Impact of COVID-19 on Pharmaceutical Manufacturing

How is the pharmaceutical manufacturing industry around the world expected to continue production during the COVID-19 pandemic? What control measures should be in place to help prevent or mitigate the potential adverse effects of COVID-19 on the safety and quality of products?

In April 2020, the UK Medicines and Healthcare products Regulatory Agency (MHRA) published guidance on “Exceptional GMP flexibilities for medicines manufacturers during the coronavirus (COVID-19) outbreak”. These temporary flexibilities allow manufacturers to increase the capability of their quality systems to ensure a continual supply of products using quality risk management (QRM) principles and to navigate through international travel restrictions. Any decisions to use these GMP flexibilities should involve the Qualified Person (QP) and should be reported to the MHRA.

MHRA’s Flexibilities with Manufacture and Importation

• Re-testing of raw materials may be limited to identification only, supplemented by qualified supplier’s certificate of analysis (CoA) for other material quality attributes
  • This reduced testing should be based on risk, supplier history, material criticality and finished product quality control strategy.
• Products may be transported from manufacturing site to another authorised site under quarantine before completion of QC tests and batch certification
  • Products should not be placed on the market until certified by the QP.

MHRA’s Flexibilities with Pharmaceutical Quality System (PQS)

• The following quality system components may be put on hold:
  • Investigations of “minor” non-conformances and incidents
    • A QA assessment should be performed to determine product impact and events put on hold should be tracked. Any trends in events should be investigated.
  • On-site supplier audits
    • Suppliers of critical materials may be assessed via desktop audits. The re-prioritisation of audits after travel restrictions are lifted should be risk-based.
  • Internal audit and GMP refresher training
  • Commitments to addressing ‘Other’ deficiencies from regulatory inspections
    • These should be recorded in the quality system and corrected after the pandemic.
  • Routine SOP reviews may be extended.

In the same month, the UK Medicines and Healthcare products Regulatory Agency (MHRA) also published a guidance on “Exceptional good distribution practice (GDP) flexibilities for medicines during the coronavirus (COVID-19) outbreak”. This guidance details the flexibility the MHRA are willing to take on GDP requirements during the pandemic. Any decisions to use these GDP flexibilities should be reported to the MHRA and should be documented, with rationale, in existing local procedures for recording unexpected events.

MHRA’s Flexibilities with Supply Chain

• Periodic supplier and customer requalifications may be deferred, with regular review of MHRA’s notifications on suspended wholesale dealer authorisations or any General Pharmaceutical Council registration updates
• Medicines pulled out of wholesale distribution chain within 10 days may be returned to saleable stock.

MHRA’s Flexibilities with Transportation

• Products may be transported without temperature control when ambient temperature is less than 20°C
• ‘Do not refrigerate’ products transported when ambient temperature is less than 8°C should be identified
  • This should be supported by a risk assessment and appropriate mitigation measures should be implemented.
• A wholesaler dealer authorisation (WDA(H)) may not be required for products held at a transit hub for up to 96 hours
  • This should be supported by a risk assessment of storage conditions and security, and appropriate mitigation measures should be implemented.

MHRA’s Flexibilities with Facilities and Equipment

• Qualification and validation of storage and distribution equipment may be limited to expedite equipment use
  • This should be supported by a risk assessment and appropriate mitigation measures should be implemented.
  • Retrospective qualification and validation of the equipment should be performed as soon as possible.
• The following quality system components may be put on hold:
  • Investigations of “minor” deviations or non-conformances
    • Product impact should be determined following assessment by the RP, and events put on hold should be tracked. Any trends in events should be investigated.
  • Commitments to addressing ‘Other’ deficiencies from regulatory inspections
    • These should be recorded in the quality system and corrected after the pandemic.
  • Routine SOP reviews may be extended.
  • Internal audit and GDP refresher training
    • The training of new personnel on GDP principles and training of procedural updates should continue.
  • Electronic signatures may be used in accordance with data integrity principles.

The EU’s European Medicines Agency (EMA) followed the UK’s example and introduced the following temporary GMP and GDP flexibilities to ensure continued supply of crucial medicines for treatment of COVID-19. This is documented in their notice to stakeholders “Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the Covid-19 Pandemic”. Any flexibilities utilised should be documented within the PQS and approved by the QP. QRM principles should be applied and risk mitigation measure should be implemented.

• Limited prospective qualification of relocated or extended production facilities/equipment
  • Regular qualifications should be resumed after COVID-19 restrictions are lifted.
• Limited prospective qualification of premises and equipment used for storage and distribution of medicines
  • There should be sufficient ongoing monitoring to ensure that medicines are stored and transported under the required conditions.
• Concurrent validation of manufacturing process
• The following quality system components may be put on hold:
  • Maintenance, requalification, revalidation, recalibration
  • Periodic PQS document reviews
  • Periodic re-training
  • On-site audits (may be replaced by remote audits)
  • Stability testing, where justified, to focus resources on product release testing
  • Routine SOP reviews may be extended
  • CAPAs to address ‘low-risk’ deviations
  • Investigations for ‘minor’ events

In June 2020, the US Food and Drug Administration (FDA) published a guidance document on “Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing”. This guidance provides the following recommendations that are not legally binding but should be considered for the prevention of drug contamination and/or for prevention of transmission:

• Restriction of sick employees from production areas and exclude from production areas employees who have tested positive to COVID
• Monitoring employees for symptoms of COVID
• Ensuring employees practise good sanitation and health habits, in compliance with cGMP requirements
• Evaluation of cGMP controls already in place, for example:
  • cleanroom process controls such as air filtration, positive air pressure and movement of air
  • contamination or cross-contamination controls
  • microbiological controls
  • viral control strategies for manufacturing of biological products
• Review of facility and equipment cleaning and sanitation and update of procedures to include more frequent cleaning, sanitisation, and/or sterilisation of frequently contacted surfaces in the production areas such as door handles, equipment latches, bench/countertops, and control panels
• Cleaning and sanitising non-production areas (such as offices, lifts, break rooms, changing rooms, and restrooms) more frequently
• Prioritisation of single-use masks for sterile manufacturing operations
  • To mitigate supply issues, drug manufacturers may re-sterilise or disinfect masks and reuse them for non-sterile drug operations.

As for the Therapeutics Goods Administration (TGA) in Australia, their overseas GMP inspections and QMS audits have been suspended until further notice. Licensed domestic manufacturers are subject to remote GMP inspections during the pandemic. The TGA are also keeping a close eye on medicine shortages and potential impacts to medicine supply to Australian consumers.

 

Want more?

To read more from this PharmOut author, check out the following blogs:

• Whitepaper – ISO13485 & US FDA CFR 820 Comparison
• Faecal Microbiota Transplants – How are Products Regulated?
• Unique Device Identification (UDI) system for medical devices in Australia