRC of the MHRA will carry out a further assessment and, if
necessary, an investigation-Will be informed with the outcome
• Only defects can be reported in line with the guidance
An example of a recall:
• ViroPharma SPRL is recalling specific batches of Buccolam Oromucosal Solution.
• Following a routine inspection of the company’s contract manufacturing site in the UK. The inspection
identified the possibility for chemical contamination.
• No evidence of contamination has been identified within Buccolam Oromucosal Solution on the
market.
Recalls – Healthcare Professionals’ Responsibilities
The Drug Alert will contain an outline of what actions should be taken; this may also be followed up
with further details from the licence holder in a subsequent communication.
Action to be taken by the pharmacist on receipt of product recall alert:
1 2 3 4
Check that no stock has Follow alert cascade Sign the recall notice, Retain these records for
been sold (by checking guidance. Communicate add the date checked at least five years
invoices, shelves, effectively with other and scan/file it
quarantine, return to clinical staff responsible
wholesaler for areas with defective
product
FORMATIVE SAQ
• Suppose you are the manufacturer and therefore supplier of packaged medicines for
distribution in community pharmacies and hospital pharmacies and an array of suitable
clinics, is there any part of the mass manufacturing process that is less significant than
others? Explain your answer briefly. (5 Marks, Integrated)
Page 2 of 59
, lOMoAR cPSD| 6860957
LECTURE 2 – MANUFACTURING OF MEDICINES CONSIDERATIONS
- Active ingredient
- Diluent
- Excipients
- Premises
- Personnel
- Equipment/Process
- Equipment/Packaging
- Transport
- Storage
- Final Product
Top 5 Reasons for a Class I Product Recall
1) Super or sub-potent formulations
2) Particulate contamination
3) Contamination of APIs (Active pharmaceutical ingredient)
4) Sterility failure in injectable products
5) Contamination with TBA
LECTURE 3 & 4 – GOOD OVERALL PRACTICE (GXP) AND
QUALITY BY DESIGN (QbD)
Page 3 of 59
, lOMoAR cPSD| 6860957
Three recalled products might include:
• Severe discoloration and loss of potency of the active pharmaceutical ingredient (active; API)
thyroxine, this has initially been ascribed to increased water content issues, leading to drug
hydrolysis and / or process issues affecting granulation inconsistency and therefore uniformity
problems (uniformity of content) in the finished tablets.
• Photo-catalytic degradation of anti-acne drug (isotretinoin) filled soft gelatin capsules as
samples were stored near a UV lamp / intense sunlight in the warehouse. This lead to
hypodosed capsules and a multitude of breakdown substances picked up by HPLC and TLC
testing in-house, when stability testing of longer-term stored product was undertaken.
• Precipitation of an ampoule based product an antibody-based drug – gemtuzumab ozogamicin
(chemotherapeutic and leukaemia drug in sterile vial) protein based injection product based on a
failure to store the sterilised vials under refrigeration temperature leading to large-scale
flocculation by buffer salts and excipients and finally precipitation. Injection of such a poor-
quality product poses a serious threat to patient health. The customer/patients and the general
practitioners involved issued complaints to the company.
The Process Manufacturing Chronology involved in manufacturing a product (quality aspects).
Emphasis on QA (Quality Assurance) and QC (Quality Control):
Important awareness:
1. Quality by design (QbD), “Right-First-Time” and MII/MI2
2. GMP and ‘three golden rules’
3. Quality Gurus, “Fit-for–Purpose”, “Zero-tolerance” and Deming
4. Quality: basic definitions and TQMS
5. Shewhart’s Cycle of effective validation
Making novel compounds into real drugs:
Development Phase…
- Discovery & screening
- “Lead” selection
- Pre-clinical
- New drug entry
- Proof of principle
- Development review decision
- Pre-NDA
- New drug application filed
- Post-NDA
…Routine use.
GMP (Good Manufacturing Practice):
Page 4 of 59
