Quality Risk Assessment

New Draft PIC/S Annex 1 – Part 2 of 8

Continuing our blog series into the new draft PIC/S Annex 1 revision, (see part 1 here), part 2 looks at Chapters 3 & 4. As we move into the detailed chapters (chapter 4 and beyond), we will use categorization tables to identify and describe the significance of each change. The categories are:

  • Brand New – clauses which do not have any significant correlation to an existing clause from the 2007 version of Annex 1. Each clause is categorized for potential impact individually.
  • Negligible Change – clauses that will not, or are unlikely to, require action to ensure compliance. These may be exact or near copies of previous clauses, or they may be reworded clauses where the intent has not changed.
  • Minor Change – clauses which are likely only to affect a small number of manufacturers and require only a relatively small effort to become compliant.
  • Moderate Change – Still a relatively small number of affected manufacturers, but requiring greater effort for compliance.
  • Significant Change – Even with the significant changes, there will be some manufacturers whose practices already align with the new clauses. These changes will be significant because the number of manufacturers currently non-compliant is notably higher than for other changes, and/or the effort to address compliance is likely to be substantial compared with other changes.

Draft Annex 1 – Chapter 3 – Pharmaceutical Quality System

This chapter is entirely new. While it aligns Annex 1 with the concepts in ICH Q10, the chapter should not require any significant departure from current practices for the significant majority of organisations. A company who finds themselves non-compliant with these clauses is likely deficient against previous Annex 1 revisions too.

The concepts of PQS, QRM and investigations are described with specific connection to sterile manufacturing. For example, clause 3.2 requires assessment of impact of OOS/OOT microbiological results for both the scenario in question, but also more holistically related to historical batches. Some of the requirements in clause 3.1 can be linked back to the CCS document.

Draft Annex 1 – Chapter 4 – Personnel

With the introductory chapters out of the way, the more detailed and specific clauses start in this chapter. Chapter 4 contains 16 clauses, compared with 10 from the 2007 version. Only 4 clauses are brand new, with others previously located in different sections of Annex.


Brand New Clauses in Chapter 4

DraftSubjectPotential impact
4.1Manufacturers required to have sufficient and appropriate qualified/ experienced personnelNone – has long been an inherent requirement of the basic GMP principles (clause 2.1). This clause references sterile manufacturing and testing (arguably unnecessarily)
4.4Detailed description of gowning and aseptic practice qualification, and ongoing monitoring. Significantly, requires Grade A operators to be monitored on every exitModerate – like that most organisations both qualify operators and monitor Grade A personnel on every exit. However, neither are uniformly global practices and both require considerable resource to implement and maintain.
4.5Rules for disqualification of cleanroom personnelModerate – likely that most organisations have disqualification rules, but they may not be fully consistent with this clause.
4.6Establishment of procedures for non-qualified personnel entering cleanroomsMinor – likely that most organisations have such procedures, but some may not.


Causes with Negligible Change in Chapter 4

Draft2007SubjectExplanation of “Negligible Change” Status
4.738Operator health conditions and checkingAlmost exact copy. Some word usage clarified. Requirement for health checks changed from “desirable” to “should be performed”.
4.839Entry to sterile facilities after high risk activitiesFurther defined the scope of high risk activities, but almost the same statement.
4.1142Cleanroom clothing type, quality and useExact copy


Point of Contention: Clause 4.8 describes requirements associated with entry to sterile facilities after engagement with high risk activities. Unfortunately, the wording offers only what is already expected when entering a sterile facility (to follow procedure). An opportunity is available to highlight that where the described high risks are involved, special additional entry activities may be required based on QRM.


Clauses with Minor Change in Chapter 4

Draft2007SubjectChangeExplanation of “Minor Change” Status
4.236Number of personnel in cleanroomsExpanded to reference QRM for determination, document in CCS and validate. Additional emphasis on importance for aseptic processingCommonly already done, may prompt QRM and validation for some.
4.940Personal items in clean areasThe previous list has been expanded to include “other personal items such as mobile phones”Lack of clarity over whether mobile phones should be prohibited altogether, or whether controlled use of company phones as communication devices in lower level clean areas (e.g. Grade D) may still be permitted.
4.1673Operator behavior in cleanroomsAdds statement regarding the potential to change air currentsEnables inspectors to seek airflow visualization studies where there is contention on operator intervention


Clauses with Moderate Changes in Chapter 4

Draft2007SubjectChangeExplanation of “Moderate Change” Status
4.337Training of all personnel involved in correct manufacture of sterile productsAdds qualification and assessment as an expectation and expands some definitions of rolesQualification and assessment of cleaning, maintenance and monitoring staff may not be universal. The concept of assessment may be open to some interpretation
4.1344Outdoor clothing and facility clothingAdds recommendation for dedicated socks prior to entry to Grade CThis is not universal practice and may require changes to gowning requirements in many cases
4.1444Grade A/B garmentsAdds requirement for sterile eyewear and garment change at least every work sessionSterile eyewear has not been mandated in the past. Previously only masks and gloves were mandated for such frequent change. While many companies currently conform with the new requirement, there will be some organisations that have to make changes to gowning procedures.
4.1545Washing and sterilization of clean room garmentsAlmost verbatim version of previous clause, but adds requirement to check integrity after washing, prior to sterilisationAs a mandated GMP requirement, this will need to be proceduralised, either by the outsourced laundry, or internally, if the washing is done in-house


Point of Contention: Clause 4.13 states that where clothing (presumably facility clothing) is re-used, “this should be considered as part of the qualification”. But there is no link to what qualification is being referenced. The nearest related reference to qualification is in section 4.10, but the statement in 4.13 adds nothing to the 4.10 requirement, and therefore appears redundant, or poorly described.


Clauses with Significant Change in Chapter 4

Draft2007SubjectChangeExplanation of “Significant Change” Status
4.1041Handwashing, changing and managing garmentsAdds requirement for visual inspection of garments for cleanliness and integrity (on top of sterilization check)Many organisations do cleanliness/integrity checks in a cursory or informal way. Now that it is mandated, will require more detailed procedures and arguably documented confirmation that it has been done
4.1243Gowning requirements for all classified areasPractically no change for C or D. A/B is changed in that: sterile eyewear is mandated, eyewear and masks shall cover all facial skin, and footwear must be sterilized (disinfection is no longer sufficient).Most organisations already do (a), but even those who do may not meet (b). Some adjustment to application and/or components may be required. Item (c) is unlikely to be an issue in most countries, but the practice of using disinfected footwear is common in Asia, and will require modification.


To consider: Does your gowning procedure for Grade A/B result in the coverage of all facial skin? If not, is the change required procedural, or will it require new garment components?

Despite being entirely new, Chapter 3 should not be a concern for compliant manufacturers. Chapter 4 has a high level of change when compared with the Personnel section from the 2007 Annex but, for the most part, those changes are not unexpected. The new and changed clauses are largely a reflection of improved practices that have arisen from industry interpretation of the less specific clauses from the 2007 Annex.

Initial Blog

Draft Annex 1 – Part 1 

Draft Annex 1 – Part 2 (this post)

Draft Annex 1 – Part 3

Draft Annex 1 – Part 4

Draft Annex 1 – Part 5

Draft Annex 1 – Part 6

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8